Reviews

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Primum non nocere: First, do no harm—a principle taught across the world to all medical students. It reminds the health care provider to consider the possible harm that any intervention might produce. Never is it more relevant in the mind of a clinician than when prescribing a medication for a pregnant woman. We are, after all, brought up in a society averse to medical risk.

When managing a pregnant patient, should the baby be the highest priority, whatever the mother may face? Or to take the extreme opposite position, should the mother be treated with the best possible options and the baby ignored?

And what about the views of the patient? There is a widespread cultural belief about the vulnerability of the mother and fetus during pregnancy. Therefore, when faced with the decision of whether to use a medication or not, what is the best recourse for the pregnant patient? Should she be the “good mother” and avoid all risk to the baby, or should she be the “responsible mother” who follows medical advice and takes treatment as recommended?

In truth, the path to safe management of a pregnant patient is rarely so dichotomous. In most cases, what is best for the mother is also best for the baby. However, caring for a pregnant or lactating woman can be challenging for clinicians facing insufficient information regarding medication safety, overestimation of the risk of medication by both the patient and the care provider, and increasing litigation costs.

This article provides key principles to guide clinicians caring for pregnant patients, as we find ourselves increasingly dependent on pharmacotherapy. It also includes sources of information clinicians can turn to when they need additional pregnancy safety data about a certain drug and when they want advice about conditions commonly seen in pregnancy and medications that can be justifiably used in those circumstances.

KEY CONCEPTS FOR PRESCRIBING IN PREGNANCY

The following concepts are key to prescribing for a pregnant patient:

No protective barrier exists between the maternal and fetal environments

The placenta contains a semipermeable membrane that selectively allows some substances to pass from the maternal to the fetal blood and excludes others. However, it is not really a “protective mechanism” when it comes to medications. Assume that the fetus will have exposure, at least to some degree.

In general, drugs that are lipophilic, of a low molecular weight, or not ionized at physiologic pH cross the placenta more efficiently than others. Heparin and insulin are notable exceptions to the rule that most drugs cross the placenta. They do not.

The gestational stage may determine the effect of a medication on the fetus

In animals and in humans, exposure of the embryo or fetus to a teratogen may produce a permanent abnormality of structure or function.

First-trimester exposures are most worrisome for structural malformations. However, fetal neurologic and behavioral development, fetal survival, and function of specific organs can be affected even after the first trimester. For example, while first-trimester exposure to angiotensin-converting enzyme inhibitors has been linked to a slight increase in congenital heart defects, exposure in the second or third trimester can result in fetal oligohydramnios, neonatal anuria, pulmonary hypoplasia, intrauterine growth restriction, and fetal death.

Physiologic changes of pregnancy affect the pharmacokinetics of medications

Pregnancy is associated with increased plasma volume, increased glomerular filtration rate, and dilutional hypoalbuminemia, which can all affect the bioavailability of medications. Absorption of oral agents also may be affected by slowed gastric motility in pregnancy.

Although these physiologic alterations do not routinely warrant a change in drug dosage, they may be important considerations when choosing an appropriate agent. For example, medications taken in multiple doses per day are more likely to have a sustained effect than once-daily medications, which would be rapidly cleared in a pregnant patient.

Sole reliance on the FDA pregnancy safety category may be inadequate

To help clinicians prescribe medications for pregnant women, the US Food and Drug Administration (FDA) assigns medications to one of five categories of risk (A, B, C, D, or X) (Table 1). Unfortunately, this classification system has several shortcomings:

• The categories are often seen as a grading system in which the risk increases from the lowest in category A to highest in category X, and the safety information in the accompanying narrative is not always appreciated by prescribers.
• Clinicians incorrectly assume that drugs in a particular category carry a similar risk. However, 65% to 70% of all medications are in category C. This category includes medications with adverse animal data or no animal data at all. In addition, adverse animal data may vary in severity from decreased fetal weight to major structural malformation and fetal loss, indicating a difference in expected risk.
• Most of the data on medication safety in pregnancy comes from animal studies, case reports, case series, case-control studies, or pregnancy registries, and each of these sources has significant limitations.
• The categories do not distinguish between supporting data from animal studies and human studies. For instance, a category-B drug may have animal studies that show no risk but no adequate human studies, or may have animal studies showing risk but human studies that do not.

