Case

A 56-year-old woman presented to the ED with palpitations and lightheadedness, which began upon awakening that morning. The patient had a history of atrial fibrillation (AF), and believed this was the cause of her symptoms. Over the past 18 months, the patient had twice undergone successful cardioversion for AF with a rapid ventricular response (RVR); both cardioversions were performed by her cardiologist.

The patient denied experiencing any chest pain, shortness of breath, nausea, or vomiting. Her medical history was significant only for AF. Regarding her medication history, the patient had been prescribed metoprolol, but admitted that she frequently forgot to take it. She further stated that she was not taking aspirin or anticoagulation therapy for AF. She denied past or current alcohol consumption or tobacco use.

On physical examination, the patient’s vital signs were: heart rate (HR), 186 beats/min; blood pressure, 137/82 mm Hg; respiratory rate, 20 breaths/min, and temperature, afebrile. Oxygen saturation was 96% on room air. The head, eye, ears, nose, and throat examination was normal. Auscultation of the lungs revealed clear breath sounds bilaterally. On examination of the heart, the patient had an irregularly irregular rhythm that was tachycardic; no murmurs, rubs, or gallops were appreciated. The abdomen was soft and nontender. There was no edema or redness of the lower extremities.

The emergency physician (EP) placed the patient on a cardiac monitor and administered 2 L of oxygen via nasal cannula. An electrocardiogram (ECG), portable chest X-ray (CXR), and laboratory evaluation were ordered, and an intravenous (IV) line was established. The ECG revealed AF with RVR, without evidence of ischemia. The CXR was interpreted as normal. Laboratory studies, including complete blood count, basic metabolic profile, and serum troponin levels, were likewise within normal limits.

Based on the patient’s history and evaluation, the EP decided to cardiovert the patient rather than attempt rate control with IV medications. The patient consented to the cardioversion, based on the two previous successful cardioversions performed by her cardiologist. The EP gave the patient midazolam 2 mg IV and performed synchronized cardioversion at 200 joules. The patient converted to normal sinus rhythm with an HR of 86 beats/min. She was observed in the ED for 1 hour, given metoprolol 50 mg by mouth, and discharged home with instructions to follow up with her cardiologist the following week.

The next day, the patient suffered a large ischemic stroke in the distribution of the left middle cerebral artery, resulting in a dense right hemiparesis. The neurological deficit was significant, necessitating the patient’s placement in a nursing home.

The patient and her family sued the EP for malpractice for not anticoagulating the patient prior to and following cardioversion. A $3.3 million settlement was agreed upon prior to trial.

Discussion

Patients commonly present to the ED for complaints related to AF. In some cases, the EP is the first to diagnose the patient’s AF; in other cases, the patient has a history of AF and is presenting with a complication. The focus of this discussion is solely on the management of AF with RVR.

When managing a patient in AF with RVR, the EP must consider three issues: ventricular rate control (VRC), rhythm control, and anticoagulation. Selecting the best treatment strategy will depend on the patient’s hemodynamic stability, duration of her or his symptoms, local custom and preference, and the length of time the AF has been present.

Ventricular Rate Control and Cardioversion

For many stable patients, VRC is frequently the treatment of choice, with a goal HR of less than 100 beats/min. Intravenous diltiazem, esmolol, or metoprolol can be used to achieve VRC in patients in AF. Because these drugs only control ventricular rate and do not typically cardiovert, the risk of embolization is small.

Synchronized cardioversion has the benefit of providing both rate and rhythm control, but at the expense of the increased risk of arterial embolization. Some patients, including those with rheumatic heart disease, mitral stenosis, prosthetic heart valves, severe left ventricular dysfunction, or a history of thromboembolism, are at a constant high risk of developing a thromboembolism.¹

Risk-Benefit Ratio and Anticoagulation Therapy

To help determine the risk-benefit ratio in patients without the risk factors mentioned above, the EP should calculate the CHADS₂ (congestive heart failure [CHF], hypertension, age, diabetes mellitus [DM], prior stroke, transient ischemic attack [TIA], or thromboembolism [doubled]) score or CHA₂DS₂-VAS_C (CHF, hypertension, age 75 years or older [two scores], DM, previous stroke, TIA, or thromboembolism [doubled], vascular disease, age 65-74 years, sex [female]) score to help identify patients at risk for arterial embolic complications (Table).

For patients who have been in AF for less than 48 hours and who are at a very low-embolic risk (CHA₂DS₂-VAS_C score of 0), some experts suggest cardioversion without anticoagulation. However, other experts recommend anticoagulation prior to cardioversion—even in low-risk patients. Unfortunately, there is disagreement between professional organizations, with the American Heart Association/American College of Cardiology/Heart Rhythm Society stating that cardioversion may be performed with or without procedural anticoagulation,² while the 2016 European Society of Cardiology guidelines recommend immediate initiation of anticoagulants in all such patients scheduled for cardioversion.³

The reasoning in favor of anticoagulation prior to cardioversion is supported by an observational study by Airaksinen et al⁴ of 2,481 patients undergoing cardioversion for AF of less than 48 hours duration. This study demonstrated a definite thromboembolic event in 38 (0.7%) of the patients within 30 days (median of 2 days). The thromboembolic event was stroke in 31 of the 38 patients.⁴ Airaksinen et al⁴ found that age older than 60 years, female sex, heart failure (HF), and DM were the strongest predictors of embolization. The risk of stroke in patients without HF and those younger than age 60 years was only 0.2%.⁴

In a similar observational study by Hansen et al⁵ of 16,274 patients in AF undergoing cardioversion with and without anticoagulation therapy, the absence of post­cardio­version anticoagulation increased the risk of thromboembolism 2-fold—regardless of CHA₂DS₂-VAS_C scores.

