Drug Therapy

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

 

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

 

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

 

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

A 25-year-old man being treated in the hospital for catatonia and flaccid paralysis developed fever and a lobar consolidation, prompting treatment with piperacillin-tazobactam. A dermatology consult was called 3 days later when the patient developed a rash on the forehead (Figure 1), cheeks, chin, and upper trunk, raising concern for a drug-related eruption.

Close examination of the rash revealed bright red plaques studded with sheets of monomorphic pustules. Possible causes other than drug therapy were considered, including folliculitis, acneiform eruption, and pustular psoriasis. Bacterial culture of a pustule was negative, but punch biopsy of a pustule revealed an abundance of round and oval budding yeast forms consistent with Malassezia (formerly called Pityrosporum) “stuffing” the hair follicles and forming cleared spaces in the dermis surrounded by an exuberant lymphohistiocytic infiltrate (Figures 2 and 3). Special stains were negative for bacteria and mycelial forms. The clinicopathologic findings were diagnostic of Malassezia folliculitis with formation of dermal abscesses.

The patient was treated with intravenous itraconazole 200 mg daily for 7 days and topical benzoyl peroxide 5% gel, with ketoconazole 2% cream for maintenance therapy. The treatment brought improvement of the rash.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

A 25-year-old man being treated in the hospital for catatonia and flaccid paralysis developed fever and a lobar consolidation, prompting treatment with piperacillin-tazobactam. A dermatology consult was called 3 days later when the patient developed a rash on the forehead (Figure 1), cheeks, chin, and upper trunk, raising concern for a drug-related eruption.

Close examination of the rash revealed bright red plaques studded with sheets of monomorphic pustules. Possible causes other than drug therapy were considered, including folliculitis, acneiform eruption, and pustular psoriasis. Bacterial culture of a pustule was negative, but punch biopsy of a pustule revealed an abundance of round and oval budding yeast forms consistent with Malassezia (formerly called Pityrosporum) “stuffing” the hair follicles and forming cleared spaces in the dermis surrounded by an exuberant lymphohistiocytic infiltrate (Figures 2 and 3). Special stains were negative for bacteria and mycelial forms. The clinicopathologic findings were diagnostic of Malassezia folliculitis with formation of dermal abscesses.

The patient was treated with intravenous itraconazole 200 mg daily for 7 days and topical benzoyl peroxide 5% gel, with ketoconazole 2% cream for maintenance therapy. The treatment brought improvement of the rash.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

A 25-year-old man being treated in the hospital for catatonia and flaccid paralysis developed fever and a lobar consolidation, prompting treatment with piperacillin-tazobactam. A dermatology consult was called 3 days later when the patient developed a rash on the forehead (Figure 1), cheeks, chin, and upper trunk, raising concern for a drug-related eruption.

Close examination of the rash revealed bright red plaques studded with sheets of monomorphic pustules. Possible causes other than drug therapy were considered, including folliculitis, acneiform eruption, and pustular psoriasis. Bacterial culture of a pustule was negative, but punch biopsy of a pustule revealed an abundance of round and oval budding yeast forms consistent with Malassezia (formerly called Pityrosporum) “stuffing” the hair follicles and forming cleared spaces in the dermis surrounded by an exuberant lymphohistiocytic infiltrate (Figures 2 and 3). Special stains were negative for bacteria and mycelial forms. The clinicopathologic findings were diagnostic of Malassezia folliculitis with formation of dermal abscesses.

The patient was treated with intravenous itraconazole 200 mg daily for 7 days and topical benzoyl peroxide 5% gel, with ketoconazole 2% cream for maintenance therapy. The treatment brought improvement of the rash.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

 

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

 

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

 

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,¹ a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.

Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.^1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.¹

While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.

This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.

CAN LEAD TO DELIRIUM TREMENS

In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.⁴ If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.^5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).⁷

Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,⁸ and subsequent episodes of alcohol withdrawal tend to be progressively worse.

Withdrawal symptoms

Alcohol withdrawal syndrome encompasses a spectrum of symptoms and conditions, from minor (eg, insomnia, tremulousness) to severe (seizures, DTs).² The symptoms typically depend on the amount of alcohol consumed, the time since the last drink, and the number of previous detoxifications.⁹

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,¹ states that to establish a diagnosis of alcohol withdrawal syndrome, a patient must meet four criteria: 

• The patient must have ceased or reduced alcohol intake after heavy or prolonged use.
• Two or more of the following must develop within a few hours to a few days: autonomic hyperactivity (sweating or pulse greater than 100 beats per minute); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; grand mal seizure.
• The above symptoms must cause significant distress or functional impairment.
• The symptoms must not be related to another medical condition.

Some of the symptoms described in the second criterion above can occur while the patient still has a measurable blood alcohol level, usually within 6 hours of cessation of drinking.¹⁰ Table 1 describes the timetable of onset of symptoms and their severity.²

The elderly may be affected more severely

While the progression of the symptoms described above is commonly used for medical inpatients, the timeline may be different in an elderly patient. Compared with younger patients, elderly patients may have higher blood alcohol concentrations owing to lower total body water, so small amounts of alcohol can produce significant effects.^11,12 Brower et al¹² found that elderly patients experienced more withdrawal symptoms, especially cognitive impairment, weakness, and high blood pressure, and for 3 days longer.

In the elderly, alcohol may have a greater impact on the central nervous system because of increased permeability of the blood-brain barrier. And importantly, elderly patients tend to have more concomitant diseases and take more medications, all of which can affect alcohol metabolism.

ASSESSMENT SCALES FOR ALCOHOL WITHDRAWAL SYNDROME

A number of clinical scales for evaluating alcohol withdrawal have been developed. Early ones such as the 30-item Total Severity Assessment (TSA) scale and the 11-item Selected Severity Assessment (SSA) scale were limited because they were extremely detailed, burdensome to nursing staff to administer, and contained items such as daily “sleep disturbances” that were not acute enough to meet specific monitoring needs or to guide drug therapy.^13,14

The Clinical Institute Withdrawal Assessment for alcohol (CIWA-A) scale, with 15 items, was derived from the SSA scale and includes acute items for assessment as often as every half-hour.¹⁵

The CIWA-Ar scale (Table 2) was developed from the CIWA-A scale by Sullivan et al.¹⁵ Using both observation and interview, it focuses on 10 areas: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, headache, disorientation, tactile disturbances, auditory disturbances, and visual disturbances. Scores can range from 0 to 67; a higher score indicates worse withdrawal symptoms and outcomes and therefore necessitates escalation of treatment.

The CIWA-Ar scale is now the one most commonly used in clinical trials^16–20 and, we believe, in practice. Other scales, including the CIWA-AD and the Alcohol Withdrawal Scale have been validated but are not widely used in practice.^14,21

BASELINE ASSESSMENT AND EARLY SUPPORTIVE CARE

A thorough history and physical examination should be performed on admission in patients known to be or suspected of being alcohol-dependent to assess the patient’s affected body systems. The time elapsed since the patient’s last alcohol drink helps predict the onset of withdrawal complications.

Baseline laboratory tests for most patients with suspected alcohol withdrawal syndrome should include a basic blood chemistry panel, complete blood cell count, and possibly an alcohol and toxicology screen, depending on the patient’s history and presentation.

Hydration and nutritional support are important in patients presenting with alcohol withdrawal syndrome. Severe disturbances in electrolytes can lead to serious complications, including cardiac arrhythmia. Close monitoring and electrolyte replacement as needed are recommended for hospitalized alcoholic patients and should follow hospital protocols.²²

Thiamine and folic acid status deserve special attention, since long-standing malnutrition is common in alcoholic patients. Thiamine deficiency can result in Wernicke encephalopathy and Korsakoff syndrome, characterized by delirium, ataxia, vision changes, and amnesia. Alcohol withdrawal guidelines recommend giving thiamine intravenously for the first 2 to 5 days after admission.²³ In addition, thiamine must be given before any intravenous glucose product, as thiamine is a cofactor in carbohydrate metabolism.²³ Folic acid should also be supplemented, as chronic deficiencies may lead to megaloblastic or macrocytic anemia.

Most patients with a CIWA-Ar score ≥ 8 benefit from benzodiazepine therapy

CIWA-Ar scale. To provide consistent monitoring and ongoing treatment, clinicians and institutions are encouraged to use a simple assessment scale that detects and quantifies alcohol withdrawal syndrome and that can be used for reassessment after an intervention.²¹ The CIWA-Ar scale should be used to facilitate “symptom-triggered therapy” in which, depending on the score, the patient receives pharmacologic treatment followed by a scheduled reevaluation.^23,24 Most patients with a CIWA-Ar score of 8 or higher benefit from benzodiazepine therapy.^16,18,19

PRIMARY DRUG THERAPIES FOR MEDICAL INPATIENTS

Benzodiazepines are the first-line agents

Benzodiazepines are the first-line agents recommended for preventing and treating alcohol withdrawal syndrome.²³ Their various pharmacokinetic profiles, wide therapeutic indices, and safety compared with older sedative hypnotics make them the preferred class.^23,25 No single benzodiazepine is preferred over the others for treating alcohol withdrawal syndrome: studies have shown benefits using short-acting, intermediate-acting, and long-acting agents. The choice of drug is variable and patient-specific.^16,18,26

Benzodiazepines promote and enhance binding of the inhibitory neurotransmitter GABA to GABA_A receptors in the central nervous system.²⁷ As a class, benzodiazepines are all structurally related and produce the same effects—namely, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.²⁷

The most studied benzodiazepines for treating and preventing alcohol withdrawal syndrome are chlordiazepoxide, oxazepam, and lorazepam,^16–20 whereas diazepam was used in older studies.²³

Diazepam and chlordiazepoxide are metabolized by oxidation, each sharing the long-acting active metabolite desmethyldiazepam (half-life 72 hours), and short-acting metabolite oxazepam (half-life 8 hours).²⁷ In addition, the parent drugs also have varying pharmacokinetic profiles: diazepam has a half-life of more than 30 hours and chlordiazepoxide a half-life of about 8 hours. Chlordiazepoxide and diazepam’s combination of both long- and short-acting benzodiazepine activity provides long-term efficacy in attenuating withdrawal symptoms, but chlordiazepoxide’s shorter parent half-life allows more frequent dosing.

Lorazepam (half-life 10–20 hours) and oxazepam (half-life 5–20 hours) undergo glucu­ronide conjugation and do not have metabolites.^27,28 Table 3 provides a pharmacokinetic summary.^27,28

Various dosage regimens are used in giving benzodiazepines, the most common being symptom-triggered therapy, governed by assessment scales, and scheduled around-the-clock therapy.²⁹ Current evidence supports symptom-triggered therapy in most inpatients who are not critically ill, as it can reduce both benzodiazepine use and adverse drug events and can reduce the length of stay.^16,19

Trials of symptom-triggered benzodiazepine therapy

Most inpatient trials of symptom-triggered therapy (Table 4)^3,16–20 used the CIWA-Ar scale for monitoring. In some of the studies, benzodiazepines were given if the score was 8 or higher, but others used cut points as high as 15 or higher. Doses:

• Chlordiazepoxide (first dose 25–100 mg)
• Lorazepam (first dose 0.5–2 mg)
• Oxazepam (30 mg).

After each dose, patients were reevaluated at intervals of 30 minutes to 8 hours.

Most of these trials showed no difference in rates of adverse drug events such as seizures, hallucinations, and lethargy with symptom-triggered therapy compared with scheduled therapy.^16,18,20 They also found either no difference in the incidence of delirium tremens, or a lower incidence of delirium tremens with symptom-triggered therapy than with scheduled therapy.^16–18,20

Weaver et al¹⁹ found no difference in length of stay between scheduled therapy and symptom-triggered therapy, but Saitz et al¹⁶ reported a median benzodiazepine treatment duration of 9 hours with symptom-triggered therapy vs 68 hours with fixed dosing. Thus, the study by Saitz et al suggests that hospitalization might be shorter with symptom-triggered therapy.

Many of the trials had notable limitations related to the diversity of patients enrolled and the protocols for both symptom-triggered therapy and fixed dosing. Some trials enrolled only inpatients in detoxification programs; others focused on inpatients with acute medical illness. The inpatient alcohol treatment trials^16,18 excluded medically ill patients and those with concurrent psychiatric illness,^16,18 and one excluded patients with seizures.¹⁶ One of the inpatient alcohol treatment program trials¹⁶ excluded patients on beta-blockers or clonidine because of concern that these drugs could mask withdrawal symptoms, whereas trials in medically ill patients allowed these same drugs.^17,19,20

Most of the patients were men (approximately 75%, but ranging from 74% to 100%), and therefore the study results may not be as applicable to women.^16–20 Most participants were middle-aged, with average ages in all studies between 46 and 55. Finally, the studies used a wide range of medications and dosing, with patient monitoring intervals ranging from every 30 minutes to every 8 hours.^16–20

In a 2010 Cochrane analysis, Amato et al²⁹ concluded that the limited evidence available favors symptom-triggered regimens over fixed-dosing regimens, but that differences in isolated trials should be interpreted very cautiously.