Looking at the pregnancy risk classifications used in the United States (ie, the FDA system), Australia, and Sweden, researchers compared the classification of 236 drugs between the three systems and found that only one in four drugs was similarly classified into the same risk category. This discrepancy further brings into question the usefulness and reliability of these classifications.¹

Finally, none of the classification systems tells us the potential harm from withholding a medication in pregnancy.

RESOURCES TO ASSESS MEDICATION SAFETY IN PREGNANCY

The FDA has proposed changes in the labeling of medications related to pregnancy and lactation.² The proposed changes would eliminate the current categories and instead require a summary of the risks, the effects of the drug on the fetus, and clinical considerations for use during pregnancy. In addition, labeling would include a description of the medication’s effects on milk production, the amount of drug present in milk, and possible effects on the infant.

Until such changes are in place, what other resources can a busy clinician turn to for support?

The official drug labeling (or the package insert), also published in the Physicians’ Desk Reference, is one source of information, but it rarely provides up-to-date information about teratogenic risks in human pregnancies.

Several online databases review, summarize, and periodically update information from the peer-reviewed medical literature.^3–7 The REPRORISK system^4–7 maintained by Micromedex (Greenwood Village, CO) provides access to several databases that contain information about a wide range of individual medications: REPROTEXT, REPROTOX,⁵ Shepard’s Catalog of Teratogenic Agents,⁷ and the Teratogen Information System (TERIS).⁴ Online access and a smartphone “app” for these databases are available for a subscription fee. Summaries for individual medications can be ordered directly from TERIS, also for a fee. Several other resources are available in textbook format.^8–10

In addition, health care providers can obtain information from or can refer pregnant and breastfeeding patients to a teratology information service for information and counseling about medication exposures. MotherToBaby,¹¹ a service of the nonprofit Organization of Teratology Information Specialists, provides fact sheets, free phone consultation, risk assessment, and counseling by trained teratogen information specialists about environmental exposures, including prescription and over-the-counter medications and dietary and herbal supplements. Counselors from these services gather and synthesize information about exposures from the databases mentioned above, from the peer-reviewed medical literature, from drug manufacturers, and from other sources.

With the advent of electronic medical records and computerized provider order entry, clinical decision support systems hold promise as an additional resource for safe prescribing in pregnancy.

Fortunately, the list of teratogenic medications that are absolutely contraindicated in pregnancy remains small (Table 2).^12,13

THE FOUR-QUESTION APPROACH TO CARING FOR THE PREGNANT PATIENT

Is the symptom self-limited or amenable to nonpharmacologic management?

It has been said that we live in a culture where every symptom warrants a pill. If this is true, there can be no better time for reevaluating this practice than during pregnancy.

Many of the medications most commonly used in pregnancy are for upper-respiratory-tract infections, headache, or psychological distress. Pregnancy is the ideal time to educate patients about the limited effectiveness of most cough-and-cold remedies and the inappropriateness of antibiotics for colds and viral bronchitis. It is also an ideal time for a trial of lifestyle modifications, relaxation, and biofeedback for a chronic headache problem. For cases of mild to moderate depression, it may be worth considering treatment with psychotherapy rather than medications.

Offering patients the option of no treatment or nonpharmacologic treatment for self-limited symptoms is an option worth considering.

How do the patient’s (and your) values and understanding affect the decision?

Is the patient willing to take medication? What are her beliefs with regard to her problem and how it should be managed in pregnancy?

Women and clinicians bring many worries and prejudices to the use of medications in pregnancy. The experiences of the patient and her family and friends may present huge obstacles to needed medication use in pregnancy. Misinformation in the media and from family members, friends, and other health care providers are other obstacles. The only way to deal with this issue is to ask your patient directly about her fears and concerns regarding each prescription written.

Clinicians also need to address fears or prejudices they themselves may have about medication safety in pregnancy. These may arise from a single bad experience in caring for a pregnant woman, discomfort with uncertainty, or a belief that pregnant women should avoid any and all risks of exposures, even when the mother’s condition warrants pharmacologic treatment.