Summary

While the management of AF with a duration of more than 48 hours should always include some type of anticoagulation therapy (pre- or postcardioversion, or both), the role of anticoagulation in low-risk patients with AF of less than 48 hours is not as clear. As this situation is not uncommon, the emergency medicine and cardiology physicians should consider developing a mutually agreed upon protocol on how best to manage these patients at their institution. When considering cardioversion without pre- or postanticoagulation in low-risk patients with AF, EPs should always involve the patient in the decision-making process.

Case

A 56-year-old woman presented to the ED with palpitations and lightheadedness, which began upon awakening that morning. The patient had a history of atrial fibrillation (AF), and believed this was the cause of her symptoms. Over the past 18 months, the patient had twice undergone successful cardioversion for AF with a rapid ventricular response (RVR); both cardioversions were performed by her cardiologist.

The patient denied experiencing any chest pain, shortness of breath, nausea, or vomiting. Her medical history was significant only for AF. Regarding her medication history, the patient had been prescribed metoprolol, but admitted that she frequently forgot to take it. She further stated that she was not taking aspirin or anticoagulation therapy for AF. She denied past or current alcohol consumption or tobacco use.

On physical examination, the patient’s vital signs were: heart rate (HR), 186 beats/min; blood pressure, 137/82 mm Hg; respiratory rate, 20 breaths/min, and temperature, afebrile. Oxygen saturation was 96% on room air. The head, eye, ears, nose, and throat examination was normal. Auscultation of the lungs revealed clear breath sounds bilaterally. On examination of the heart, the patient had an irregularly irregular rhythm that was tachycardic; no murmurs, rubs, or gallops were appreciated. The abdomen was soft and nontender. There was no edema or redness of the lower extremities.

The emergency physician (EP) placed the patient on a cardiac monitor and administered 2 L of oxygen via nasal cannula. An electrocardiogram (ECG), portable chest X-ray (CXR), and laboratory evaluation were ordered, and an intravenous (IV) line was established. The ECG revealed AF with RVR, without evidence of ischemia. The CXR was interpreted as normal. Laboratory studies, including complete blood count, basic metabolic profile, and serum troponin levels, were likewise within normal limits.

Based on the patient’s history and evaluation, the EP decided to cardiovert the patient rather than attempt rate control with IV medications. The patient consented to the cardioversion, based on the two previous successful cardioversions performed by her cardiologist. The EP gave the patient midazolam 2 mg IV and performed synchronized cardioversion at 200 joules. The patient converted to normal sinus rhythm with an HR of 86 beats/min. She was observed in the ED for 1 hour, given metoprolol 50 mg by mouth, and discharged home with instructions to follow up with her cardiologist the following week.

The next day, the patient suffered a large ischemic stroke in the distribution of the left middle cerebral artery, resulting in a dense right hemiparesis. The neurological deficit was significant, necessitating the patient’s placement in a nursing home.

The patient and her family sued the EP for malpractice for not anticoagulating the patient prior to and following cardioversion. A $3.3 million settlement was agreed upon prior to trial.

Discussion

Patients commonly present to the ED for complaints related to AF. In some cases, the EP is the first to diagnose the patient’s AF; in other cases, the patient has a history of AF and is presenting with a complication. The focus of this discussion is solely on the management of AF with RVR.

When managing a patient in AF with RVR, the EP must consider three issues: ventricular rate control (VRC), rhythm control, and anticoagulation. Selecting the best treatment strategy will depend on the patient’s hemodynamic stability, duration of her or his symptoms, local custom and preference, and the length of time the AF has been present.

Ventricular Rate Control and Cardioversion

For many stable patients, VRC is frequently the treatment of choice, with a goal HR of less than 100 beats/min. Intravenous diltiazem, esmolol, or metoprolol can be used to achieve VRC in patients in AF. Because these drugs only control ventricular rate and do not typically cardiovert, the risk of embolization is small.

Synchronized cardioversion has the benefit of providing both rate and rhythm control, but at the expense of the increased risk of arterial embolization. Some patients, including those with rheumatic heart disease, mitral stenosis, prosthetic heart valves, severe left ventricular dysfunction, or a history of thromboembolism, are at a constant high risk of developing a thromboembolism.¹

Risk-Benefit Ratio and Anticoagulation Therapy

To help determine the risk-benefit ratio in patients without the risk factors mentioned above, the EP should calculate the CHADS₂ (congestive heart failure [CHF], hypertension, age, diabetes mellitus [DM], prior stroke, transient ischemic attack [TIA], or thromboembolism [doubled]) score or CHA₂DS₂-VAS_C (CHF, hypertension, age 75 years or older [two scores], DM, previous stroke, TIA, or thromboembolism [doubled], vascular disease, age 65-74 years, sex [female]) score to help identify patients at risk for arterial embolic complications (Table).