Therapeutic ethanol

Aside from the lack of evidence to support its use in alcohol withdrawal syndrome, prescribing oral ethanol to alcoholic patients clearly poses an ethical dilemma. However, giving ethanol intravenously has been studied, mostly in surgical trauma patients.³⁰

Early reports described giving intravenous ethanol on a gram-to-gram basis to match the patient’s consumption before admission to prevent alcohol withdrawal syndrome. But later studies reported prevention of alcohol withdrawal syndrome with very small amounts of intravenous ethanol.^30,31 While clinical trials have been limited to ICU patients, ethanol infusion at an initial rate of 2.5 to 5 g per hour and titrated up to 10 g per hour has appeared to be safe and effective for preventing alcohol withdrawal syndrome.^30,31 The initial infusion rate of 2.5 to 5 g per hour is equivalent to 4 to 10 alcoholic beverages per 24 hours.

Nevertheless, ethanol infusion carries the potential for toxicities (eg, gastric irritation, precipitation of acute hepatic failure, hypoglycemia, pancreatitis, bone marrow suppression,  prolonged wound healing) and drug interactions (eg, with anticoagulants and anticonvulsants). Thus, ethanol is neither widely used nor recommended.^25,31

 

ADJUNCTIVE THERAPIES

Many medications are used adjunctively in the acute setting, both for symptoms of alcohol withdrawal syndrome and for agitation.

Haloperidol

No clinical trial has yet examined haloperidol monotherapy in patients with alcohol withdrawal syndrome in either general medical units or intensive care units. Yet haloperidol remains important and is recommended as an adjunct therapy for agitation.^23,32 Dosing of haloperidol in protocols for surgical patients ranged from 2 to 5 mg intravenously every 0.5 to 2 hours, with a maximum dosage of 0.5 mg per kg per 24 hours.^7,33

Alpha-2 agonists

Alpha-2 agonists are thought to reduce sympathetic overdrive and the autonomic symptoms associated with alcohol withdrawal syndrome, and these agents (primarily clonidine) have been studied in the treatment of alcohol withdrawal syndrome.^34,35

Clonidine. In a Swedish study,³⁴ 26 men ages 20 to 55 who presented with the tremor, sweating, dysphoria, tension, anxiety, and tachycardia associated with alcohol withdrawal syndrome received clonidine 4 µg per kg twice daily or carbamazepine 200 mg three to four times daily in addition to an antiepileptic. Adjunctive use of a benzodiazepine was allowed at night in both groups. No statistically significant difference in symptom reduction was noted between the two groups, and there was no difference in total benzodiazepine use.

Dexmedetomidine, given intravenously, has been tested as an adjunct to benzodiazepine treatment in severe alcohol withdrawal syndrome. It has been shown to decrease the amount of total benzodiazepine needed compared with benzodiazepine therapy alone, but no differences have been seen in length of hospital stay.^36–39 However, research on this drug so far is limited to ICU patients.

Beta-blockers

Beta-blockers have been used in inpatients with alcohol withdrawal syndrome to reduce heart rate and potentially reduce alcohol craving. However, the data are limited and conflicting.

Atenolol 50 to 100 mg daily, in a study in 120 patients, reduced length of stay (4 vs 5 days), reduced benzodiazepine use, and improved vital signs and behavior compared with placebo.⁴⁰

Propranolol 40 mg every 6 hours reduced arrhythmias but increased hallucinations when used alone in a study in 47 patients.⁴¹ When used in combination with chlordiazepoxide, no benefit was seen in arrhythmia reduction.⁴¹

Barbiturates and other antiepileptics

Data continue to emerge on antiepileptics as both monotherapy and adjunctive therapy for alcohol withdrawal syndrome. Barbiturates as monotherapy were largely replaced by benzodiazepines in view of the narrow therapeutic index of barbiturates and their full agonist effect on the GABA receptor complex. However, phenobarbital has been evaluated in patients presenting with severe alcohol withdrawal syndrome or resistant alcohol withdrawal (ie, symptoms despite large or repeated doses of benzodiazepines) as an adjunct to benzodiazepines.^42,43

In addition, a newer trial⁴⁴ involved giving a single dose of phenobarbital in the emergency department in combination with a CIWA-Ar–based benzodiazepine protocol, compared with the benzodiazepine protocol alone. The group that received phenobarbital had fewer ICU admissions; its evaluation is ongoing.

The three other medications with the most data are carbamazepine, valproic acid, and gabapentin.^45,46 However, the studies were small and the benefit was modest. Although these agents are possible alternatives in protracted alcohol withdrawal syndrome, no definite conclusion can be made regarding their place in therapy.⁴⁶

RECOMMENDATIONS FOR DRUG THERAPY AND SUPPORTIVE CARE

Which benzodiazepine to use?

No specific benzodiazepine is recommended, but studies best support the long-acting drug chlordiazepoxide

No specific benzodiazepine is recommended over the others for managing alcohol withdrawal syndrome, but studies best support the long-acting agent chlordiazepoxide.^16,17,20 Other benzodiazepines such as lorazepam and oxazepam have proved to be beneficial, but drugs should be selected on the basis of patient characteristics and drug metabolism.^18,19,27

Patients with severe liver dysfunction and the elderly may have slower oxidative metabolism, so the effects of medications that are primarily oxidized, such as chlordiazepoxide and diazepam, may be prolonged. Therefore, lorazepam and oxazepam would be preferred in these groups.⁴⁷ While most patients with alcohol withdrawal syndrome and liver dysfunction do not have advanced cirrhosis, we recommend liver function testing (serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels)  and screening for liver disease, given the drug metabolism and package insert caution for use in those with impaired hepatic function.⁴⁸

Patients with end-stage renal disease (stage 5 chronic kidney disease) or acute kidney injury should not receive parenteral diazepam or lorazepam. The rationale is the potential accumulation of propylene glycol, the solvent used in these formulations.

In the elderly, the Beers list of drugs to avoid in older adults includes benzodiazepines, not differentiating individual benzodiazepines in terms of risk.⁴⁹ However, chlordiazepoxide may be preferable to diazepam due to its shorter parent half-life and lower lipophilicity.²⁷ Few studies have been done using benzodiazepines in elderly patients with alcohol withdrawal syndrome, but those published have shown either equivalent dosing required compared with younger patients or more severe withdrawal for which they received greater amounts of chlordiazepoxide.^9,12 Lorazepam and oxazepam have less potential to accumulate in the elderly compared with the nonelderly due to the drugs’ metabolic profiles; lorazepam is the preferred agent because of its faster onset of action.⁴⁷ Ultimately, the choice of benzodiazepine in elderly patients with alcohol withdrawal syndrome should be based on patient-specific characteristics.

How should benzodiazepines be dosed?

While the CIWA-Ar thresholds and subsequent dosing of benzodiazepines varied in different studies, we recommend starting benzodiazepine therapy at a CIWA-Ar score of 8 or higher, with subsequent dosing based on score reassessment. Starting doses of benzodiazepines should be chlordiazepoxide 25 to 50 mg, lorazepam 1 to 2 mg, or oxazepam 15 mg.^16–20

Subsequent doses should be titrated upward, increasing by 1.5 to 2 times the previous dose and monitored at least every 1 to 2 hours after dose adjustments. Once a patient is stable and the CIWA-Ar score is less than 8, monitoring intervals can be extended to every 4 to 8 hours. If the CIWA-Ar score is more than 20, studies suggest the need for patient reevaluation for transfer to the ICU; however, some health systems have a lower threshold for this intervention.^7,14,50

Dosing algorithms and CIWA-Ar goals may vary slightly from institution to institution, but it has been shown that symptom-triggered therapy works best when hospitals have a protocol for it and staff are adequately trained to assess patients with alcohol withdrawal syndrome.^7,50,51 Suggestions for dose ranges and symptom-triggered therapy are shown in Table 5.

In case of benzodiazepine overdose or potential benzodiazepine-induced delirium, flumazenil could be considered.⁵²

Patients who should not receive symptom-triggered therapy include immediate postoperative patients in whom clinicians cannot properly assess withdrawal symptoms and patients with a history of DTs.⁵¹ While controversy exists regarding the use of symptom-triggered therapy in patients with complicated medical comorbidities, there are data to support symptom-triggered therapy in some ICU patients, as it has resulted in less benzodiazepine use and reduced mechanical ventilation.^53,54

There are limited data to support phenobarbital in treating resistant alcohol withdrawal syndrome, either alone or concurrently with benzodiazepines, in escalating doses ranging from 65 to 260 mg, with a maximum daily dose of 520 mg.^42,55,56

Haloperidol

For patients exhibiting agitation despite benzodiazepine therapy, giving haloperidol adjunctively can be beneficial.

Haloperidol can be used in medical patients as an adjunctive therapy for agitation, but caution is advised because of the potential for a lowering of the seizure threshold, extrapyramidal effects, and risk of QTc prolongation leading to arrhythmias. Patients considered at highest risk for torsades de pointes may have a QTc of 500 msec or greater.⁵⁷

Patients should also be screened for factors that have been shown to be independent predictors of QTc prolongation (female sex, diagnosis of myocardial infarction, septic shock or left ventricular dysfunction, other QT-prolonging drugs, age > 68, baseline QTc ≥ 450 msec, and hypokalemia).⁵⁸ If combined predictors have been identified, it is recommended that haloperidol be avoided.

If haloperidol is to be given, a baseline electrocardiogram and electrolyte panel should be obtained, with daily electrocardiograms thereafter, as well as ongoing review of the patient’s medications to minimize drug interactions that could further increase the risk for QTc prolongation.

Suggested haloperidol dosing is 2 to 5 mg intravenously every 0.5 to 2 hours with a maximum dose of 0.5 mg/kg/24 hours.^8,33 A maximum of 35 mg of intravenous haloperidol should be used in a 24-hour period to avoid QTc prolongation.⁵⁷

Antihypertensive therapy

Many patients receive symptomatic relief of autonomic hyperreactivity with benzodiazepines. However, some may require additional antihypertensive therapy for cardiac adrenergic symptoms (hypertension, tachycardia) if symptoms do not resolve by treating other medical problems commonly seen in patients with alcohol withdrawal syndrome, such as dehydration and electrolyte imbalances.⁷

Published protocols suggest giving clonidine 0.1 mg orally every hour up to three times as needed until systolic blood pressure is less than 140 mm Hg (less than 160 mm Hg if the patient is over age 60) and diastolic pressure is less than 90 mm Hg.⁵¹ Once the patient is stabilized, the dosing can be scheduled to a maximum of 2.4 mg daily.⁵⁹ However, we believe that the use of clonidine should be restricted to patients who have a substantial increase in blood pressure over baseline or are nearing a hypertensive urgency or emergency (pressures > 180/120 mm Hg) and should not be used to treat other general symptoms associated with alcohol withdrawal syndrome.⁴²

In addition, based on limited evidence, we recommend using beta-blockers only in patients with symptomatic tachycardia or as an adjunct in hypertension management.^40,41

Therapies to avoid in acutely ill medical patients

Ethanol is not recommended. Instead, intravenous benzodiazepines should be given in patients presenting with severe alcohol withdrawal syndrome.

Antiepileptics, including valproic acid, carbamazepine, and pregabalin, lack benefit in these patients either as monotherapy or as adjunctive therapy and so are not recommended.^45,60–62

Magnesium supplementation (in patients with normal serum magnesium levels) should not be given, as no clinical benefit has been shown.⁶³

Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,¹ a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.

Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.^1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.¹

While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.

This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.

CAN LEAD TO DELIRIUM TREMENS

In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.⁴ If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.^5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).⁷

Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,⁸ and subsequent episodes of alcohol withdrawal tend to be progressively worse.

Withdrawal symptoms

Alcohol withdrawal syndrome encompasses a spectrum of symptoms and conditions, from minor (eg, insomnia, tremulousness) to severe (seizures, DTs).² The symptoms typically depend on the amount of alcohol consumed, the time since the last drink, and the number of previous detoxifications.⁹

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,¹ states that to establish a diagnosis of alcohol withdrawal syndrome, a patient must meet four criteria: 

• The patient must have ceased or reduced alcohol intake after heavy or prolonged use.
• Two or more of the following must develop within a few hours to a few days: autonomic hyperactivity (sweating or pulse greater than 100 beats per minute); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; grand mal seizure.
• The above symptoms must cause significant distress or functional impairment.
• The symptoms must not be related to another medical condition.