Being informed, both scientifically and about one’s own biases or tendencies, is an essential foundation for rational prescribing in pregnancy.

Is the problem affected by pregnancy, and how?

Pregnancy can affect many medical conditions, and in different ways. Conditions such as asthma, migraine headache, and cardiac arrhythmia are exacerbated in pregnancy, placing the mother and fetus at increased risk of morbidity. Conditions such as Graves disease and hypertension may improve as pregnancy progresses, and medications often can be withdrawn as the patient progresses further along in gestation.

Understanding the effect of pregnancy on a particular problem may help the clinician to make an informed decision about medication use in pregnancy.

How does the problem affect pregnancy?

Considering the risk of untreated disease to the pregnancy may help in decision-making.

Many medical conditions can negatively affect the development of the fetus. A glaring example is diabetes mellitus, with poor glycemic control being linked to congenital malformations, spontaneous abortion, and fetal demise. Chronic conditions with periodic exacerbations such as asthma or epilepsy place the fetus at increased risk during a flare-up.

Therefore, for chronic conditions, continuing maintenance therapy is best. Preconception counseling in such cases is crucial, so that a drug with adequate safety data can be substituted before pregnancy. In this way, any risk to the mother or the embryo from exacerbation of disease as such adjustments are made is avoided.

For conditions arising de novo in pregnancy, the underlying principle remains the same. Is the risk of pharmacotherapy more than the risk of untreated disease? Invariably, the answer to this question supports medication use, and an educated provider will be able to choose a treatment that is justifiable in most circumstances.

CHOOSING A MEDICATION

Fetal well-being depends on maternal well-being. It therefore helps to think of medication use in pregnancy as “justified or not” rather than “safe or not.” Table 3 lists some conditions commonly seen in pregnancy, selected drugs of choice that can be safely used for treating those conditions, and alternates that may be justified in some circumstances.^5,6,14–18

GOOD PRACTICES WHEN PRESCRIBING IN PREGNANCY

Prescribing in pregnancy will be most successful when both the patient and the prescribing physician consider the fetal benefit gained from optimizing maternal health. Good prescribing practices to ensure optimum therapeutic benefit when caring for a pregnant patient are to:

• Involve the patient in decision-making. Recognize her concerns, worries, and preferences regarding her illness and its treatment.
• Inform the patient of the risk of an untreated medical condition, weighed against the risk of medication.
• Choose medications with the most available safety data. Let the patient know what resources you have referred to in choosing the medication.
• It is advisable to perform a search each time a prescription is written for a pregnant or lactating woman.
• When possible, have the discussion in the preconception period.
• Consider the dynamic physiology of gestation. Choose the right drug for the right trimester.
• Discuss the plan with the patient and other providers.
• Define clear criteria for when to discontinue the treatment.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

Disclosures
The authors report no financial relationship whose products are mentioned in this article or with manufacturers of competing products.

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

Disclosures
The authors report no financial relationship whose products are mentioned in this article or with manufacturers of competing products.

Frontotemporal dementia (FTD) is a neu­rologic disease that affects the frontal and the temporal lobes of the cerebral cortex.¹ This disorder is observed most often in people between age 45 to 65, but also can manifest in younger or older persons.¹ The cause varies among a range of pathologies affecting the anterior portions of the brain.²

Presentations
FTD presents with changes in personality, social skills, ability to concentrate, motiva­tion, reasoning, and language abnormal­ity.³ Memory loss is less prominent in this condition compared with other dementias; therefore, identification may be a diagnos­tic challenge. FTD can be misdiagnosed as a psychiatric illness or not recognized because social symptoms dominate over cognitive dysfunction. As the disease progresses, patients may become increasingly unable to plan or organize activities of daily living, behave appropriately, and react normally in social interactions.¹

FTD has 3 diagnostic variants^1-4:

Behavioral variant. Known as Pick dis­ease or the “frontal variant,”^1,2 this type of FTD manifests as changes in personality, improper behavior in social settings, per­sonal neglect, or impulsivity, such as shop­lifting or hypersexuality.