For patients who have been in AF for less than 48 hours and who are at a very low-embolic risk (CHA₂DS₂-VAS_C score of 0), some experts suggest cardioversion without anticoagulation. However, other experts recommend anticoagulation prior to cardioversion—even in low-risk patients. Unfortunately, there is disagreement between professional organizations, with the American Heart Association/American College of Cardiology/Heart Rhythm Society stating that cardioversion may be performed with or without procedural anticoagulation,² while the 2016 European Society of Cardiology guidelines recommend immediate initiation of anticoagulants in all such patients scheduled for cardioversion.³

The reasoning in favor of anticoagulation prior to cardioversion is supported by an observational study by Airaksinen et al⁴ of 2,481 patients undergoing cardioversion for AF of less than 48 hours duration. This study demonstrated a definite thromboembolic event in 38 (0.7%) of the patients within 30 days (median of 2 days). The thromboembolic event was stroke in 31 of the 38 patients.⁴ Airaksinen et al⁴ found that age older than 60 years, female sex, heart failure (HF), and DM were the strongest predictors of embolization. The risk of stroke in patients without HF and those younger than age 60 years was only 0.2%.⁴

In a similar observational study by Hansen et al⁵ of 16,274 patients in AF undergoing cardioversion with and without anticoagulation therapy, the absence of post­cardio­version anticoagulation increased the risk of thromboembolism 2-fold—regardless of CHA₂DS₂-VAS_C scores.

Summary

While the management of AF with a duration of more than 48 hours should always include some type of anticoagulation therapy (pre- or postcardioversion, or both), the role of anticoagulation in low-risk patients with AF of less than 48 hours is not as clear. As this situation is not uncommon, the emergency medicine and cardiology physicians should consider developing a mutually agreed upon protocol on how best to manage these patients at their institution. When considering cardioversion without pre- or postanticoagulation in low-risk patients with AF, EPs should always involve the patient in the decision-making process.

Case

A 56-year-old woman presented to the ED with palpitations and lightheadedness, which began upon awakening that morning. The patient had a history of atrial fibrillation (AF), and believed this was the cause of her symptoms. Over the past 18 months, the patient had twice undergone successful cardioversion for AF with a rapid ventricular response (RVR); both cardioversions were performed by her cardiologist.

The patient denied experiencing any chest pain, shortness of breath, nausea, or vomiting. Her medical history was significant only for AF. Regarding her medication history, the patient had been prescribed metoprolol, but admitted that she frequently forgot to take it. She further stated that she was not taking aspirin or anticoagulation therapy for AF. She denied past or current alcohol consumption or tobacco use.

On physical examination, the patient’s vital signs were: heart rate (HR), 186 beats/min; blood pressure, 137/82 mm Hg; respiratory rate, 20 breaths/min, and temperature, afebrile. Oxygen saturation was 96% on room air. The head, eye, ears, nose, and throat examination was normal. Auscultation of the lungs revealed clear breath sounds bilaterally. On examination of the heart, the patient had an irregularly irregular rhythm that was tachycardic; no murmurs, rubs, or gallops were appreciated. The abdomen was soft and nontender. There was no edema or redness of the lower extremities.

The emergency physician (EP) placed the patient on a cardiac monitor and administered 2 L of oxygen via nasal cannula. An electrocardiogram (ECG), portable chest X-ray (CXR), and laboratory evaluation were ordered, and an intravenous (IV) line was established. The ECG revealed AF with RVR, without evidence of ischemia. The CXR was interpreted as normal. Laboratory studies, including complete blood count, basic metabolic profile, and serum troponin levels, were likewise within normal limits.

Based on the patient’s history and evaluation, the EP decided to cardiovert the patient rather than attempt rate control with IV medications. The patient consented to the cardioversion, based on the two previous successful cardioversions performed by her cardiologist. The EP gave the patient midazolam 2 mg IV and performed synchronized cardioversion at 200 joules. The patient converted to normal sinus rhythm with an HR of 86 beats/min. She was observed in the ED for 1 hour, given metoprolol 50 mg by mouth, and discharged home with instructions to follow up with her cardiologist the following week.

The next day, the patient suffered a large ischemic stroke in the distribution of the left middle cerebral artery, resulting in a dense right hemiparesis. The neurological deficit was significant, necessitating the patient’s placement in a nursing home.

The patient and her family sued the EP for malpractice for not anticoagulating the patient prior to and following cardioversion. A $3.3 million settlement was agreed upon prior to trial.

Discussion

Patients commonly present to the ED for complaints related to AF. In some cases, the EP is the first to diagnose the patient’s AF; in other cases, the patient has a history of AF and is presenting with a complication. The focus of this discussion is solely on the management of AF with RVR.

When managing a patient in AF with RVR, the EP must consider three issues: ventricular rate control (VRC), rhythm control, and anticoagulation. Selecting the best treatment strategy will depend on the patient’s hemodynamic stability, duration of her or his symptoms, local custom and preference, and the length of time the AF has been present.

Ventricular Rate Control and Cardioversion

For many stable patients, VRC is frequently the treatment of choice, with a goal HR of less than 100 beats/min. Intravenous diltiazem, esmolol, or metoprolol can be used to achieve VRC in patients in AF. Because these drugs only control ventricular rate and do not typically cardiovert, the risk of embolization is small.