Some of the symptoms described in the second criterion above can occur while the patient still has a measurable blood alcohol level, usually within 6 hours of cessation of drinking.¹⁰ Table 1 describes the timetable of onset of symptoms and their severity.²

The elderly may be affected more severely

While the progression of the symptoms described above is commonly used for medical inpatients, the timeline may be different in an elderly patient. Compared with younger patients, elderly patients may have higher blood alcohol concentrations owing to lower total body water, so small amounts of alcohol can produce significant effects.^11,12 Brower et al¹² found that elderly patients experienced more withdrawal symptoms, especially cognitive impairment, weakness, and high blood pressure, and for 3 days longer.

In the elderly, alcohol may have a greater impact on the central nervous system because of increased permeability of the blood-brain barrier. And importantly, elderly patients tend to have more concomitant diseases and take more medications, all of which can affect alcohol metabolism.

ASSESSMENT SCALES FOR ALCOHOL WITHDRAWAL SYNDROME

A number of clinical scales for evaluating alcohol withdrawal have been developed. Early ones such as the 30-item Total Severity Assessment (TSA) scale and the 11-item Selected Severity Assessment (SSA) scale were limited because they were extremely detailed, burdensome to nursing staff to administer, and contained items such as daily “sleep disturbances” that were not acute enough to meet specific monitoring needs or to guide drug therapy.^13,14

The Clinical Institute Withdrawal Assessment for alcohol (CIWA-A) scale, with 15 items, was derived from the SSA scale and includes acute items for assessment as often as every half-hour.¹⁵

The CIWA-Ar scale (Table 2) was developed from the CIWA-A scale by Sullivan et al.¹⁵ Using both observation and interview, it focuses on 10 areas: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, headache, disorientation, tactile disturbances, auditory disturbances, and visual disturbances. Scores can range from 0 to 67; a higher score indicates worse withdrawal symptoms and outcomes and therefore necessitates escalation of treatment.

The CIWA-Ar scale is now the one most commonly used in clinical trials^16–20 and, we believe, in practice. Other scales, including the CIWA-AD and the Alcohol Withdrawal Scale have been validated but are not widely used in practice.^14,21

BASELINE ASSESSMENT AND EARLY SUPPORTIVE CARE

A thorough history and physical examination should be performed on admission in patients known to be or suspected of being alcohol-dependent to assess the patient’s affected body systems. The time elapsed since the patient’s last alcohol drink helps predict the onset of withdrawal complications.

Baseline laboratory tests for most patients with suspected alcohol withdrawal syndrome should include a basic blood chemistry panel, complete blood cell count, and possibly an alcohol and toxicology screen, depending on the patient’s history and presentation.

Hydration and nutritional support are important in patients presenting with alcohol withdrawal syndrome. Severe disturbances in electrolytes can lead to serious complications, including cardiac arrhythmia. Close monitoring and electrolyte replacement as needed are recommended for hospitalized alcoholic patients and should follow hospital protocols.²²

Thiamine and folic acid status deserve special attention, since long-standing malnutrition is common in alcoholic patients. Thiamine deficiency can result in Wernicke encephalopathy and Korsakoff syndrome, characterized by delirium, ataxia, vision changes, and amnesia. Alcohol withdrawal guidelines recommend giving thiamine intravenously for the first 2 to 5 days after admission.²³ In addition, thiamine must be given before any intravenous glucose product, as thiamine is a cofactor in carbohydrate metabolism.²³ Folic acid should also be supplemented, as chronic deficiencies may lead to megaloblastic or macrocytic anemia.

Most patients with a CIWA-Ar score ≥ 8 benefit from benzodiazepine therapy

CIWA-Ar scale. To provide consistent monitoring and ongoing treatment, clinicians and institutions are encouraged to use a simple assessment scale that detects and quantifies alcohol withdrawal syndrome and that can be used for reassessment after an intervention.²¹ The CIWA-Ar scale should be used to facilitate “symptom-triggered therapy” in which, depending on the score, the patient receives pharmacologic treatment followed by a scheduled reevaluation.^23,24 Most patients with a CIWA-Ar score of 8 or higher benefit from benzodiazepine therapy.^16,18,19

PRIMARY DRUG THERAPIES FOR MEDICAL INPATIENTS

Benzodiazepines are the first-line agents

Benzodiazepines are the first-line agents recommended for preventing and treating alcohol withdrawal syndrome.²³ Their various pharmacokinetic profiles, wide therapeutic indices, and safety compared with older sedative hypnotics make them the preferred class.^23,25 No single benzodiazepine is preferred over the others for treating alcohol withdrawal syndrome: studies have shown benefits using short-acting, intermediate-acting, and long-acting agents. The choice of drug is variable and patient-specific.^16,18,26

Benzodiazepines promote and enhance binding of the inhibitory neurotransmitter GABA to GABA_A receptors in the central nervous system.²⁷ As a class, benzodiazepines are all structurally related and produce the same effects—namely, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.²⁷

The most studied benzodiazepines for treating and preventing alcohol withdrawal syndrome are chlordiazepoxide, oxazepam, and lorazepam,^16–20 whereas diazepam was used in older studies.²³

Diazepam and chlordiazepoxide are metabolized by oxidation, each sharing the long-acting active metabolite desmethyldiazepam (half-life 72 hours), and short-acting metabolite oxazepam (half-life 8 hours).²⁷ In addition, the parent drugs also have varying pharmacokinetic profiles: diazepam has a half-life of more than 30 hours and chlordiazepoxide a half-life of about 8 hours. Chlordiazepoxide and diazepam’s combination of both long- and short-acting benzodiazepine activity provides long-term efficacy in attenuating withdrawal symptoms, but chlordiazepoxide’s shorter parent half-life allows more frequent dosing.

Lorazepam (half-life 10–20 hours) and oxazepam (half-life 5–20 hours) undergo glucu­ronide conjugation and do not have metabolites.^27,28 Table 3 provides a pharmacokinetic summary.^27,28

Various dosage regimens are used in giving benzodiazepines, the most common being symptom-triggered therapy, governed by assessment scales, and scheduled around-the-clock therapy.²⁹ Current evidence supports symptom-triggered therapy in most inpatients who are not critically ill, as it can reduce both benzodiazepine use and adverse drug events and can reduce the length of stay.^16,19

Trials of symptom-triggered benzodiazepine therapy

Most inpatient trials of symptom-triggered therapy (Table 4)^3,16–20 used the CIWA-Ar scale for monitoring. In some of the studies, benzodiazepines were given if the score was 8 or higher, but others used cut points as high as 15 or higher. Doses:

• Chlordiazepoxide (first dose 25–100 mg)
• Lorazepam (first dose 0.5–2 mg)
• Oxazepam (30 mg).

After each dose, patients were reevaluated at intervals of 30 minutes to 8 hours.

Most of these trials showed no difference in rates of adverse drug events such as seizures, hallucinations, and lethargy with symptom-triggered therapy compared with scheduled therapy.^16,18,20 They also found either no difference in the incidence of delirium tremens, or a lower incidence of delirium tremens with symptom-triggered therapy than with scheduled therapy.^16–18,20

Weaver et al¹⁹ found no difference in length of stay between scheduled therapy and symptom-triggered therapy, but Saitz et al¹⁶ reported a median benzodiazepine treatment duration of 9 hours with symptom-triggered therapy vs 68 hours with fixed dosing. Thus, the study by Saitz et al suggests that hospitalization might be shorter with symptom-triggered therapy.

Many of the trials had notable limitations related to the diversity of patients enrolled and the protocols for both symptom-triggered therapy and fixed dosing. Some trials enrolled only inpatients in detoxification programs; others focused on inpatients with acute medical illness. The inpatient alcohol treatment trials^16,18 excluded medically ill patients and those with concurrent psychiatric illness,^16,18 and one excluded patients with seizures.¹⁶ One of the inpatient alcohol treatment program trials¹⁶ excluded patients on beta-blockers or clonidine because of concern that these drugs could mask withdrawal symptoms, whereas trials in medically ill patients allowed these same drugs.^17,19,20

Most of the patients were men (approximately 75%, but ranging from 74% to 100%), and therefore the study results may not be as applicable to women.^16–20 Most participants were middle-aged, with average ages in all studies between 46 and 55. Finally, the studies used a wide range of medications and dosing, with patient monitoring intervals ranging from every 30 minutes to every 8 hours.^16–20

In a 2010 Cochrane analysis, Amato et al²⁹ concluded that the limited evidence available favors symptom-triggered regimens over fixed-dosing regimens, but that differences in isolated trials should be interpreted very cautiously.

Therapeutic ethanol

Aside from the lack of evidence to support its use in alcohol withdrawal syndrome, prescribing oral ethanol to alcoholic patients clearly poses an ethical dilemma. However, giving ethanol intravenously has been studied, mostly in surgical trauma patients.³⁰

Early reports described giving intravenous ethanol on a gram-to-gram basis to match the patient’s consumption before admission to prevent alcohol withdrawal syndrome. But later studies reported prevention of alcohol withdrawal syndrome with very small amounts of intravenous ethanol.^30,31 While clinical trials have been limited to ICU patients, ethanol infusion at an initial rate of 2.5 to 5 g per hour and titrated up to 10 g per hour has appeared to be safe and effective for preventing alcohol withdrawal syndrome.^30,31 The initial infusion rate of 2.5 to 5 g per hour is equivalent to 4 to 10 alcoholic beverages per 24 hours.

Nevertheless, ethanol infusion carries the potential for toxicities (eg, gastric irritation, precipitation of acute hepatic failure, hypoglycemia, pancreatitis, bone marrow suppression,  prolonged wound healing) and drug interactions (eg, with anticoagulants and anticonvulsants). Thus, ethanol is neither widely used nor recommended.^25,31

 

ADJUNCTIVE THERAPIES

Many medications are used adjunctively in the acute setting, both for symptoms of alcohol withdrawal syndrome and for agitation.

Haloperidol

No clinical trial has yet examined haloperidol monotherapy in patients with alcohol withdrawal syndrome in either general medical units or intensive care units. Yet haloperidol remains important and is recommended as an adjunct therapy for agitation.^23,32 Dosing of haloperidol in protocols for surgical patients ranged from 2 to 5 mg intravenously every 0.5 to 2 hours, with a maximum dosage of 0.5 mg per kg per 24 hours.^7,33

Alpha-2 agonists

Alpha-2 agonists are thought to reduce sympathetic overdrive and the autonomic symptoms associated with alcohol withdrawal syndrome, and these agents (primarily clonidine) have been studied in the treatment of alcohol withdrawal syndrome.^34,35

Clonidine. In a Swedish study,³⁴ 26 men ages 20 to 55 who presented with the tremor, sweating, dysphoria, tension, anxiety, and tachycardia associated with alcohol withdrawal syndrome received clonidine 4 µg per kg twice daily or carbamazepine 200 mg three to four times daily in addition to an antiepileptic. Adjunctive use of a benzodiazepine was allowed at night in both groups. No statistically significant difference in symptom reduction was noted between the two groups, and there was no difference in total benzodiazepine use.

Dexmedetomidine, given intravenously, has been tested as an adjunct to benzodiazepine treatment in severe alcohol withdrawal syndrome. It has been shown to decrease the amount of total benzodiazepine needed compared with benzodiazepine therapy alone, but no differences have been seen in length of hospital stay.^36–39 However, research on this drug so far is limited to ICU patients.

Beta-blockers

Beta-blockers have been used in inpatients with alcohol withdrawal syndrome to reduce heart rate and potentially reduce alcohol craving. However, the data are limited and conflicting.

Atenolol 50 to 100 mg daily, in a study in 120 patients, reduced length of stay (4 vs 5 days), reduced benzodiazepine use, and improved vital signs and behavior compared with placebo.⁴⁰

Propranolol 40 mg every 6 hours reduced arrhythmias but increased hallucinations when used alone in a study in 47 patients.⁴¹ When used in combination with chlordiazepoxide, no benefit was seen in arrhythmia reduction.⁴¹

Barbiturates and other antiepileptics

Data continue to emerge on antiepileptics as both monotherapy and adjunctive therapy for alcohol withdrawal syndrome. Barbiturates as monotherapy were largely replaced by benzodiazepines in view of the narrow therapeutic index of barbiturates and their full agonist effect on the GABA receptor complex. However, phenobarbital has been evaluated in patients presenting with severe alcohol withdrawal syndrome or resistant alcohol withdrawal (ie, symptoms despite large or repeated doses of benzodiazepines) as an adjunct to benzodiazepines.^42,43

In addition, a newer trial⁴⁴ involved giving a single dose of phenobarbital in the emergency department in combination with a CIWA-Ar–based benzodiazepine protocol, compared with the benzodiazepine protocol alone. The group that received phenobarbital had fewer ICU admissions; its evaluation is ongoing.

The three other medications with the most data are carbamazepine, valproic acid, and gabapentin.^45,46 However, the studies were small and the benefit was modest. Although these agents are possible alternatives in protracted alcohol withdrawal syndrome, no definite conclusion can be made regarding their place in therapy.⁴⁶

RECOMMENDATIONS FOR DRUG THERAPY AND SUPPORTIVE CARE

Which benzodiazepine to use?