Primary progressive aphasia. Two types of language dysfunction are observed in FTD:
   • Semantic dementia (SD)³: Left-sided SD presents with “meaningless speech” or “word substitutions” (eg, “chair” instead of “table”). Right-sided SD, however, is char­acterized by forgetting the faces of familiar people or objects.
   • Primary nonfluent aphasia³: Language fluency is compromised. Persons with such language dysfunction cannot produce words easily, and their speech is stumbling and nonfluent.

FTD with motor neuron disease.⁴ The most common type of motor neuron dis­ease associated with FTD is amyotrophic lateral sclerosis. Afflicted patients exhibit muscle weakness, spasms, and rigidity. This leads to difficulty in swallowing or breathing because the diaphragm and pharynx are paralyzed. Other diseases associated with FTD include corticobasal degeneration and progressive supranu­clear palsy.

Diagnosis
In DSM-5, FTD has been renamed “fronto­temporal lobar degeneration” under the cat­egory of “Major and Mild Neurocognitive Disorders.”⁵ The workup begins with a his­tory, physical examination, and mental sta­tus assessment. Physical signs can include frontal-release, primitive reflexes. Early in the disease course, a palmomental reflex often is observed; later, as disease progress, the rooting reflex or palmar grasp may become apparent.^1,5

Diagnosing FTD requires recognizing its symptoms and ruling out conditions such as Alzheimer’s disease, depression, and schizophrenia.⁶ Laboratory studies may help identify other conditions. Brain imaging, such as MRI, can depict fronto­temporal pathology and rule in or exclude other diseases.^3,5

Psychometric testing can evaluate mem­ory or cognitive ability, which might be unremarkable during the initial phases of FTD.⁴ Further psychological assessments may provide objective verification of frontal lobe deficiencies in social skills or activities of daily living.³ Positron emission tomogra­phy and single-photon emission computed tomography may demonstrate areas of decreased activity or hypoperfusion in fron­tal and temporal lobes.⁷

Interventions
Treatment of FTD is limited to symp­tomatic therapy⁸; there are no specific, approved countermeasures available. Comorbid conditions, such as diabetes mellitus or hypertension, should be treated medically. Social interventions such as day care, increased supervision, and emotional support from the family can be effective adjuvants.²

Disclosures
The authors report no financial relationship whose products are mentioned in this article or with manufacturers of competing products.

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Fewer than 20% of people seeking help for depression and anxiety disorders receive cognitive-behavioral therapy (CBT), the most established evidence-based psychother­apeutic treatment.¹ Efforts are being made to increase access to CBT,² but a substantial barrier remains: therapist training is a strong predictor of treatment outcome, and many therapists offering CBT services are not sufficiently trained to deliver multiple manual-based interventions with adequate fidelity to the model. Proposed solutions to this barrier include:
   • abbreviated versions of CBT training for practitioners in primary care and community settings
   • culturally adapted CBT training for community health workers³
   • Internet-based CBT and telemedicine (telephone and video conferencing)²
   • mobile phone applications that use text messaging, social support, and physiological monitoring as adjuncts to clinical practice or stand-alone interventions.⁴

New models of CBT also are emerging, including transdi­agnostic CBT and metacognitive approaches (mindfulness-based cognitive therapy and acceptance and commitment therapy), and several new foci for exposure therapy.

In light of these ongoing modulations, this article is intended to help clinicians make informed decisions about CBT when selecting treatment for patients with depressive and anxiety disorders (Box⁵ ). We review the evidence of CBT’s efficacy for acute-phase treatment and relapse pre­vention; explain the common elements considered essential to CBT practice; describe CBT adaptations for specific anxiety disorders; and provide an overview of recent advances in conceptual­izing and adapting CBT.

Efficacy for mood and anxiety disorders
Depression. Dozens of randomized con­trolled trials (RCT) and other studies support CBT’s efficacy in treating major depressive disorder (MDD). For acute treatment:
   • CBT is more effective in producing remission when compared with no treat­ment, treatment as usual, or nonspecific psychotherapy.
   • For mild to moderate depression, CBT is equivalent to antidepressant medi­cation in terms of response and remission rates.
   • Combining antidepressant therapy with CBT increases treatment adherence.⁶

Less well known may be that a success­ful response to CBT in the acute phase may have a protective effect against depression recurrences. A 2013 meta-analysis that totaled 506 individuals with depressive disorders found a trend toward signifi­cantly lower relapse rates when CBT was discontinued after acute therapy, com­pared with antidepressant therapy that continued beyond the acute phase.⁷ 

Anxiety. Among psychotherapies, CBT’s superior efficacy for anxiety disorders is well-established. CBT and its specific-disorder adaptations are considered first-line treatment.⁸

CBT’s essential elements
CBT focuses on distorted cognitions about the self, the world, and the future, and on behaviors that lead to or maintain symptoms.