Synchronized cardioversion has the benefit of providing both rate and rhythm control, but at the expense of the increased risk of arterial embolization. Some patients, including those with rheumatic heart disease, mitral stenosis, prosthetic heart valves, severe left ventricular dysfunction, or a history of thromboembolism, are at a constant high risk of developing a thromboembolism.¹

Risk-Benefit Ratio and Anticoagulation Therapy

To help determine the risk-benefit ratio in patients without the risk factors mentioned above, the EP should calculate the CHADS₂ (congestive heart failure [CHF], hypertension, age, diabetes mellitus [DM], prior stroke, transient ischemic attack [TIA], or thromboembolism [doubled]) score or CHA₂DS₂-VAS_C (CHF, hypertension, age 75 years or older [two scores], DM, previous stroke, TIA, or thromboembolism [doubled], vascular disease, age 65-74 years, sex [female]) score to help identify patients at risk for arterial embolic complications (Table).

For patients who have been in AF for less than 48 hours and who are at a very low-embolic risk (CHA₂DS₂-VAS_C score of 0), some experts suggest cardioversion without anticoagulation. However, other experts recommend anticoagulation prior to cardioversion—even in low-risk patients. Unfortunately, there is disagreement between professional organizations, with the American Heart Association/American College of Cardiology/Heart Rhythm Society stating that cardioversion may be performed with or without procedural anticoagulation,² while the 2016 European Society of Cardiology guidelines recommend immediate initiation of anticoagulants in all such patients scheduled for cardioversion.³

The reasoning in favor of anticoagulation prior to cardioversion is supported by an observational study by Airaksinen et al⁴ of 2,481 patients undergoing cardioversion for AF of less than 48 hours duration. This study demonstrated a definite thromboembolic event in 38 (0.7%) of the patients within 30 days (median of 2 days). The thromboembolic event was stroke in 31 of the 38 patients.⁴ Airaksinen et al⁴ found that age older than 60 years, female sex, heart failure (HF), and DM were the strongest predictors of embolization. The risk of stroke in patients without HF and those younger than age 60 years was only 0.2%.⁴

In a similar observational study by Hansen et al⁵ of 16,274 patients in AF undergoing cardioversion with and without anticoagulation therapy, the absence of post­cardio­version anticoagulation increased the risk of thromboembolism 2-fold—regardless of CHA₂DS₂-VAS_C scores.

Summary

While the management of AF with a duration of more than 48 hours should always include some type of anticoagulation therapy (pre- or postcardioversion, or both), the role of anticoagulation in low-risk patients with AF of less than 48 hours is not as clear. As this situation is not uncommon, the emergency medicine and cardiology physicians should consider developing a mutually agreed upon protocol on how best to manage these patients at their institution. When considering cardioversion without pre- or postanticoagulation in low-risk patients with AF, EPs should always involve the patient in the decision-making process.

MITCHEL L. ZOLER

FRONTLINE MEDICAL NEWS

Mobile stroke units—specially equipped ambulances that bring a diagnostic computed tomography (CT) scanner and therapeutic thrombolysis directly to patients in the field—have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost-effectiveness.

The first US mobile stroke unit (MSU) launched in Houston, Texas in early 2014 (following the world’s first in Berlin, Germany, which began running in early 2011), and by early 2017, at least eight other US MSUs were in operation, most of them put into service during the prior 15 months. United States MSU locations now include Cleveland, Ohio; Denver, Colorado; Memphis, Tennessee; New York, New York; Toledo, Ohio; Trenton, New Jersey; and Northwestern Medicine and Rush University Medical Center in the western Chicago, Illinois region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to initiate thrombolytic therapy with tissue plasminogen activator (tPA), and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get an MSU on the road for the first time; they are also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every US MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged “godfather” of all US MSUs.

“We believe that MSUs are very worthwhile and that the clinical and economic benefits of earlier stroke treatment [made possible with MSUs] could offset the costs, but we need to show this,” admitted May Nour, MD, a vascular and interventional neurologist at the University of California, Los Angeles (UCLA), and director of the soon-to-launch Los Angeles MSU.

The concept behind MSUs is simple: Each one carries a CT scanner on board so that once the vehicle’s staff identifies a patient with clinical signs of a significant-acute ischemic stroke in the field and confirms that the timing of the stroke onset suggests eligibility for tPA treatment, a CT scan can immediately be run on-site to finalize tPA eligibility. The MSU staff can then begin infusing the drug in the ambulance as it speeds the patient to an appropriate hospital.

In addition, many MSUs now carry a scanner that can perform a CT angiogram (CTA) to locate the occluding clot. If a large vessel occlusion is found, the crew can bring the patient directly to a comprehensive stroke center for a thrombectomy. If thrombectomy is not appropriate, the MSU crew may take the patient to a primary stroke center where thrombectomy is not available.

Another advantage to MSUs, in addition to quicker initiation of thrombolysis, is “getting patients to where they need to go faster and more directly,” said Dr Nour.

“Instead of bringing patients first to a hospital that’s unable to do thrombectomy and where treatment gets slowed down, with an MSU you can give tPA on the street and go straight to a thrombectomy center,” agreed Jeffrey L. Saver, MD, professor of neurology and director of the stroke unit at UCLA. “The MSU offers the tantalizing possibility that you can give tPA with no time hit because you can give it on the way directly to a comprehensive stroke center,” Dr Saver said during a session at the meeting.

Early Data on Effectiveness

Dr Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data the Berlin group published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU to similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of tPA treatment did not begin until the patient reached a hospital. The German analysis showed that, in the observational Pre-hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference.¹ However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 1 or lower when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance

Dr Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90-day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at EDs operated by the Cleveland Clinic, a statistically significant difference.² However, this report included no data on clinical outcomes.