No specific benzodiazepine is recommended, but studies best support the long-acting drug chlordiazepoxide

No specific benzodiazepine is recommended over the others for managing alcohol withdrawal syndrome, but studies best support the long-acting agent chlordiazepoxide.^16,17,20 Other benzodiazepines such as lorazepam and oxazepam have proved to be beneficial, but drugs should be selected on the basis of patient characteristics and drug metabolism.^18,19,27

Patients with severe liver dysfunction and the elderly may have slower oxidative metabolism, so the effects of medications that are primarily oxidized, such as chlordiazepoxide and diazepam, may be prolonged. Therefore, lorazepam and oxazepam would be preferred in these groups.⁴⁷ While most patients with alcohol withdrawal syndrome and liver dysfunction do not have advanced cirrhosis, we recommend liver function testing (serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels)  and screening for liver disease, given the drug metabolism and package insert caution for use in those with impaired hepatic function.⁴⁸

Patients with end-stage renal disease (stage 5 chronic kidney disease) or acute kidney injury should not receive parenteral diazepam or lorazepam. The rationale is the potential accumulation of propylene glycol, the solvent used in these formulations.

In the elderly, the Beers list of drugs to avoid in older adults includes benzodiazepines, not differentiating individual benzodiazepines in terms of risk.⁴⁹ However, chlordiazepoxide may be preferable to diazepam due to its shorter parent half-life and lower lipophilicity.²⁷ Few studies have been done using benzodiazepines in elderly patients with alcohol withdrawal syndrome, but those published have shown either equivalent dosing required compared with younger patients or more severe withdrawal for which they received greater amounts of chlordiazepoxide.^9,12 Lorazepam and oxazepam have less potential to accumulate in the elderly compared with the nonelderly due to the drugs’ metabolic profiles; lorazepam is the preferred agent because of its faster onset of action.⁴⁷ Ultimately, the choice of benzodiazepine in elderly patients with alcohol withdrawal syndrome should be based on patient-specific characteristics.

How should benzodiazepines be dosed?

While the CIWA-Ar thresholds and subsequent dosing of benzodiazepines varied in different studies, we recommend starting benzodiazepine therapy at a CIWA-Ar score of 8 or higher, with subsequent dosing based on score reassessment. Starting doses of benzodiazepines should be chlordiazepoxide 25 to 50 mg, lorazepam 1 to 2 mg, or oxazepam 15 mg.^16–20

Subsequent doses should be titrated upward, increasing by 1.5 to 2 times the previous dose and monitored at least every 1 to 2 hours after dose adjustments. Once a patient is stable and the CIWA-Ar score is less than 8, monitoring intervals can be extended to every 4 to 8 hours. If the CIWA-Ar score is more than 20, studies suggest the need for patient reevaluation for transfer to the ICU; however, some health systems have a lower threshold for this intervention.^7,14,50

Dosing algorithms and CIWA-Ar goals may vary slightly from institution to institution, but it has been shown that symptom-triggered therapy works best when hospitals have a protocol for it and staff are adequately trained to assess patients with alcohol withdrawal syndrome.^7,50,51 Suggestions for dose ranges and symptom-triggered therapy are shown in Table 5.

In case of benzodiazepine overdose or potential benzodiazepine-induced delirium, flumazenil could be considered.⁵²

Patients who should not receive symptom-triggered therapy include immediate postoperative patients in whom clinicians cannot properly assess withdrawal symptoms and patients with a history of DTs.⁵¹ While controversy exists regarding the use of symptom-triggered therapy in patients with complicated medical comorbidities, there are data to support symptom-triggered therapy in some ICU patients, as it has resulted in less benzodiazepine use and reduced mechanical ventilation.^53,54

There are limited data to support phenobarbital in treating resistant alcohol withdrawal syndrome, either alone or concurrently with benzodiazepines, in escalating doses ranging from 65 to 260 mg, with a maximum daily dose of 520 mg.^42,55,56

Haloperidol

For patients exhibiting agitation despite benzodiazepine therapy, giving haloperidol adjunctively can be beneficial.

Haloperidol can be used in medical patients as an adjunctive therapy for agitation, but caution is advised because of the potential for a lowering of the seizure threshold, extrapyramidal effects, and risk of QTc prolongation leading to arrhythmias. Patients considered at highest risk for torsades de pointes may have a QTc of 500 msec or greater.⁵⁷

Patients should also be screened for factors that have been shown to be independent predictors of QTc prolongation (female sex, diagnosis of myocardial infarction, septic shock or left ventricular dysfunction, other QT-prolonging drugs, age > 68, baseline QTc ≥ 450 msec, and hypokalemia).⁵⁸ If combined predictors have been identified, it is recommended that haloperidol be avoided.

If haloperidol is to be given, a baseline electrocardiogram and electrolyte panel should be obtained, with daily electrocardiograms thereafter, as well as ongoing review of the patient’s medications to minimize drug interactions that could further increase the risk for QTc prolongation.

Suggested haloperidol dosing is 2 to 5 mg intravenously every 0.5 to 2 hours with a maximum dose of 0.5 mg/kg/24 hours.^8,33 A maximum of 35 mg of intravenous haloperidol should be used in a 24-hour period to avoid QTc prolongation.⁵⁷

Antihypertensive therapy

Many patients receive symptomatic relief of autonomic hyperreactivity with benzodiazepines. However, some may require additional antihypertensive therapy for cardiac adrenergic symptoms (hypertension, tachycardia) if symptoms do not resolve by treating other medical problems commonly seen in patients with alcohol withdrawal syndrome, such as dehydration and electrolyte imbalances.⁷

Published protocols suggest giving clonidine 0.1 mg orally every hour up to three times as needed until systolic blood pressure is less than 140 mm Hg (less than 160 mm Hg if the patient is over age 60) and diastolic pressure is less than 90 mm Hg.⁵¹ Once the patient is stabilized, the dosing can be scheduled to a maximum of 2.4 mg daily.⁵⁹ However, we believe that the use of clonidine should be restricted to patients who have a substantial increase in blood pressure over baseline or are nearing a hypertensive urgency or emergency (pressures > 180/120 mm Hg) and should not be used to treat other general symptoms associated with alcohol withdrawal syndrome.⁴²

In addition, based on limited evidence, we recommend using beta-blockers only in patients with symptomatic tachycardia or as an adjunct in hypertension management.^40,41

Therapies to avoid in acutely ill medical patients

Ethanol is not recommended. Instead, intravenous benzodiazepines should be given in patients presenting with severe alcohol withdrawal syndrome.

Antiepileptics, including valproic acid, carbamazepine, and pregabalin, lack benefit in these patients either as monotherapy or as adjunctive therapy and so are not recommended.^45,60–62

Magnesium supplementation (in patients with normal serum magnesium levels) should not be given, as no clinical benefit has been shown.⁶³

Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,¹ a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.

Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.^1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.¹

While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.

This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.

CAN LEAD TO DELIRIUM TREMENS

In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.⁴ If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.^5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).⁷

Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,⁸ and subsequent episodes of alcohol withdrawal tend to be progressively worse.

Withdrawal symptoms

Alcohol withdrawal syndrome encompasses a spectrum of symptoms and conditions, from minor (eg, insomnia, tremulousness) to severe (seizures, DTs).² The symptoms typically depend on the amount of alcohol consumed, the time since the last drink, and the number of previous detoxifications.⁹

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,¹ states that to establish a diagnosis of alcohol withdrawal syndrome, a patient must meet four criteria: 

• The patient must have ceased or reduced alcohol intake after heavy or prolonged use.
• Two or more of the following must develop within a few hours to a few days: autonomic hyperactivity (sweating or pulse greater than 100 beats per minute); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; grand mal seizure.
• The above symptoms must cause significant distress or functional impairment.
• The symptoms must not be related to another medical condition.

Some of the symptoms described in the second criterion above can occur while the patient still has a measurable blood alcohol level, usually within 6 hours of cessation of drinking.¹⁰ Table 1 describes the timetable of onset of symptoms and their severity.²

The elderly may be affected more severely

While the progression of the symptoms described above is commonly used for medical inpatients, the timeline may be different in an elderly patient. Compared with younger patients, elderly patients may have higher blood alcohol concentrations owing to lower total body water, so small amounts of alcohol can produce significant effects.^11,12 Brower et al¹² found that elderly patients experienced more withdrawal symptoms, especially cognitive impairment, weakness, and high blood pressure, and for 3 days longer.

In the elderly, alcohol may have a greater impact on the central nervous system because of increased permeability of the blood-brain barrier. And importantly, elderly patients tend to have more concomitant diseases and take more medications, all of which can affect alcohol metabolism.

ASSESSMENT SCALES FOR ALCOHOL WITHDRAWAL SYNDROME

A number of clinical scales for evaluating alcohol withdrawal have been developed. Early ones such as the 30-item Total Severity Assessment (TSA) scale and the 11-item Selected Severity Assessment (SSA) scale were limited because they were extremely detailed, burdensome to nursing staff to administer, and contained items such as daily “sleep disturbances” that were not acute enough to meet specific monitoring needs or to guide drug therapy.^13,14

The Clinical Institute Withdrawal Assessment for alcohol (CIWA-A) scale, with 15 items, was derived from the SSA scale and includes acute items for assessment as often as every half-hour.¹⁵

The CIWA-Ar scale (Table 2) was developed from the CIWA-A scale by Sullivan et al.¹⁵ Using both observation and interview, it focuses on 10 areas: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, headache, disorientation, tactile disturbances, auditory disturbances, and visual disturbances. Scores can range from 0 to 67; a higher score indicates worse withdrawal symptoms and outcomes and therefore necessitates escalation of treatment.

The CIWA-Ar scale is now the one most commonly used in clinical trials^16–20 and, we believe, in practice. Other scales, including the CIWA-AD and the Alcohol Withdrawal Scale have been validated but are not widely used in practice.^14,21

BASELINE ASSESSMENT AND EARLY SUPPORTIVE CARE

A thorough history and physical examination should be performed on admission in patients known to be or suspected of being alcohol-dependent to assess the patient’s affected body systems. The time elapsed since the patient’s last alcohol drink helps predict the onset of withdrawal complications.

Baseline laboratory tests for most patients with suspected alcohol withdrawal syndrome should include a basic blood chemistry panel, complete blood cell count, and possibly an alcohol and toxicology screen, depending on the patient’s history and presentation.

Hydration and nutritional support are important in patients presenting with alcohol withdrawal syndrome. Severe disturbances in electrolytes can lead to serious complications, including cardiac arrhythmia. Close monitoring and electrolyte replacement as needed are recommended for hospitalized alcoholic patients and should follow hospital protocols.²²

Thiamine and folic acid status deserve special attention, since long-standing malnutrition is common in alcoholic patients. Thiamine deficiency can result in Wernicke encephalopathy and Korsakoff syndrome, characterized by delirium, ataxia, vision changes, and amnesia. Alcohol withdrawal guidelines recommend giving thiamine intravenously for the first 2 to 5 days after admission.²³ In addition, thiamine must be given before any intravenous glucose product, as thiamine is a cofactor in carbohydrate metabolism.²³ Folic acid should also be supplemented, as chronic deficiencies may lead to megaloblastic or macrocytic anemia.

Most patients with a CIWA-Ar score ≥ 8 benefit from benzodiazepine therapy

CIWA-Ar scale. To provide consistent monitoring and ongoing treatment, clinicians and institutions are encouraged to use a simple assessment scale that detects and quantifies alcohol withdrawal syndrome and that can be used for reassessment after an intervention.²¹ The CIWA-Ar scale should be used to facilitate “symptom-triggered therapy” in which, depending on the score, the patient receives pharmacologic treatment followed by a scheduled reevaluation.^23,24 Most patients with a CIWA-Ar score of 8 or higher benefit from benzodiazepine therapy.^16,18,19

PRIMARY DRUG THERAPIES FOR MEDICAL INPATIENTS

Benzodiazepines are the first-line agents

Benzodiazepines are the first-line agents recommended for preventing and treating alcohol withdrawal syndrome.²³ Their various pharmacokinetic profiles, wide therapeutic indices, and safety compared with older sedative hypnotics make them the preferred class.^23,25 No single benzodiazepine is preferred over the others for treating alcohol withdrawal syndrome: studies have shown benefits using short-acting, intermediate-acting, and long-acting agents. The choice of drug is variable and patient-specific.^16,18,26

Benzodiazepines promote and enhance binding of the inhibitory neurotransmitter GABA to GABA_A receptors in the central nervous system.²⁷ As a class, benzodiazepines are all structurally related and produce the same effects—namely, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.²⁷

The most studied benzodiazepines for treating and preventing alcohol withdrawal syndrome are chlordiazepoxide, oxazepam, and lorazepam,^16–20 whereas diazepam was used in older studies.²³

Diazepam and chlordiazepoxide are metabolized by oxidation, each sharing the long-acting active metabolite desmethyldiazepam (half-life 72 hours), and short-acting metabolite oxazepam (half-life 8 hours).²⁷ In addition, the parent drugs also have varying pharmacokinetic profiles: diazepam has a half-life of more than 30 hours and chlordiazepoxide a half-life of about 8 hours. Chlordiazepoxide and diazepam’s combination of both long- and short-acting benzodiazepine activity provides long-term efficacy in attenuating withdrawal symptoms, but chlordiazepoxide’s shorter parent half-life allows more frequent dosing.