Cognitive interventions seek to identify thoughts and beliefs that trigger emotional and behavioral reactions. A person with social anxiety disorder, for example, might believe that people will notice if he makes even a minor social mistake and then reject him, which will make him feel worthless. CBT can help him subject these beliefs to rational analysis and develop more adap­tive beliefs, such as: “It is not certain that I will behave so badly that people would notice, but if that happened, the likeli­hood of being outright rejected is probably low. If—in the worst-case scenario—I was rejected, I am not worthless; I’m just a fal­lible human being.” 

CBT’s behavioral component can be con­ceptualized as behavioral activation (BA), a structured approach to help the patient:
   • increase behaviors and experiences that are rewarding
   • overcome barriers to engaging in these new behaviors
   • and decrease behaviors that maintain symptoms.

BA can be a useful intervention for indi­viduals with depression characterized by lack of engagement or capacity for pleasurable experiences. During pregnancy and the postpartum period, for example, a woman undergoes physical, social, and environmental changes that might gradu­ally deprive her of sources of pleasure and other reinforcing activities. BA would focus on developing creative solutions to regain access to or create new opportuni­ties for rewarding experiences and to avoid behaviors (such as social withdrawal or physical activity restriction) that perpetuate depressed mood.

Common elements. Cognitive and behav­ioral interventions focus on problem solv­ing, individualized case conceptualization (Figure 1), and collaborative empiricism.⁹

Collaborative empiricism is the way in which the patient and therapist work together to continually refine this work­ing hypothesis. The pair works together to investigate the hypotheses and all aspects of the therapeutic relationship.

Although no specific technique defines CBT, a common practice is to educate a person about interrelationships between behaviors/activities, thoughts, and mood. A mood activity log (Figure 2) can illuminate links between moods and activities and be useful with targeting interventions. For a person with social anxiety, for example, a mood activity log could assist in developing a hierarchy of feared social situations and avoidance intensity. Systematic exposure therapy would follow, beginning with the least frightening/intense situation, accompa­nied by teaching new coping skills (such as relaxation strategies).

CBT adaptations for anxiety disorders
Elements of CBT have been adapted for a variety of anxiety disorders, based on specific symptoms and features (Table).^10-15

Panic disorder. Panic control treatment is considered the first-line intervention for panic disorder’s defining features: spontaneous panic attacks, worry about future occurrence of attacks, and perceived catastrophic consequences (such as heart attack, fainting).¹⁰ This CBT adaptation includes:
   • patient education about the nature of panic
   • breathing retraining to foster exposure to feared bodily sensations and avoided activities and places
   • cognitive restructuring of danger-related thoughts (such as “I’m going to faint,” or “It would be catastrophic if I did”).

Obsessive-compulsive disorder. Exposure and response prevention (ERP) is the first-line treatment for obsessive-compulsive disorder (OCD).¹¹ In traditional therapist-guided ERP, patients expose themselves to perceived contaminants while refraining from inappropriate compulsive behaviors (such as hand washing).

Cognitive interventions also can be an effective treatment of obsessions, with­out patients having to engage in exposure to their horrific thoughts and images.¹⁶ Consider, for example, a new mother who upon seeing the kitchen knife has the intrusive thought, “What if I stabbed my baby?” Instead of the traditional exposure approach for OCD (ie, having her vividly imagine stabbing her baby until her anxiety level subsided), the cognitive intervention would be to educate her about the nor­malcy of intrusive thoughts, particularly in the postpartum period.