Running the Financial Numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality-adjusted life years. We calculated a cost of $35,000 per quality-adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

During his talk at the same session, Dr Grotta ran through the numbers for the Houston program. They spent $1.1 million to put their MSU into service in early 2014, and, based on the expenses accrued since then, he estimated an annual staffing cost of about $400,000 and an annual operating cost of about $100,000, for a total estimated 5-year cost of about $3.6 million. Staffing of the Houston MSU started with a registered nurse, CT technician, paramedic, and vascular neurologist, although, like most other US MSUs, the onboard neurologist has since been replaced by a second paramedic, and the neurological diagnostic consult is done via a telemedicine link.

Income from transport reimbursement, currently $500 per trip, and reimbursements of $17,000 above costs for administering tPA and of roughly $40,000 above costs for performing thrombectomy, are balancing these costs. Based on an estimated additional one thrombolysis case per month and one additional thrombectomy case per month, the MSU yields a potential incremental income to the hospital running the MSU of about $3.8 million over 5 years—enough to balance the operating cost, Dr Grotta said.

A key part of controlling costs is having the neurological consult done via a telemedicine link rather than by neurologist at the MSU. “Telemedicine reduces operational costs and improves efficiency,” noted M. Shazam Hussain, MD, interim director of the Cerebrovascular Center at the Cleveland Clinic. “Cost-effectiveness is a very important part of the concept” of MSUs, he said at the session.

The Houston group reported results from a study that directly compared the diagnostic performance of an onboard neurologist with that of a telemedicine neurologist linked-in remotely during MSU deployments for 174 patients. For these cases, the two neurologists each made an independent diagnosis that the researchers then compared. The two diagnoses concurred for 88% of the cases, Tzu-Ching Wu, MD, reported at the meeting. This rate of agreement matched the incidence of concordance between two neurologists who independently assessed the same patients at the hospital,³ said Dr Wu, a vascular neurologist and director of the telemedicine program at the University of Texas Health Science Center in Houston.

“The results support using telemedicine as the primary means of assessment on the MSU,” said Dr Wu. “This may enhance MSU efficiency and reduce costs.” His group’s next study of MSU telemedicine will compare the time needed to make a diagnostic decision using the two approaches, which Dr Wu reported was something not formally examined in the study.

However, telemedicine assessment of CT results gathered in an MSU has one major limitation: the time needed to transmit the huge amount of information from a CTA.

The MSU used by clinicians at the University of Tennessee, Memphis, incorporates an extremely powerful battery that enables “full CT scanner capability with a moving gantry,” said Andrei V. Alexandrov, MD, professor and chairman of neurology at the university. With this set up “we can do in-the-field multiphasic CT angiography from the aortic arch up within 4 minutes. The challenge of doing this is simple. It’s 1.7 gigabytes of data,” which would take a prohibitively long time to transmit from a remote site, he explained. As a result, the complete set of images from the field CTA is delivered on a memory stick to the attending hospital neurologist once the MSU returns.

Waiting for More Data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially nonsustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system, including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March.⁴ “Even if MSUs meet an acceptable societal threshold for cost-effectiveness, cost-efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD. They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 tPA treatments and 349 cancellations before arrival, noted Dr Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr Brandler, an emergency medicine physician at Stony Brook (NY) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost-effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of US patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver, Houston, and Memphis. Although currently designed to enroll 697 patients, Dr Grotta said he hopes to bring the number up to 1,000 patients.

“We are following the health care use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

References

1. Kunz A, Ebinger M, Geisler F, et al. Functional outcomes of pre-hospital thrombolysis in a mobile stroke treatment unit compared with conventional care: an observational registry study. Lancet Neurol. 2016;15(10):1035-1043. doi:10.1016/S1474-4422(16)30129-6.

2. Taqui A, Cerejo R, Itrat A, et al; Cleveland Pre-Hospital Acute Stroke Treatment (PHAST) Group. Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis. Neurology. 2017 March 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003786.

3. Ramadan AR, Denny MC, Vahidy F, et al. Agreement among stroke faculty and fellows in treating ischemic stroke patients with tissue-type plasminogen activator and thrombectomy. Stroke. 2017;48(1):222-224. doi:10.1161/STROKEAHA.116.015214.

4. Southerland AM, Brandler ES. The cost-efficiency of mobile stroke units: Where the rubber meets the road. Neurology. 2017 Mar 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003833.

Pulmonary Embolism Common in Patients With Acute Exacerbations of COPD

JIM KLING

FRONTLINE MEDICAL NEWS

About 16% of patients with unexplained acute exacerbations of chronic obstructive pulmonary disease (AECOPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

Approximately 70% of AECOPD cases develop in response to an infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research. There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AECOPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AECOPD from a previous systematic review published in Chest in 2009.

The meta-analysis revealed that 16.1% of patients with AECOPD were also diagnosed with PE (95% confidence interval [CI], 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis (DVT), the pooled prevalence of DVT was 10.5% (95% CI, 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35% were in the main pulmonary artery, and 31.7% were in the lobar and interlobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AECOPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AECOPD patients with PE (81% vs 40% in those without PE). A second study showed a similar association (24% in PE vs 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AECOPD, because it would be undesirable to perform [CT pulmonary angiography] in every patient with an AECOPD,” the researchers wrote.

Aleva FE, Voets LW, Simons SO, de Mast Q, van der Ven AJ, Heijdra YF. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: A systematic review and meta-analysis. Chest. 2017;151(3):544-554. doi:10.1016/j.chest.2016.07.034.