Lorazepam (half-life 10–20 hours) and oxazepam (half-life 5–20 hours) undergo glucu­ronide conjugation and do not have metabolites.^27,28 Table 3 provides a pharmacokinetic summary.^27,28

Various dosage regimens are used in giving benzodiazepines, the most common being symptom-triggered therapy, governed by assessment scales, and scheduled around-the-clock therapy.²⁹ Current evidence supports symptom-triggered therapy in most inpatients who are not critically ill, as it can reduce both benzodiazepine use and adverse drug events and can reduce the length of stay.^16,19

Trials of symptom-triggered benzodiazepine therapy

Most inpatient trials of symptom-triggered therapy (Table 4)^3,16–20 used the CIWA-Ar scale for monitoring. In some of the studies, benzodiazepines were given if the score was 8 or higher, but others used cut points as high as 15 or higher. Doses:

• Chlordiazepoxide (first dose 25–100 mg)
• Lorazepam (first dose 0.5–2 mg)
• Oxazepam (30 mg).

After each dose, patients were reevaluated at intervals of 30 minutes to 8 hours.

Most of these trials showed no difference in rates of adverse drug events such as seizures, hallucinations, and lethargy with symptom-triggered therapy compared with scheduled therapy.^16,18,20 They also found either no difference in the incidence of delirium tremens, or a lower incidence of delirium tremens with symptom-triggered therapy than with scheduled therapy.^16–18,20

Weaver et al¹⁹ found no difference in length of stay between scheduled therapy and symptom-triggered therapy, but Saitz et al¹⁶ reported a median benzodiazepine treatment duration of 9 hours with symptom-triggered therapy vs 68 hours with fixed dosing. Thus, the study by Saitz et al suggests that hospitalization might be shorter with symptom-triggered therapy.

Many of the trials had notable limitations related to the diversity of patients enrolled and the protocols for both symptom-triggered therapy and fixed dosing. Some trials enrolled only inpatients in detoxification programs; others focused on inpatients with acute medical illness. The inpatient alcohol treatment trials^16,18 excluded medically ill patients and those with concurrent psychiatric illness,^16,18 and one excluded patients with seizures.¹⁶ One of the inpatient alcohol treatment program trials¹⁶ excluded patients on beta-blockers or clonidine because of concern that these drugs could mask withdrawal symptoms, whereas trials in medically ill patients allowed these same drugs.^17,19,20

Most of the patients were men (approximately 75%, but ranging from 74% to 100%), and therefore the study results may not be as applicable to women.^16–20 Most participants were middle-aged, with average ages in all studies between 46 and 55. Finally, the studies used a wide range of medications and dosing, with patient monitoring intervals ranging from every 30 minutes to every 8 hours.^16–20

In a 2010 Cochrane analysis, Amato et al²⁹ concluded that the limited evidence available favors symptom-triggered regimens over fixed-dosing regimens, but that differences in isolated trials should be interpreted very cautiously.

Therapeutic ethanol

Aside from the lack of evidence to support its use in alcohol withdrawal syndrome, prescribing oral ethanol to alcoholic patients clearly poses an ethical dilemma. However, giving ethanol intravenously has been studied, mostly in surgical trauma patients.³⁰

Early reports described giving intravenous ethanol on a gram-to-gram basis to match the patient’s consumption before admission to prevent alcohol withdrawal syndrome. But later studies reported prevention of alcohol withdrawal syndrome with very small amounts of intravenous ethanol.^30,31 While clinical trials have been limited to ICU patients, ethanol infusion at an initial rate of 2.5 to 5 g per hour and titrated up to 10 g per hour has appeared to be safe and effective for preventing alcohol withdrawal syndrome.^30,31 The initial infusion rate of 2.5 to 5 g per hour is equivalent to 4 to 10 alcoholic beverages per 24 hours.

Nevertheless, ethanol infusion carries the potential for toxicities (eg, gastric irritation, precipitation of acute hepatic failure, hypoglycemia, pancreatitis, bone marrow suppression,  prolonged wound healing) and drug interactions (eg, with anticoagulants and anticonvulsants). Thus, ethanol is neither widely used nor recommended.^25,31

 

ADJUNCTIVE THERAPIES

Many medications are used adjunctively in the acute setting, both for symptoms of alcohol withdrawal syndrome and for agitation.

Haloperidol

No clinical trial has yet examined haloperidol monotherapy in patients with alcohol withdrawal syndrome in either general medical units or intensive care units. Yet haloperidol remains important and is recommended as an adjunct therapy for agitation.^23,32 Dosing of haloperidol in protocols for surgical patients ranged from 2 to 5 mg intravenously every 0.5 to 2 hours, with a maximum dosage of 0.5 mg per kg per 24 hours.^7,33

Alpha-2 agonists

Alpha-2 agonists are thought to reduce sympathetic overdrive and the autonomic symptoms associated with alcohol withdrawal syndrome, and these agents (primarily clonidine) have been studied in the treatment of alcohol withdrawal syndrome.^34,35

Clonidine. In a Swedish study,³⁴ 26 men ages 20 to 55 who presented with the tremor, sweating, dysphoria, tension, anxiety, and tachycardia associated with alcohol withdrawal syndrome received clonidine 4 µg per kg twice daily or carbamazepine 200 mg three to four times daily in addition to an antiepileptic. Adjunctive use of a benzodiazepine was allowed at night in both groups. No statistically significant difference in symptom reduction was noted between the two groups, and there was no difference in total benzodiazepine use.

Dexmedetomidine, given intravenously, has been tested as an adjunct to benzodiazepine treatment in severe alcohol withdrawal syndrome. It has been shown to decrease the amount of total benzodiazepine needed compared with benzodiazepine therapy alone, but no differences have been seen in length of hospital stay.^36–39 However, research on this drug so far is limited to ICU patients.

Beta-blockers

Beta-blockers have been used in inpatients with alcohol withdrawal syndrome to reduce heart rate and potentially reduce alcohol craving. However, the data are limited and conflicting.

Atenolol 50 to 100 mg daily, in a study in 120 patients, reduced length of stay (4 vs 5 days), reduced benzodiazepine use, and improved vital signs and behavior compared with placebo.⁴⁰

Propranolol 40 mg every 6 hours reduced arrhythmias but increased hallucinations when used alone in a study in 47 patients.⁴¹ When used in combination with chlordiazepoxide, no benefit was seen in arrhythmia reduction.⁴¹

Barbiturates and other antiepileptics

Data continue to emerge on antiepileptics as both monotherapy and adjunctive therapy for alcohol withdrawal syndrome. Barbiturates as monotherapy were largely replaced by benzodiazepines in view of the narrow therapeutic index of barbiturates and their full agonist effect on the GABA receptor complex. However, phenobarbital has been evaluated in patients presenting with severe alcohol withdrawal syndrome or resistant alcohol withdrawal (ie, symptoms despite large or repeated doses of benzodiazepines) as an adjunct to benzodiazepines.^42,43

In addition, a newer trial⁴⁴ involved giving a single dose of phenobarbital in the emergency department in combination with a CIWA-Ar–based benzodiazepine protocol, compared with the benzodiazepine protocol alone. The group that received phenobarbital had fewer ICU admissions; its evaluation is ongoing.

The three other medications with the most data are carbamazepine, valproic acid, and gabapentin.^45,46 However, the studies were small and the benefit was modest. Although these agents are possible alternatives in protracted alcohol withdrawal syndrome, no definite conclusion can be made regarding their place in therapy.⁴⁶

RECOMMENDATIONS FOR DRUG THERAPY AND SUPPORTIVE CARE

Which benzodiazepine to use?

No specific benzodiazepine is recommended, but studies best support the long-acting drug chlordiazepoxide

No specific benzodiazepine is recommended over the others for managing alcohol withdrawal syndrome, but studies best support the long-acting agent chlordiazepoxide.^16,17,20 Other benzodiazepines such as lorazepam and oxazepam have proved to be beneficial, but drugs should be selected on the basis of patient characteristics and drug metabolism.^18,19,27

Patients with severe liver dysfunction and the elderly may have slower oxidative metabolism, so the effects of medications that are primarily oxidized, such as chlordiazepoxide and diazepam, may be prolonged. Therefore, lorazepam and oxazepam would be preferred in these groups.⁴⁷ While most patients with alcohol withdrawal syndrome and liver dysfunction do not have advanced cirrhosis, we recommend liver function testing (serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels)  and screening for liver disease, given the drug metabolism and package insert caution for use in those with impaired hepatic function.⁴⁸

Patients with end-stage renal disease (stage 5 chronic kidney disease) or acute kidney injury should not receive parenteral diazepam or lorazepam. The rationale is the potential accumulation of propylene glycol, the solvent used in these formulations.

In the elderly, the Beers list of drugs to avoid in older adults includes benzodiazepines, not differentiating individual benzodiazepines in terms of risk.⁴⁹ However, chlordiazepoxide may be preferable to diazepam due to its shorter parent half-life and lower lipophilicity.²⁷ Few studies have been done using benzodiazepines in elderly patients with alcohol withdrawal syndrome, but those published have shown either equivalent dosing required compared with younger patients or more severe withdrawal for which they received greater amounts of chlordiazepoxide.^9,12 Lorazepam and oxazepam have less potential to accumulate in the elderly compared with the nonelderly due to the drugs’ metabolic profiles; lorazepam is the preferred agent because of its faster onset of action.⁴⁷ Ultimately, the choice of benzodiazepine in elderly patients with alcohol withdrawal syndrome should be based on patient-specific characteristics.

How should benzodiazepines be dosed?

While the CIWA-Ar thresholds and subsequent dosing of benzodiazepines varied in different studies, we recommend starting benzodiazepine therapy at a CIWA-Ar score of 8 or higher, with subsequent dosing based on score reassessment. Starting doses of benzodiazepines should be chlordiazepoxide 25 to 50 mg, lorazepam 1 to 2 mg, or oxazepam 15 mg.^16–20

Subsequent doses should be titrated upward, increasing by 1.5 to 2 times the previous dose and monitored at least every 1 to 2 hours after dose adjustments. Once a patient is stable and the CIWA-Ar score is less than 8, monitoring intervals can be extended to every 4 to 8 hours. If the CIWA-Ar score is more than 20, studies suggest the need for patient reevaluation for transfer to the ICU; however, some health systems have a lower threshold for this intervention.^7,14,50

Dosing algorithms and CIWA-Ar goals may vary slightly from institution to institution, but it has been shown that symptom-triggered therapy works best when hospitals have a protocol for it and staff are adequately trained to assess patients with alcohol withdrawal syndrome.^7,50,51 Suggestions for dose ranges and symptom-triggered therapy are shown in Table 5.

In case of benzodiazepine overdose or potential benzodiazepine-induced delirium, flumazenil could be considered.⁵²

Patients who should not receive symptom-triggered therapy include immediate postoperative patients in whom clinicians cannot properly assess withdrawal symptoms and patients with a history of DTs.⁵¹ While controversy exists regarding the use of symptom-triggered therapy in patients with complicated medical comorbidities, there are data to support symptom-triggered therapy in some ICU patients, as it has resulted in less benzodiazepine use and reduced mechanical ventilation.^53,54

There are limited data to support phenobarbital in treating resistant alcohol withdrawal syndrome, either alone or concurrently with benzodiazepines, in escalating doses ranging from 65 to 260 mg, with a maximum daily dose of 520 mg.^42,55,56

Haloperidol

For patients exhibiting agitation despite benzodiazepine therapy, giving haloperidol adjunctively can be beneficial.

Haloperidol can be used in medical patients as an adjunctive therapy for agitation, but caution is advised because of the potential for a lowering of the seizure threshold, extrapyramidal effects, and risk of QTc prolongation leading to arrhythmias. Patients considered at highest risk for torsades de pointes may have a QTc of 500 msec or greater.⁵⁷

Patients should also be screened for factors that have been shown to be independent predictors of QTc prolongation (female sex, diagnosis of myocardial infarction, septic shock or left ventricular dysfunction, other QT-prolonging drugs, age > 68, baseline QTc ≥ 450 msec, and hypokalemia).⁵⁸ If combined predictors have been identified, it is recommended that haloperidol be avoided.

If haloperidol is to be given, a baseline electrocardiogram and electrolyte panel should be obtained, with daily electrocardiograms thereafter, as well as ongoing review of the patient’s medications to minimize drug interactions that could further increase the risk for QTc prolongation.