Generalized anxiety disorder. CBT for generalized anxiety disorder (GAD) targets patients’ overestimation of the likelihood of negative events and the belief that these events, should they occur, would be cata­strophic and render them unable to cope.¹²

Motivational interviewing (MI) appears to be a useful adjunct to precede traditional CBT, particularly for severe worriers.¹⁷ MI attempts to help individuals with GAD rec­ognize their ambivalence about giving up worry. This technique acknowledges and validates perceived benefits of worry (eg, “It helps me prepare for the worst, so I won’t be emotionally devastated if it happens”), but also explores how worry is destructive.

Emerging CBT models for anxiety disorders
Metacognitive treatment. Evidence, such as presented by Dobson,¹⁸ suggests that the field of CBT is shifting towards a meta­cognitive model of change and treatment. A metacognitive approach goes beyond changing thinking and emphasizes thoughts about thoughts and experiences. Examples include mindfulness-based cognitive ther­apy (MBCT) and acceptance and commit­ment therapy (ACT).

MBCT typically consists of an 8-week program of 2-hour sessions each week and 1 full-day retreat. MBCT is modeled after Kabat-Zinn’s widely disseminated and empirically supported mindfulness based stress reduction course.¹⁹ MBCT was devel­oped as a relapse prevention program for patients who had recovered from depres­sion. Unlike traditional cognitive therapy for depression that targets changing the content of automatic thoughts and core beliefs, in MBCT patients are aware of negative auto­matic thoughts and find ways to change their relationship with these thoughts, learn­ing that thoughts are not facts. This process mainly is carried out by practicing mind­fulness meditation exercises. Importantly, MBCT goes beyond mindful acceptance of negative thoughts and teaches patients mind­ful acceptance of all internal experiences.

A fundamental difference between ACT and traditional CBT is the approach to cognitions.²⁰ Although CBT focuses on changing the content of maladaptive thoughts, such as “I am a worthless per­son,” ACT focuses on changing the function of thoughts. ACT strives to help patients to accept their internal experiences—whether unwanted thoughts, feelings, bodily sen­sations, or memories—while committing themselves to pursuing their life goals and values. Strategies aim to help patients step back from their thoughts and observe them as just thoughts. The patient who thinks, “I am worthless” would be instructed to prac­tice saying “I am having the thought I am worthless.” Therefore the thought no longer controls the person’s behavior.

These approaches train the patient to keenly observe distressing thoughts and experiences—not necessarily with the goal of changing them but to accept them and act in a way that is consistent with his (her) goals and values. A meta-analysis of 39 stud­ies found mindfulness-based therapy effec­tive in improving symptoms in participants with anxiety and mood disorders.²¹ Similarly, ACT has demonstrated efficacy with mixed anxiety disorders.²²

Transdiagnostic CBT. Recent research18 sug­gests that mood and anxiety disorders may have more commonalities than differences in underlying biological and psychological traits. Because the symptoms of anxiety and depressive disorders tend to overlap, and their rate of comorbidity may be as high as 55%,23 so-called transdiagnostic treatments have been developed. Transdiagnostic treat­ments target impairing symptoms that cut across different diagnoses. For example, patients with depression, anxiety, or sub­stance abuse might share a common dif­ficulty with regulating and coping with negative emotions.

In a preliminary comparison trial,²⁴ 46 patients with social anxiety disorder, panic disorder, or GAD were randomly assigned to transdiagnostic CBT (n = 23) or diagnosis-specific CBT (n = 23). Treatments were based on widely used manuals and offered in 2-hour group sessions across 12 weeks. Transdiagnostic CBT was found to be as effective as specific CBT protocols in terms of symptom improvement. Participants attended an average of 8.46 sessions, with similar attendance in each protocol. Fourteen participants (30%) discontin­ued treatment, similar to attrition rates reported in other trials of transdiagnostic and diagnosis-specific CBT.

Transdiagnostic treatments may facilitate the dissemination of empirically supported treatments because therapists would not be required to have training and supervision to competency in delivering multiple manuals for specific anxiety disorders. This could be attractive to busy practitioners with limited time to learn new treatments.
 