Norepinephrine Shortage Linked to Mortality in Patients With Septic Shock

AMY KARON

FRONTLINE MEDICAL NEWS

A national shortage of norepinephrine in the United States was associated with higher rates of mortality among patients hospitalized with septic shock, investigators reported.

Rates of in-hospital mortality in 2011 were 40% during quarters when hospitals were facing shortages and 36% when they were not, Emily Vail, MD, and her associates said at the International Symposium on Intensive Care and Emergency Medicine. The report was published simultaneously in JAMA.

The link between norepinephrine shortage and death from septic shock persisted even after the researchers accounted for numerous clinical and demographic factors (adjusted odds ratio, 1.2; 95% CI, 1.01 to 1.30; P = .03), wrote Dr Vail of Columbia University, New York.

Drug shortages are common in the United States, but few studies have explored their effects on patient outcomes. Investigators compared mortality rates among affected patients during 3-month intervals when hospitals were and were not using at least 20% less norepinephrine than baseline. The researchers used Premier Healthcare Database, which includes both standard claims and detailed, dated logs of all services billed to patients or insurance, with minimal missing data.

A total of 77% patients admitted with septic shock received norepinephrine before the shortage. During the lowest point of the shortage, 56% of patients received it, the researchers reported. Clinicians most often used phenylephrine instead, prescribing it to up to 54% of patients during the worst time of the shortage. The absolute increase in mortality during the quarters of shortage was 3.7% (95% CI, 1.5%-6.0%).

Several factors might explain the link between norepinephrine shortage and mortality, the investigators said. The vasopressors chosen to replace norepinephrine might result directly in worse outcomes, but a decrease in norepinephrine use also might be a proxy for relevant variables such as delayed use of vasopressors, lack of knowledge of how to optimally dose vasopressors besides norepinephrine, or the absence of a pharmacist dedicated to helping optimize the use of limited supplies.

The study did not uncover a dose-response association between greater decreases in norepinephrine use and increased mortality, the researchers noted. “This may be due to a threshold effect of vasopressor shortage on mortality, or lack of power due to relatively few hospital quarters at the extreme levels of vasopressor shortage,” they wrote.

Because the deaths captured included only those that occurred in-hospital, “the results may have underestimated mortality, particularly for hospitals that tend to transfer patients early to other skilled care facilities,” the researchers noted.

The cohort of patients was limited to those who received vasopressors for 2 or more days and excluded patients who died on the first day of vasopressor treatment, the researchers said.

Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA.  21 March 2017. [Epub ahead of print]. doi:10.1001/jama.2017.2841.

MITCHEL L. ZOLER

FRONTLINE MEDICAL NEWS

Mobile stroke units—specially equipped ambulances that bring a diagnostic computed tomography (CT) scanner and therapeutic thrombolysis directly to patients in the field—have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost-effectiveness.

The first US mobile stroke unit (MSU) launched in Houston, Texas in early 2014 (following the world’s first in Berlin, Germany, which began running in early 2011), and by early 2017, at least eight other US MSUs were in operation, most of them put into service during the prior 15 months. United States MSU locations now include Cleveland, Ohio; Denver, Colorado; Memphis, Tennessee; New York, New York; Toledo, Ohio; Trenton, New Jersey; and Northwestern Medicine and Rush University Medical Center in the western Chicago, Illinois region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to initiate thrombolytic therapy with tissue plasminogen activator (tPA), and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get an MSU on the road for the first time; they are also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every US MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged “godfather” of all US MSUs.

“We believe that MSUs are very worthwhile and that the clinical and economic benefits of earlier stroke treatment [made possible with MSUs] could offset the costs, but we need to show this,” admitted May Nour, MD, a vascular and interventional neurologist at the University of California, Los Angeles (UCLA), and director of the soon-to-launch Los Angeles MSU.

The concept behind MSUs is simple: Each one carries a CT scanner on board so that once the vehicle’s staff identifies a patient with clinical signs of a significant-acute ischemic stroke in the field and confirms that the timing of the stroke onset suggests eligibility for tPA treatment, a CT scan can immediately be run on-site to finalize tPA eligibility. The MSU staff can then begin infusing the drug in the ambulance as it speeds the patient to an appropriate hospital.

In addition, many MSUs now carry a scanner that can perform a CT angiogram (CTA) to locate the occluding clot. If a large vessel occlusion is found, the crew can bring the patient directly to a comprehensive stroke center for a thrombectomy. If thrombectomy is not appropriate, the MSU crew may take the patient to a primary stroke center where thrombectomy is not available.

Another advantage to MSUs, in addition to quicker initiation of thrombolysis, is “getting patients to where they need to go faster and more directly,” said Dr Nour.

“Instead of bringing patients first to a hospital that’s unable to do thrombectomy and where treatment gets slowed down, with an MSU you can give tPA on the street and go straight to a thrombectomy center,” agreed Jeffrey L. Saver, MD, professor of neurology and director of the stroke unit at UCLA. “The MSU offers the tantalizing possibility that you can give tPA with no time hit because you can give it on the way directly to a comprehensive stroke center,” Dr Saver said during a session at the meeting.

Early Data on Effectiveness

Dr Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data the Berlin group published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU to similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of tPA treatment did not begin until the patient reached a hospital. The German analysis showed that, in the observational Pre-hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference.¹ However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 1 or lower when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance

Dr Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90-day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at EDs operated by the Cleveland Clinic, a statistically significant difference.² However, this report included no data on clinical outcomes.