Suggested haloperidol dosing is 2 to 5 mg intravenously every 0.5 to 2 hours with a maximum dose of 0.5 mg/kg/24 hours.^8,33 A maximum of 35 mg of intravenous haloperidol should be used in a 24-hour period to avoid QTc prolongation.⁵⁷

Antihypertensive therapy

Many patients receive symptomatic relief of autonomic hyperreactivity with benzodiazepines. However, some may require additional antihypertensive therapy for cardiac adrenergic symptoms (hypertension, tachycardia) if symptoms do not resolve by treating other medical problems commonly seen in patients with alcohol withdrawal syndrome, such as dehydration and electrolyte imbalances.⁷

Published protocols suggest giving clonidine 0.1 mg orally every hour up to three times as needed until systolic blood pressure is less than 140 mm Hg (less than 160 mm Hg if the patient is over age 60) and diastolic pressure is less than 90 mm Hg.⁵¹ Once the patient is stabilized, the dosing can be scheduled to a maximum of 2.4 mg daily.⁵⁹ However, we believe that the use of clonidine should be restricted to patients who have a substantial increase in blood pressure over baseline or are nearing a hypertensive urgency or emergency (pressures > 180/120 mm Hg) and should not be used to treat other general symptoms associated with alcohol withdrawal syndrome.⁴²

In addition, based on limited evidence, we recommend using beta-blockers only in patients with symptomatic tachycardia or as an adjunct in hypertension management.^40,41

Therapies to avoid in acutely ill medical patients

Ethanol is not recommended. Instead, intravenous benzodiazepines should be given in patients presenting with severe alcohol withdrawal syndrome.

Antiepileptics, including valproic acid, carbamazepine, and pregabalin, lack benefit in these patients either as monotherapy or as adjunctive therapy and so are not recommended.^45,60–62

Magnesium supplementation (in patients with normal serum magnesium levels) should not be given, as no clinical benefit has been shown.⁶³

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

 

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

 

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

Anticoagulation is highly effective for the prevention of thrombotic events, however, bleeding risk is always present. Tools have been developed for the assessment of bleeding risk during anticoagulation therapy, but they have limitations. Several instruments have been validated in patients with AF and are summarized in Table 1 [17–19].

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Due to the lack of head-to-head studies comparing the DOACs, clinicians must cautiously rely on indirect comparisons of these agents. Important considerations include differences in landmark study design, population, and outcomes. Table 2 [14–16,27] highlights some of the study design differences.

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Table 3 and Table 4 [28–31,56] provide a summary of major bleeding rates reported in landmark trials for the total and age-specific populations. Both apixaban and edoxaban (60 mg and 30 mg) were associated with significantly fewer major bleeding events compared to warfarin (apixaban: 2.1%/year versus 3.1%/year, P < 0.001; edoxaban: 60 mg 2.75%/year and 30 mg 1.61%/year versus 3.43%/year, P < 0.001) [16,27]. Dabigatran and rivaroxaban had similar major bleeding rates compared to warfarin (3.1%/year versus 3.5%/year, P = 0.31 and 5.6% versus 5.4%, P = 0.58, respectively). A pooled analysis of the DOACs reported that major bleeding in patients ≥ 75 years was at least similar to warfarin (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.74–1.17) [32].

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Although DOACs offer advantages over warfarin [41], there is still no assurance regarding the promise of reduced or similar risk of bleeding with DOACs compared with warfarin in the geriatric population. Generalizability of bleeding rates reported in landmark studies leads to underestimating the risk of bleeding in geriatric patients [42]. For example, in one case series 67% of the bleeding complications with dabigatran were in patients ≥ 80 years old [43]. Furthermore, although subgroup analyses were performed evaluating geriatric patients in the landmark studies, these analyses are inherently biased. First, they represent post-hoc analyses and are not adequately powered. Second, geriatric patients included in landmark studies may have lower CHADS2 scores compared to those seen in clinical practice. Third, patients with severe renal dysfunction (ie, CrCl < 25–30 mL/min) were excluded from many landmark studies. However, several large observational studies have found that the DOACs pose no disproportionate risk of bleeding the geriatric population versus warfarin [44–46]. A review of major bleeding complications reported from landmark clinical trials are summarized Table 3 [29–31, 47–50]. Figure 1 depicts the hazard ratios for stroke and major hemorrhage reported in geriatric subgroup analyses in the landmark studies [29–31,44–46]. Below we describe geriatric subgroup data for each DOAC. Analyses of geriatric subroups are yet to be published in full for edoxaban.

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Only 27% of apixaban is renally cleared, and the manufacturer does not indicate dose adjustments for patients with renal insufficiency [57]. Therefore, apixaban is the favorable anticoagulant in the elderly population with renal disease. Prescribing information recommends reducing the dose from 5 mg twice daily to 2.5 mg twice daily for nonvalvular AF patients, if patients meet 2 of the following criteria: age ≥ 80 years of age, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL (Table 5) [57]. In patients with end-stage renal disease (ESRD) maintained on hemodialysis, the recommended dose of apixaban is 5 mg twice daily, unless the patient is ≥ 80 years or has a body weight ≤ 60 kg, in which case the dose should be reduced to 2.5 mg twice daily. Clinicians should consider the source of the aforementioned dosing strategy as patients with a CrCl < 25 mL/min were excluded from the ARISTOTLE study. Dosing in hemodialysis is supported by a small study that showed an increase in AUC of 36% after a single dose. The extent of drug accumulation is unknown and dialysis only clears a small portion of apixaban (~14%).

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Polypharmacy is defined as concomitantly using multiple medications. The likelihood of an adverse drug reaction increases exponentially with the number of drugs taken, independent of the class of medication [66]. Older adults use over the counter (46%) and herbal supplements (52%) while taking prescription medications and 50% of them are noted to have a drug interaction with anticoagulants. This leads to approximately 1 out of 25 older adults at risk for significant drug-drug interactions [67]. Some DOACs have recommendations for dosage reductions in the setting of advanced age (Table 6). Therefore, it is reasonable to assume that advanced age and drug interactions may place patients at greater risk of treatment failure. Further investigations are needed to understand polypharmacy and drug-drug interactions in geriatric patients [68]; however, clinicians should be aware of the potential pharmacokinetic interactions with DOACs (Table 7) [56–59]. 

Clinicians should review the patient’s entire medication profile and discontinue any unnecessary medications that may interact with one another if possible. There are several pharmacodymanic interactions that should also be considered. Concomitant use of antiplatelets and NSAIDs with DOACs may increase bleeding risk. In many cases NSAIDs may be discontinued. Patients on dual antiplatelet therapy and an anticoagulant are at an increased risk of bleeding. Clinicians should question the need for dual antiplatelet therapy with anticoagulation. The WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial suggested that triple therapy (eg, oral anticoagulant plus aspirin plus clopidogrel) is associated with greater risks than benefits in individuals with AF and coronary stents [69, 70].

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

With life expectancy among the elderly continuing to improve, the number of patients requiring chronic anti-coagulation will continue to rise. Understanding the strengths and limitations of oral anticoagulants and the literature to support their use is essential to select the most appropriate agent in the geriatric patient. When selecting an anticoagulant strategy, clinicians should consider clinical data, patient factors, and patient preferences. Figure 2 provides a suggested anticoagulant selection pathway to complement the clinical decision process [83,84].

 

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

 

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

 

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

Anticoagulation is highly effective for the prevention of thrombotic events, however, bleeding risk is always present. Tools have been developed for the assessment of bleeding risk during anticoagulation therapy, but they have limitations. Several instruments have been validated in patients with AF and are summarized in Table 1 [17–19].

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Due to the lack of head-to-head studies comparing the DOACs, clinicians must cautiously rely on indirect comparisons of these agents. Important considerations include differences in landmark study design, population, and outcomes. Table 2 [14–16,27] highlights some of the study design differences.

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Table 3 and Table 4 [28–31,56] provide a summary of major bleeding rates reported in landmark trials for the total and age-specific populations. Both apixaban and edoxaban (60 mg and 30 mg) were associated with significantly fewer major bleeding events compared to warfarin (apixaban: 2.1%/year versus 3.1%/year, P < 0.001; edoxaban: 60 mg 2.75%/year and 30 mg 1.61%/year versus 3.43%/year, P < 0.001) [16,27]. Dabigatran and rivaroxaban had similar major bleeding rates compared to warfarin (3.1%/year versus 3.5%/year, P = 0.31 and 5.6% versus 5.4%, P = 0.58, respectively). A pooled analysis of the DOACs reported that major bleeding in patients ≥ 75 years was at least similar to warfarin (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.74–1.17) [32].

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Although DOACs offer advantages over warfarin [41], there is still no assurance regarding the promise of reduced or similar risk of bleeding with DOACs compared with warfarin in the geriatric population. Generalizability of bleeding rates reported in landmark studies leads to underestimating the risk of bleeding in geriatric patients [42]. For example, in one case series 67% of the bleeding complications with dabigatran were in patients ≥ 80 years old [43]. Furthermore, although subgroup analyses were performed evaluating geriatric patients in the landmark studies, these analyses are inherently biased. First, they represent post-hoc analyses and are not adequately powered. Second, geriatric patients included in landmark studies may have lower CHADS2 scores compared to those seen in clinical practice. Third, patients with severe renal dysfunction (ie, CrCl < 25–30 mL/min) were excluded from many landmark studies. However, several large observational studies have found that the DOACs pose no disproportionate risk of bleeding the geriatric population versus warfarin [44–46]. A review of major bleeding complications reported from landmark clinical trials are summarized Table 3 [29–31, 47–50]. Figure 1 depicts the hazard ratios for stroke and major hemorrhage reported in geriatric subgroup analyses in the landmark studies [29–31,44–46]. Below we describe geriatric subgroup data for each DOAC. Analyses of geriatric subroups are yet to be published in full for edoxaban.

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Only 27% of apixaban is renally cleared, and the manufacturer does not indicate dose adjustments for patients with renal insufficiency [57]. Therefore, apixaban is the favorable anticoagulant in the elderly population with renal disease. Prescribing information recommends reducing the dose from 5 mg twice daily to 2.5 mg twice daily for nonvalvular AF patients, if patients meet 2 of the following criteria: age ≥ 80 years of age, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL (Table 5) [57]. In patients with end-stage renal disease (ESRD) maintained on hemodialysis, the recommended dose of apixaban is 5 mg twice daily, unless the patient is ≥ 80 years or has a body weight ≤ 60 kg, in which case the dose should be reduced to 2.5 mg twice daily. Clinicians should consider the source of the aforementioned dosing strategy as patients with a CrCl < 25 mL/min were excluded from the ARISTOTLE study. Dosing in hemodialysis is supported by a small study that showed an increase in AUC of 36% after a single dose. The extent of drug accumulation is unknown and dialysis only clears a small portion of apixaban (~14%).

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Polypharmacy is defined as concomitantly using multiple medications. The likelihood of an adverse drug reaction increases exponentially with the number of drugs taken, independent of the class of medication [66]. Older adults use over the counter (46%) and herbal supplements (52%) while taking prescription medications and 50% of them are noted to have a drug interaction with anticoagulants. This leads to approximately 1 out of 25 older adults at risk for significant drug-drug interactions [67]. Some DOACs have recommendations for dosage reductions in the setting of advanced age (Table 6). Therefore, it is reasonable to assume that advanced age and drug interactions may place patients at greater risk of treatment failure. Further investigations are needed to understand polypharmacy and drug-drug interactions in geriatric patients [68]; however, clinicians should be aware of the potential pharmacokinetic interactions with DOACs (Table 7) [56–59]. 

Clinicians should review the patient’s entire medication profile and discontinue any unnecessary medications that may interact with one another if possible. There are several pharmacodymanic interactions that should also be considered. Concomitant use of antiplatelets and NSAIDs with DOACs may increase bleeding risk. In many cases NSAIDs may be discontinued. Patients on dual antiplatelet therapy and an anticoagulant are at an increased risk of bleeding. Clinicians should question the need for dual antiplatelet therapy with anticoagulation. The WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial suggested that triple therapy (eg, oral anticoagulant plus aspirin plus clopidogrel) is associated with greater risks than benefits in individuals with AF and coronary stents [69, 70].

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

With life expectancy among the elderly continuing to improve, the number of patients requiring chronic anti-coagulation will continue to rise. Understanding the strengths and limitations of oral anticoagulants and the literature to support their use is essential to select the most appropriate agent in the geriatric patient. When selecting an anticoagulant strategy, clinicians should consider clinical data, patient factors, and patient preferences. Figure 2 provides a suggested anticoagulant selection pathway to complement the clinical decision process [83,84].

 

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

From the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ.