Bottom Line
Efficacy of cognitive-behavioral therapy (CBT) for depression and anxiety is well established. Although no specific technique defines CBT, a common practice is to educate an individual about interrelationships between behaviors/activities, thoughts, and mood. CBT techniques can be customized to treat specific anxiety disorders, such as panic disorder, obsessive-compulsive disorder, and generalized anxiety disorder.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Guidelines for diagnosing Alzheimer’s disease (AD) are undergoing the first major changes since they were developed 30 years ago. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have established workgroups to revise guidelines that were written in 1984.¹

One of the major changes to these new guidelines is men­tion of research on biomarkers for diagnosing and monitoring progression of dementia in AD. This is an exciting and pro­vocative development, but the questions practitioners who diagnose and treat AD should be asking are whether such biomarkers have utility in clinical practice today, or whether their application is a distant promise of continuing research.

Principles put forward in the guidelines
The new AD guidelines set forth in 3 major papers by the workgroups created by the NIA and AA include a change in nomenclature of AD.² The workgroups have sought to define AD with specific stages that include:
   • a preclinical/prodromal phase, in which the pathophysi­ology responsible for future cognitive changes is ongoing but lacks clinical manifestations³
   • mild cognitive impairment, now considered a distinct entity from dementia and diagnosed when a person has early signs of AD; manifestations of impaired cognition in early dis­ease are not significant enough to affect daily functioning.⁴

These newly formulated stages of AD rely on clinical judg­ment, and AD remains a clinical diagnosis. However, the new diagnostic guidelines include the use of biomarkers to mea­sure disease progression.

Biomarkers of normal biologic function and pathology
The Biomarkers Definitions Working Group defines a biomarker as:
 
… a characteristic that is objectively measured and evaluated as an indica­tor of  normal biologic processes, patho­genic processes, or pharmacologic responses to a therapeutic intervention.⁵

These characteristics include imaging studies and body fluids, such as serum and cerebrospinal fluid (CSF).

In AD, biomarkers are meant to mea­sure the pathogenic processes of:
   • accumulation and deposition of amy­loid β _protein (Aβ42) plaques
   • neuronal degeneration characterized by an increase in phosphorylated tau protein and neurofibrillary tangles.⁶

The purpose of these biomarkers is to identify ongoing disease and help the cli­nician stage patients who display a spec­trum of symptoms.

Four classes of biomarkers (Table⁷)have been identified for use in the diagnosis of, and research on, AD:
   • neuroimaging
   • CSF
   • serum
   • genetic markers.

FDG PET identifies areas of the brain in which glucose metabolism is decreased. This finding is thought to represent syn­aptic dysfunction.⁸ The true clinical utility of FDG PET appears to be as an aid in dis­tinguishing cases of AD from frontotem­poral dementia, by identifying regions of metabolic dysfunction.⁹ (Note: Medicare will reimburse for FDG PET only if 1) the patient has met diagnostic criteria for both AD and frontotemporal dementia for at least 6 months and 2) the cause of symp­toms is uncertain.¹⁰)

FDG PET also can be useful in patients with mild cognitive impairment by identi­fying hypometabolism in the temporal and parietal regions of the brain years before clin­ical AD develops.In addition to FDG, 2 other imag­ing probes—Pittsburgh compound and 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl}-ethylidene) malononi­trile (more commonly, FDDNP)—have been used with PET as research tools to demon­strate evidence of AD.¹¹

MRI has been used to measure hippocampal atrophy and cortical thinning that occurs as a patient progresses from normal cognitive function or mild cognitive impairment to full dementia.⁵ The degree of atrophy has not been well correlated with the degree of func­tional impairment.

Florbetapir F 18 Injection was approved by the FDA in October 2013, under the brand name AMYViD, for measuring the quan­tity of Aβ42 deposition in the brain. When injected, this radiopharmaceutical binds to Aβ42 and can be detected on PET.¹² Use cri­teria for AMYViD PET recently were devel­oped¹³; the technique is indicated as an additional diagnostic tool for ruling out AD.

A negative AMYViD scan indicates sparse or no Aβ42 plaques, and is inconsistent with AD. However, a positive AMYViD scan does not establish a diagnosis of AD or other cognitive disorder.¹⁴ This lack of specificity decreases the potential utility of the scan in clinical practice.