Running the Financial Numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality-adjusted life years. We calculated a cost of $35,000 per quality-adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

During his talk at the same session, Dr Grotta ran through the numbers for the Houston program. They spent $1.1 million to put their MSU into service in early 2014, and, based on the expenses accrued since then, he estimated an annual staffing cost of about $400,000 and an annual operating cost of about $100,000, for a total estimated 5-year cost of about $3.6 million. Staffing of the Houston MSU started with a registered nurse, CT technician, paramedic, and vascular neurologist, although, like most other US MSUs, the onboard neurologist has since been replaced by a second paramedic, and the neurological diagnostic consult is done via a telemedicine link.

Income from transport reimbursement, currently $500 per trip, and reimbursements of $17,000 above costs for administering tPA and of roughly $40,000 above costs for performing thrombectomy, are balancing these costs. Based on an estimated additional one thrombolysis case per month and one additional thrombectomy case per month, the MSU yields a potential incremental income to the hospital running the MSU of about $3.8 million over 5 years—enough to balance the operating cost, Dr Grotta said.

A key part of controlling costs is having the neurological consult done via a telemedicine link rather than by neurologist at the MSU. “Telemedicine reduces operational costs and improves efficiency,” noted M. Shazam Hussain, MD, interim director of the Cerebrovascular Center at the Cleveland Clinic. “Cost-effectiveness is a very important part of the concept” of MSUs, he said at the session.

The Houston group reported results from a study that directly compared the diagnostic performance of an onboard neurologist with that of a telemedicine neurologist linked-in remotely during MSU deployments for 174 patients. For these cases, the two neurologists each made an independent diagnosis that the researchers then compared. The two diagnoses concurred for 88% of the cases, Tzu-Ching Wu, MD, reported at the meeting. This rate of agreement matched the incidence of concordance between two neurologists who independently assessed the same patients at the hospital,³ said Dr Wu, a vascular neurologist and director of the telemedicine program at the University of Texas Health Science Center in Houston.

“The results support using telemedicine as the primary means of assessment on the MSU,” said Dr Wu. “This may enhance MSU efficiency and reduce costs.” His group’s next study of MSU telemedicine will compare the time needed to make a diagnostic decision using the two approaches, which Dr Wu reported was something not formally examined in the study.

However, telemedicine assessment of CT results gathered in an MSU has one major limitation: the time needed to transmit the huge amount of information from a CTA.

The MSU used by clinicians at the University of Tennessee, Memphis, incorporates an extremely powerful battery that enables “full CT scanner capability with a moving gantry,” said Andrei V. Alexandrov, MD, professor and chairman of neurology at the university. With this set up “we can do in-the-field multiphasic CT angiography from the aortic arch up within 4 minutes. The challenge of doing this is simple. It’s 1.7 gigabytes of data,” which would take a prohibitively long time to transmit from a remote site, he explained. As a result, the complete set of images from the field CTA is delivered on a memory stick to the attending hospital neurologist once the MSU returns.

Waiting for More Data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially nonsustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system, including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March.⁴ “Even if MSUs meet an acceptable societal threshold for cost-effectiveness, cost-efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD. They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 tPA treatments and 349 cancellations before arrival, noted Dr Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr Brandler, an emergency medicine physician at Stony Brook (NY) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost-effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of US patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver, Houston, and Memphis. Although currently designed to enroll 697 patients, Dr Grotta said he hopes to bring the number up to 1,000 patients.

“We are following the health care use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

References

1. Kunz A, Ebinger M, Geisler F, et al. Functional outcomes of pre-hospital thrombolysis in a mobile stroke treatment unit compared with conventional care: an observational registry study. Lancet Neurol. 2016;15(10):1035-1043. doi:10.1016/S1474-4422(16)30129-6.

2. Taqui A, Cerejo R, Itrat A, et al; Cleveland Pre-Hospital Acute Stroke Treatment (PHAST) Group. Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis. Neurology. 2017 March 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003786.

3. Ramadan AR, Denny MC, Vahidy F, et al. Agreement among stroke faculty and fellows in treating ischemic stroke patients with tissue-type plasminogen activator and thrombectomy. Stroke. 2017;48(1):222-224. doi:10.1161/STROKEAHA.116.015214.

4. Southerland AM, Brandler ES. The cost-efficiency of mobile stroke units: Where the rubber meets the road. Neurology. 2017 Mar 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003833.

Pulmonary Embolism Common in Patients With Acute Exacerbations of COPD

JIM KLING

FRONTLINE MEDICAL NEWS

About 16% of patients with unexplained acute exacerbations of chronic obstructive pulmonary disease (AECOPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

Approximately 70% of AECOPD cases develop in response to an infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research. There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AECOPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AECOPD from a previous systematic review published in Chest in 2009.

The meta-analysis revealed that 16.1% of patients with AECOPD were also diagnosed with PE (95% confidence interval [CI], 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis (DVT), the pooled prevalence of DVT was 10.5% (95% CI, 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35% were in the main pulmonary artery, and 31.7% were in the lobar and interlobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AECOPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AECOPD patients with PE (81% vs 40% in those without PE). A second study showed a similar association (24% in PE vs 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AECOPD, because it would be undesirable to perform [CT pulmonary angiography] in every patient with an AECOPD,” the researchers wrote.