 

Abstract

• Objective: To provide a clinical summary of the available data evaluating the use of direct oral anticoagulants (DOACs) in geriatric patients with nonvalvular atrial fibrillation.
• Methods: MEDLINE, Web of Science, and Google Scholar were used to identify pertinent systematic reviews, randomized controlled trials, observational studies, and pharmacokinetic studies evaluating use of DOACs in the geriatric population.
• Results: A total of 8 systemic reviews, 5 randomized controlled trials, 2 observational trials, and 5 pharmacokinetic studies of relevance were identified for inclusion in this review. The landscape of anticoagulation has dramatically changed over the past 5 years beginning with the development and marketing of an oral direct thrombin inhibitor and followed by 3 oral direct factor Xa inhibitors. Despite significant advances in this oral anticoagulation arena, many questions remain as to the best therapeutic approach in the geriatric population as the literature is lacking. This population has a higher risk of stroke; however, due to the increased risk of bleeding clinicians may often defer anticoagulant therapy due to the fear of hemorrhagic complications. Clinicians must consider the risk-benefit ratio and the associated outcomes in geriatric patients compared to other patient populations.
• Conclusions: Interpreting the available literature and understanding the benefits and limitations of the DOACs is critical when selecting the most appropriate pharmacologic strategy in geriatric patients.

 

Anticoagulants are among the top 5 drug classes associated with patient harm in the US [1] and are commonly reported as contributing to hospitalizations [2]. In just one quarter in 2012 alone, warfarin, dabigatran, and rivaroxaban accounted for 1734 of 50,289 adverse events reported to the Food and Drug Administration (FDA), including 233 deaths [3]. Appropriate use of anticoagulant agents and consideration of individual patient risk factors are essential to mitigate the occurrence of adverse consequences, especially in the geriatric population. This population is more likely to have risk factors for adverse drug events, for example, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, and diminished organ function (ie, renal and hepatic) [4,5]. Another important consideration is the lack of consensus on the definition of a “geriatric” or “elderly” patient. Although many consider a chronological age of > 65 years as the defining variable for a geriatric individual, this definition does not account for overall health status [6,7]. Clinicians should consider this shortcoming when evaluating the quality of geriatric studies. For example, a study claiming to evaluate the pharmacokinetics of a drug in a geriatric population enrolling healthy subjects aged > 65 years may result in data that do not translate to clinical practice.

Compounding the concern for iatrogenic events is the frequency of anticoagulant use in the geriatric population, as several indications are found more commonly in this age-group. Stroke prevention in nonvalvular atrial fibrillation (AF), the most common arrhythmia in the elderly, is a common indication for long-term anticoagulation [8]. The prevalence of AF increases with age and is usually higher in men than in women [9,10]. AF is generally uncommon before 60 years of age, but the prevalence increases noticeably thereafter, affecting approximately 10% of the overall population by 80 years of age [11]. The median age of patients who have AF is 75 years with approximately 70% of patients between 65 and 85 years of age [8,12]. Currently in the United States, an estimated 2.3 million people are diagnosed with AF [8]. In 2020, the AF population is predicted to increase to 7.5 million individuals with an expected prevalence of 13.5% among individuals ≥ 75 years of age, and 18.2% for those ≥ 85 years of age [13]. These data underscore the importance of considering the influence of age on the balance between efficacy and safety of anticoagulant therapy.

Direct oral anticoagulants (DOACs) represent the first alternatives to warfarin in over 6 decades. Currently available products in US include apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs possess many of the characteristics of an ideal anticoagulant, including predictable pharmacokinetics, a wider therapeutic window compared to warfarin, minimal drug interactions, a fixed dose, and no need for routine evaluation of coagulation parameters. The safety and efficacy of the DOACs for stroke prevention in nonvalvular AF have been substantiated in several landmark clinical trials [14–16]. Yet there are several important questions that need to be addressed, such as management of excessive anticoagulation, clinical outcome data with renally adjusted doses (an exclusion criterion in many landmark studies was a creatinine clearance of < 25–30 mL/min), whether monitoring of coagulation parameters could enhance efficacy and safety, and optimal dosing strategies in geriatric patients. This review provides clinicians a summary of data from landmark studies, post-marketing surveillance, and pharmacokinetic evaluations to support DOAC selection in the geriatric population.

Evaluating Bleeding Risk

Anticoagulation is highly effective for the prevention of thrombotic events, however, bleeding risk is always present. Tools have been developed for the assessment of bleeding risk during anticoagulation therapy, but they have limitations. Several instruments have been validated in patients with AF and are summarized in Table 1 [17–19].

These tools have been extensively evaluated with warfarin therapy, but their performance in predicting DOAC-related bleeding has not been definitively established. Nonetheless, until tools evaluated specifically for DOACs are developed, it is reasonable to use these for risk-prediction in combination with clinical judgment. As an example, the European Society of Cardiology guideline on the use of non–vitamin K antagonist (VKA) anticoagulants in patients with nonvalvular AF suggests that the HAS-BLED score may be used to identify risk factors for bleeding and correct those that are modifiable [20]. The HAS-BLED score is validated for VKA and non-VKA anticoagulants (early-generation oral direct thrombin inhibitor ximelgatran) [21] and is the only bleeding risk score predictive for intracranial hemorrhage [19]. In a 2013 “real world” comparison, HAS-BLED was easier to use and had better predictive accuracy that ATRIA [22].

One of the major challenges in geriatric patients is that those at highest risk for bleeding are those who would have the greatest benefit from anticoagulation [23]. The prediction scores can help clinicians balance the risk-benefit ratio for anticoagulation on a case by case basis. Although the scoring systems take into consideration several factors, including medical conditions that have been shown to significantly increase bleeding risk, including hypertension, cerebrovascular disease, ischemic stroke, serious heart disease, diabetes, renal insufficiency, alcoholism and liver disease, not all are included in every scoring scheme [23]. These conditions are more common among elderly patients, and this should be taken into account when estimating the risk-benefit ratio of oral anticoagulation [15]. Patients’ preferences should also be taken into account. It is essential for clinicians to clearly discuss treatment options with patients as data suggest that clinician and patient perceptions of anticoagulation are often mismatched [24–26].

Performance of TSOACS in Landmark Studies

Due to the lack of head-to-head studies comparing the DOACs, clinicians must cautiously rely on indirect comparisons of these agents. Important considerations include differences in landmark study design, population, and outcomes. Table 2 [14–16,27] highlights some of the study design differences.

Some specific differences in outcomes seen in landmark studies that may facilitate selection among the DOACs include the risk of major bleeding, risk of gastrointestinal bleeding, risk of acute coronary syndrome, exclusion of valvular heart disease, and noninferiority versus superiority as the primary endpoint when compared to warfarin.

Major Bleeding

Table 3 and Table 4 [28–31,56] provide a summary of major bleeding rates reported in landmark trials for the total and age-specific populations. Both apixaban and edoxaban (60 mg and 30 mg) were associated with significantly fewer major bleeding events compared to warfarin (apixaban: 2.1%/year versus 3.1%/year, P < 0.001; edoxaban: 60 mg 2.75%/year and 30 mg 1.61%/year versus 3.43%/year, P < 0.001) [16,27]. Dabigatran and rivaroxaban had similar major bleeding rates compared to warfarin (3.1%/year versus 3.5%/year, P = 0.31 and 5.6% versus 5.4%, P = 0.58, respectively). A pooled analysis of the DOACs reported that major bleeding in patients ≥ 75 years was at least similar to warfarin (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.74–1.17) [32].

Gastrointestinal Bleeding

Among all of the DOACs, gastrointestinal (GI) bleeding was significantly greater with dabigatran, edoxaban, and rivaroxaban when compared to warfarin (HR, 1.49; 95% CI, 1.21–1.84; HR, 1.23; 95% CI, 1.02–1.50; and HR, 1.61; 95% CI, 1.30–1.99, respectively; P < 0.05 for all) [14–16] in landmark studies. Based on these data, clinicians may consider the selection of apixaban in patients with a previous history of GI pathology. GI bleeding may be more common in elderly patients due to the potential for preexisting GI pathology and high local concentrations of drug [29]. Clemens and colleagues suggested an “anticoagulation GI stress test” may predict GI malignancy [33]. They found that patients on DOACs that presented with a GI bleed were more likely to present with a GI malignancy. As such, it is reasonable to screen patients with a fecal occult blood test within the first month after initiating TSOAC treatment and then annually.

Acute Coronary Syndrome

A higher rate of myocardial infarction was observed with dabigatran 150 mg versus warfarin (0.74% vs 0.53% per year; P = 0.048) in the RE-LY study [16]. Whether the increase in myocardial infarction was due to dabigatran as a causative agent or warfarin’s ability to reduce the risk of myocardial infarction to a larger extent compared with dabigatran is unknown. Nonetheless, it may be prudent to use an alternative therapy in patients with a history of acute coronary syndrome.

Valvular Heart Disease

The risk of stroke and systemic embolism is higher in patients with valvular heart disease [34]. Patients with moderate to severe mitral stenosis or mechanical prosthetic heart valves were excluded from the DOAC landmark studies. Dabigatran was evaluated for prevention of stroke and systemic embolism in patients with valvular heart disease in the RE-ALIGN study [35,36]. Patients were randomized to warfarin titrated to a target INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk or dabigatran 150 mg, 220 mg, or 300 mg twice daily adjusted to a targeted trough of ≥ 50 ng/mL. The trial was terminated early due to a worse primary outcome (composite of stroke, systemic embolism, myocardial infarction, and death) with dabigatran versus warfarin (HR, 3.37, 95% CI, 0.76–14.95; P = 0.11). In addition, bleeding rates (any bleeding) was significantly greater with dabigatran (27%) versus warfarin (12%) (P = 0.01). Based on these data and the lack of data with the other TSOACs, warfarin remains the standard of care for valvular heart disease [37]. In patients with a previous bioprosthetic valve with AF, patients with mitral insufficiency, or aortic stensosis, TSOACs may be considered [37].

Landmark Study Efficacy Endpoints

The primary endpoint in each of the landmark studies was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. For the primary endpoint only dabigatran 150 mg twice daily and apixaban 5 mg twice daily were found to be superior to warfarin for the prevention of stroke or systemic embolism in nonvalvular AF (HR, 0.66; 95% CI, 0.53–0.82; P < 0.001 and HR, 0.66; 95% CI, 0.66–0.95; P = 0.01, respectively). Both edoxaban (60 mg and 30 mg daily) and rivaroxaban were noninferior to warfarin for the primary endpoint. In terms of ischemic stroke, only dabigatran 150 mg twice daily was superior to warfarin for the reduction in ischemic stroke in patients with nonvalvular AF (HR, 0.76; 95% CI, 0.60–0.98; P = 0.03) [19]. All of the DOACs demonstrated a reduction in hemorrhagic stroke.

TSOAC Use in Elderly Patitents

Pharmacokinetic Evaluations

Several pharmacokinetic studies have evaluated the influence of age on DOAC disposition. In a study evaluating the influence of age on apixaban disposition, the area under the concentration-time curve to infinity was 32% higher in the elderly (aged 65 years or older) compared to the younger subjects (< age 40 years) [38]. These data provide the rationale for dosage adjustment in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). In a pharmacokinetic study evaluating dabigatran in patients > 65 years of age, the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12 to 14 hours, and peak concentrations (256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0–4.0 hours) [39]. These data suggest a 1.7- to twofold increase in bioavailability. The area under the curve of rivaroxaban was significantly higher in subjects > 75 years versus subjects 18-45 years, while total and renal clearance were decreased [40].However, the time to maximum factor Xa inhibition and C_max were not influenced by age.

Clinical Evaluations

Although DOACs offer advantages over warfarin [41], there is still no assurance regarding the promise of reduced or similar risk of bleeding with DOACs compared with warfarin in the geriatric population. Generalizability of bleeding rates reported in landmark studies leads to underestimating the risk of bleeding in geriatric patients [42]. For example, in one case series 67% of the bleeding complications with dabigatran were in patients ≥ 80 years old [43]. Furthermore, although subgroup analyses were performed evaluating geriatric patients in the landmark studies, these analyses are inherently biased. First, they represent post-hoc analyses and are not adequately powered. Second, geriatric patients included in landmark studies may have lower CHADS2 scores compared to those seen in clinical practice. Third, patients with severe renal dysfunction (ie, CrCl < 25–30 mL/min) were excluded from many landmark studies. However, several large observational studies have found that the DOACs pose no disproportionate risk of bleeding the geriatric population versus warfarin [44–46]. A review of major bleeding complications reported from landmark clinical trials are summarized Table 3 [29–31, 47–50]. Figure 1 depicts the hazard ratios for stroke and major hemorrhage reported in geriatric subgroup analyses in the landmark studies [29–31,44–46]. Below we describe geriatric subgroup data for each DOAC. Analyses of geriatric subroups are yet to be published in full for edoxaban.