Use of AMYViD PET in general practice also is constrained by cost, which varies by location, based on the fee for the PET scan ($1,000 to $3,000)¹⁵; to that, add the cost of a dose of AMYViD ($1,600, wholesale).¹⁶ The technique is not reimbursable, and the total out-of-pocket expense can be as much as $5,000—making an AMYViD PET prohibitive.

Cerebrospinal fluid markers
CSF biomarkers used in the evaluation of AD are Aβ42, t-tau protein, and p-tau protein.^6,17 It is generally thought that the level of Aβ42 in CSF decreases in AD—indicative of Aβ42 being deposited in the brain.8 Tau proteins are elevated in CSF as neurons are destroyed. P-tau is associated with the neurofibrillary tangles of AD; its presence in CSF is thought to represent an increase in those tangles. The combination of a low level of Aβ42 and an elevated level of p-tau in CSF is considered the signature CSF biomarker of AD.⁶

Serum markers
The search for reliable serum biomarkers of AD is the area of greatest research interest because a blood test is a less invasive form of screening. Regrettably, the utility of serum biomarkers for clinical practice has not been established.

Aβ42 can be measured in serum, but levels do not correlate well with CSF levels.¹⁸ Other serum markers that have been evaluated for clinical utility include measures of lipid metabolism, oxidation, and inflammation. With none of these is there clear correlation between the level of protein and AD.¹⁸

Fourth front: Genetics
Several alleles are associated with AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 have been shown to cause a change in the process­ing of Aβ42 and thus lead to AD.¹⁹ These mutations are inherited in an autosomal-dominant fashion and are detected in early-onset (age <65) AD.

Mutations in apolipoprotein 4-β4 also has been the subject of much research; this allele usually is associated with increased risk of the more common, later-onset AD.²⁰ Some evidence suggests that apolipoprotein 4-β4 carriers who develop AD might be at risk of earlier onset of symptoms, compared to non­carriers,²¹ but the clinical significance of that increased risk has not been established.

What utility do biomarkers have?
As we said at the beginning of this article, the question that clinicians should be asking is: “What is the current clinical utility of these sophisticated biomarkers and genetic testing?”

The answer is “little utility.” Diagnosing AD is a clinical enterprise, with, as we’ve out­lined, specific and narrow exceptions.

Recently, researchers demonstrated bio­marker evidence of AD before symptom onset in patients who have known autosomal-dominant gene mutations for AD.¹⁹ There is no evidence, however, that these biomarkers are useful for screening the general popula­tion to identify people who 1) are at risk of, or who have, AD and 2) do not have AD.

That being said, CSF and imaging bio­markers of AD are being used in clinical settings in some European countries to aid investigation of cognitive decline.

In conclusion
Here are key points to take away from this discussion of biomarkers of AD:
   • The utility of these biomarkers today is in research—although some of them might, on occasion, be useful to distinguish demen­tia caused by AD from other dementias.
   • The ultimate goal of research is to uncover a serum biomarker that can iden­tify patients in the preclinical/prodromal stage of AD, so that disease-modifying therapies and preventive measures can be initiated before symptoms manifest.
   • Science is a long way from making this goal a reality, but recent changes in the diagnostic criteria for AD will encourage research in this area of study.

Bottom Line
Researchers are working to uncover biomarkers that will identify patients in the preclinical or prodromal stage of Alzheimer’s disease, but diagnosis remains clinical. Recent changes to diagnostic criteria will encourage research in this area.

Related Resources
• Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cere­brospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease [published online May 5, 2014]. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004.
• Chase A. Alzheimer disease: Advances in imaging of AD biomarkers could aid early diagnosis. Nat Rev Neurol. 2014;10(5):239.
• De Riva V, Galloni E, Marcon M, et al. Analysis of combined CSF biomarkers in AD diagnosis. Clin Lab. 2014;60(4):629-634.
• Kristofikova Z, Ricny J, Kolarova M, et al. Interactions between amyloid-β and tau in cerebrospinal fluid of people with mild cognitive impairment and Alzheimer’s disease [pub­lished online March 26, 2014]. J Alzheimers Dis. doi: 10.3233/ JAD-132393.

Drug Brand Name
Florbetapir F 18 Injection • AMYViD

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.