Dabigatran

In a post-hoc analysis of the RE-LY trial, Eikelboom and colleagues found that patients 75 years of age and older treated with dabigatran 150 mg twice daily had a greater incidence of GI bleeding irrespective of renal function compared with those on warfarin (1.85%/year vs. 1.25%/year; P < 0.001) [29]. A higher risk in major bleeding also was seen in dabigatran patients (5.10% versus 4.37%; P = 0.07). As a result, the 2012 Beer’s Criteria lists dabigatran as a potentially inappropriate medication. An analysis was conducted of 134,414 elderly Medicare patients (defined as age > 65 years) with 37,587 person-years of follow-up who were treated with dabigatran or warfarin [44]. Approximately 60% of patients included in the analysis were over age 75 years. Dabigatran was associated with a significant reduction in ischemic stroke: HR 0.80 (CI 0.67–0.96); intracranial hemorrhage: HR 0.34 (CI 0.26–0.46); and death: HR 0.86 (CI 0.77–0.96) when compared with warfarin. As in the Eikelboom study, major gastrointestinal bleeding was significantly increased with dabigatran (HR, 1.28 [95% CI, 1.14–1.44]).

Rivaroxaban

For rivaroxaban, a subgroup analysis of patients ≥ 75 years in the ROCKET-AF trial reported similar rates of major bleeding (HR, 1.11; 95% CI, 0.92–1.34) with rivaroxaban compared with warfarin [31]. Clinically relevant non-major bleeding was significantly higher for patients aged ≥ 75 years compared with patients aged < 75 years (P = 0.01).

Apixaban

Halvorsen and colleagues found that age did not influence the benefits of apixaban in terms of efficacy and safety [47]. In the cohort of patients aged 75 years or older, major bleeding was significantly reduced compared to warfarin (HR, 0.64; 95% CI, 0.52–0.79). The safety benefits persisted even in the setting of age greater than 75 years and renal impairment. A significant reduction in major bleeding (HR, 0.35; 95% CI, 0.14–0.86) was seen in elderly patients with a CrCl; ≤ 30 mL/min (n = 221) treated with apixaban versus warfarin. Similarly, in elderly patients with a CrCl 30 to 50 mL/min (n = 1898) a significant reduction in major bleeding was reported (HR, 0.53; 95% CI, 0.37–0.76). These data are consistent with a meta-regression analysis that found a linear relationship between the relative risk of major bleeding and the magnitude of renal excretion for the DOACs (r²=0.66, P = 0.03) [48]. In this analysis, apixaban had the most favorable outcomes in terms of major bleeding compared to the other DOACs and also has the least dependence on renal function for clearance. In a pooled analysis of data from landmark trials, Ng and colleagues found that in elderly patients (defined as age > 75 years) with nonvalvular AF, only apixaban was associated with a significant reduction in both stroke and major hemorrhage (Figure 1) [49,50].

Edoxaban

Kato and colleagues performed a subgroup analysis of patients aged 75 years or older enrolled in the ENGAGE TIMI 48 study [50]. Currently the results are only published in abstract form. Regardless of treatment, the risk of major bleeding and stroke significantly increased with age (P < 0.001). An absolute risk reduction in major bleeding was reported with both 60 mg and 30 mg of edoxaban versus warfarin (4.0%/year and 2.2%/year versus 4.8%/year, respectively; no P value provided).

Therapeuti Drug Monitoring

Collectively, the data on assessment of the anticoagulant activity of DOACs using coagulation assays is evolving. These tests include but are not limited to prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TT), dilute TT, activated clotting time (ACT), anti factor Xa, and ecarin clotting time (ECT) assays. Although routine monitoring is not desirable, the ability to assess degree of anticoagulation in select patient populations may prove beneficial. Future studies are essential to confirm whether assessing DOAC activity using coagulation assays in vulnerable populations such as the elderly improves clinical outcomes. Several reviews on this subject matter have been published [51–55]. The reader is encouraged to review these data as there are significant limitations to currently available assays and incorrect interpretation may lead to suboptimal treatment decisions.

Renal and Hepatic Dysfunction

Depending on the specific agents, DOACs renal clearance varies from 27% to 80% [56–59]. Clinical trials often use the Cockcroft-Gault formula (CG) based on actual body weight to estimate renal function. Landmark trials evaluating the DOACs differed in their strategy for estimation of renal function using CG. For example, RE-LY and ROCKET-AF used actual body weight for the estimation of renal function, while ARISTOTLE did not specify which body weight to use. Estimation of renal function or glomerular filtration rate (GFR) by CG is frequently in discordance with actual renal function in the elderly [60]. MDRD (modification of diet in renal disease) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) are also common estimations that provide an estimate of GFR. In a cross-sectional study, comparing the CG, MDRD, and EPI formulas in a clinical setting, data from potential kidney donors and adult patients who underwent a GFR measurement revealed that MDRD has the smallest mean bias. The influence of age was the absolute bias for estimation of renal function for all formulas. CG is additionally influenced by body weight and body mass index. When compared to CG, MDRD actually reported more accurate predictor of GFR in adults < 70 years old [61]. However, package inserts recommend dose adjustments based on estimation of CrCl using CG formula. This poses a problem in adjusting DOAC doses in elderly patients who are subject to overestimation of renal function with this antiquated equation. Among elderly patients with renal impairment, discordance between estimated and actual renal function was higher for dabigatran and rivaroxaban than for apixaban dosages [61].

Only 27% of apixaban is renally cleared, and the manufacturer does not indicate dose adjustments for patients with renal insufficiency [57]. Therefore, apixaban is the favorable anticoagulant in the elderly population with renal disease. Prescribing information recommends reducing the dose from 5 mg twice daily to 2.5 mg twice daily for nonvalvular AF patients, if patients meet 2 of the following criteria: age ≥ 80 years of age, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL (Table 5) [57]. In patients with end-stage renal disease (ESRD) maintained on hemodialysis, the recommended dose of apixaban is 5 mg twice daily, unless the patient is ≥ 80 years or has a body weight ≤ 60 kg, in which case the dose should be reduced to 2.5 mg twice daily. Clinicians should consider the source of the aforementioned dosing strategy as patients with a CrCl < 25 mL/min were excluded from the ARISTOTLE study. Dosing in hemodialysis is supported by a small study that showed an increase in AUC of 36% after a single dose. The extent of drug accumulation is unknown and dialysis only clears a small portion of apixaban (~14%).

Renal excretion of unchanged dabigatran is the predominant pathway for elimination (~80%) [58]. The FDA-approved dosing strategy in the US for dabigatran is 150 mg twice daily in patients with a CrCl ≥ 30 mL/min, 75 mg twice daily in patients with severe renal impairment (CrCl 15–30 mL/min), and is contraindicated in patients with a CrCl < 15 mL/min [58]. By comparison, the Canadian and the European Medicines Agency have listed patients with a CrCl < 30 mL/min (severe renal impairment) as a contraindication for use. The US-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model [62,63]. The dosage was estimated by pharmacokinetic simulation to provide similar C_max and C_min concentrations compared to the 150 mg twice-daily dosage in moderate renal impairment. Compared to patients with CrCl ≥ 80 mL/min, there was a 1.29- and a 1.47-fold increase in dabigatran trough plasma concentration in the CrCl 50–80 mL/min patients and the CrCl 30–50 mL/min patients, respectively. There have been many postmarketing reports of hemorrhage with dabigatran [36,84,85]. Although reporting bias is likely due to the novelty of the agent, clinicians may take key clinical pearls away from these reports. Patients often had risk factors, including low body weight, renal impairment, and polypharmacy with interacting drugs (eg, amiodarone). These risk factors are also important with the other DOACs.

A subgroup analysis of ROCKET-AF evaluating rivaroxaban 15 mg daily in patients with a CrCl of 30–49 mL/min did not identify any differences in endpoints with the exception of fatal bleeding, which occurred less often with rivaroxaban (0.28%/yr vs. 0.74%/yr; P = 0.047) [64].

Monitoring of renal function is essential to mitigate the risk of drug accumulation. Clinicians should consider obtaining a baseline renal assessment with annual reassessments in patients with normal (CrCl ≥ 80 mL/min) or mild (CrCl 50–79 mL/min) renal impairment, and 2 to 3 times per year in patients with moderate (CrCl 30–49 mL/min) renal impairment [65]. A summary of renal dose adjustments for DOAC therapy may be found in Table 5 [56–59].

In addition to renal function, hepatic impairment can also affect the metabolism of anticoagulants. Severe hepatic impairment can lead to prolonged PT. Therefore, patients who have liver dysfunction and are treated with anticoagulation have increased risk of hemorrhagic events. Large pivotal trials on the key indications of dabigatran, apixaban, and rivaroxaban excluded patients with significant signs of hepatic impairment. Table 5 provides dosing recommendations for the different DOACs in the setting of hepatic impairment [56–59].

Polypharmacy And The Potential For Adverse Consequences

Polypharmacy is defined as concomitantly using multiple medications. The likelihood of an adverse drug reaction increases exponentially with the number of drugs taken, independent of the class of medication [66]. Older adults use over the counter (46%) and herbal supplements (52%) while taking prescription medications and 50% of them are noted to have a drug interaction with anticoagulants. This leads to approximately 1 out of 25 older adults at risk for significant drug-drug interactions [67]. Some DOACs have recommendations for dosage reductions in the setting of advanced age (Table 6). Therefore, it is reasonable to assume that advanced age and drug interactions may place patients at greater risk of treatment failure. Further investigations are needed to understand polypharmacy and drug-drug interactions in geriatric patients [68]; however, clinicians should be aware of the potential pharmacokinetic interactions with DOACs (Table 7) [56–59]. 

Clinicians should review the patient’s entire medication profile and discontinue any unnecessary medications that may interact with one another if possible. There are several pharmacodymanic interactions that should also be considered. Concomitant use of antiplatelets and NSAIDs with DOACs may increase bleeding risk. In many cases NSAIDs may be discontinued. Patients on dual antiplatelet therapy and an anticoagulant are at an increased risk of bleeding. Clinicians should question the need for dual antiplatelet therapy with anticoagulation. The WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial suggested that triple therapy (eg, oral anticoagulant plus aspirin plus clopidogrel) is associated with greater risks than benefits in individuals with AF and coronary stents [69, 70].

Costs And Cost-Effectiveness of DOACS

With the high burden of AF and the aging population, analysis of cost and value is an important consideration [76]. There are limited publications comparing the cost-effectiveness between the anticoagulation options. However, numerous cost-effectiveness studies have evaluated the individual DOACs [71–79]. Overall, the studies suggest that the DOACs are a cost-effective alternative to warfarin in the general and elderly populations. One analysis reported that dabigatran may not be cost-effective in patients with a low CHADS2 score (≤ 2) [71].

Harrington et al [80] compared the cost-effectiveness of dabigatran, rivaroxaban, and apixaban versus warfarin. This cost-effectiveness study used published clinical trial data to build a decision model, and results indicated that for patients ≥ 70 years of age with an increased risk for stroke, normal renal function, and no previous contraindications to anticoagulant therapy, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were cost-effective substitutes for warfarin for the prevention of stroke in nonvalvular AF [80]. Apixaban was the preferred anticoagulant for their hypothetical cohort of 70-year-old patients with nonvalvular AF, as it was most likely to be the cost-effective treatment option at all willing-to-pay thresholds > $40,000 per quality-adjusted life-year gained [76,81].

Prescription costs may vary depending on payor and level of insurance. If a patient does not have prescription insurance, the annual price of generic warfarin is roughly $200 to $360, depending on dosage. Approximate annual costs for the DOACs are greater than 20 times the cost of warfarin (apixaban $4500, dabigatran $4500, and rivaroxaban $4800) [82]. However, most patients on these medications are over 65 years old and have prescription coverage through Medicare Part D. Of note, patients may have more of a burden if or when they reach the “donut hole” coverage gap. Currently, once patients spend $2960 (for 2015) and $3310 (for 2016) on covered drugs they will fall into the donut hole unless they qualify for additional assistance. At this point Medicare Part D will reimburse 45% of the cost of the newer anticoagulants since generics are currently unavailable. As a result, individual affordability may become an issue. Further complicating the scenario is the inability to apply coupon and rebate cards in the setting of government-funded prescription coverage. Clinicians should discuss these issues with their patients to help select the most valuable therapy.

Conclusions And Recommendations

With life expectancy among the elderly continuing to improve, the number of patients requiring chronic anti-coagulation will continue to rise. Understanding the strengths and limitations of oral anticoagulants and the literature to support their use is essential to select the most appropriate agent in the geriatric patient. When selecting an anticoagulant strategy, clinicians should consider clinical data, patient factors, and patient preferences. Figure 2 provides a suggested anticoagulant selection pathway to complement the clinical decision process [83,84].

 

Corresponding author: Luigi Brunetti, PharmD, MPH, Rutgers University, 160 Frelinghuysen Rd, Piscataway, NJ 08854, [email protected].

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

 

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

 

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

 

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