Aleva FE, Voets LW, Simons SO, de Mast Q, van der Ven AJ, Heijdra YF. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: A systematic review and meta-analysis. Chest. 2017;151(3):544-554. doi:10.1016/j.chest.2016.07.034.

Norepinephrine Shortage Linked to Mortality in Patients With Septic Shock

AMY KARON

FRONTLINE MEDICAL NEWS

A national shortage of norepinephrine in the United States was associated with higher rates of mortality among patients hospitalized with septic shock, investigators reported.

Rates of in-hospital mortality in 2011 were 40% during quarters when hospitals were facing shortages and 36% when they were not, Emily Vail, MD, and her associates said at the International Symposium on Intensive Care and Emergency Medicine. The report was published simultaneously in JAMA.

The link between norepinephrine shortage and death from septic shock persisted even after the researchers accounted for numerous clinical and demographic factors (adjusted odds ratio, 1.2; 95% CI, 1.01 to 1.30; P = .03), wrote Dr Vail of Columbia University, New York.

Drug shortages are common in the United States, but few studies have explored their effects on patient outcomes. Investigators compared mortality rates among affected patients during 3-month intervals when hospitals were and were not using at least 20% less norepinephrine than baseline. The researchers used Premier Healthcare Database, which includes both standard claims and detailed, dated logs of all services billed to patients or insurance, with minimal missing data.

A total of 77% patients admitted with septic shock received norepinephrine before the shortage. During the lowest point of the shortage, 56% of patients received it, the researchers reported. Clinicians most often used phenylephrine instead, prescribing it to up to 54% of patients during the worst time of the shortage. The absolute increase in mortality during the quarters of shortage was 3.7% (95% CI, 1.5%-6.0%).

Several factors might explain the link between norepinephrine shortage and mortality, the investigators said. The vasopressors chosen to replace norepinephrine might result directly in worse outcomes, but a decrease in norepinephrine use also might be a proxy for relevant variables such as delayed use of vasopressors, lack of knowledge of how to optimally dose vasopressors besides norepinephrine, or the absence of a pharmacist dedicated to helping optimize the use of limited supplies.

The study did not uncover a dose-response association between greater decreases in norepinephrine use and increased mortality, the researchers noted. “This may be due to a threshold effect of vasopressor shortage on mortality, or lack of power due to relatively few hospital quarters at the extreme levels of vasopressor shortage,” they wrote.

Because the deaths captured included only those that occurred in-hospital, “the results may have underestimated mortality, particularly for hospitals that tend to transfer patients early to other skilled care facilities,” the researchers noted.

The cohort of patients was limited to those who received vasopressors for 2 or more days and excluded patients who died on the first day of vasopressor treatment, the researchers said.

Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA.  21 March 2017. [Epub ahead of print]. doi:10.1001/jama.2017.2841.

MITCHEL L. ZOLER

FRONTLINE MEDICAL NEWS

Mobile stroke units—specially equipped ambulances that bring a diagnostic computed tomography (CT) scanner and therapeutic thrombolysis directly to patients in the field—have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost-effectiveness.

The first US mobile stroke unit (MSU) launched in Houston, Texas in early 2014 (following the world’s first in Berlin, Germany, which began running in early 2011), and by early 2017, at least eight other US MSUs were in operation, most of them put into service during the prior 15 months. United States MSU locations now include Cleveland, Ohio; Denver, Colorado; Memphis, Tennessee; New York, New York; Toledo, Ohio; Trenton, New Jersey; and Northwestern Medicine and Rush University Medical Center in the western Chicago, Illinois region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to initiate thrombolytic therapy with tissue plasminogen activator (tPA), and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get an MSU on the road for the first time; they are also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every US MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged “godfather” of all US MSUs.

“We believe that MSUs are very worthwhile and that the clinical and economic benefits of earlier stroke treatment [made possible with MSUs] could offset the costs, but we need to show this,” admitted May Nour, MD, a vascular and interventional neurologist at the University of California, Los Angeles (UCLA), and director of the soon-to-launch Los Angeles MSU.

The concept behind MSUs is simple: Each one carries a CT scanner on board so that once the vehicle’s staff identifies a patient with clinical signs of a significant-acute ischemic stroke in the field and confirms that the timing of the stroke onset suggests eligibility for tPA treatment, a CT scan can immediately be run on-site to finalize tPA eligibility. The MSU staff can then begin infusing the drug in the ambulance as it speeds the patient to an appropriate hospital.

In addition, many MSUs now carry a scanner that can perform a CT angiogram (CTA) to locate the occluding clot. If a large vessel occlusion is found, the crew can bring the patient directly to a comprehensive stroke center for a thrombectomy. If thrombectomy is not appropriate, the MSU crew may take the patient to a primary stroke center where thrombectomy is not available.

Another advantage to MSUs, in addition to quicker initiation of thrombolysis, is “getting patients to where they need to go faster and more directly,” said Dr Nour.

“Instead of bringing patients first to a hospital that’s unable to do thrombectomy and where treatment gets slowed down, with an MSU you can give tPA on the street and go straight to a thrombectomy center,” agreed Jeffrey L. Saver, MD, professor of neurology and director of the stroke unit at UCLA. “The MSU offers the tantalizing possibility that you can give tPA with no time hit because you can give it on the way directly to a comprehensive stroke center,” Dr Saver said during a session at the meeting.

Early Data on Effectiveness

Dr Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data the Berlin group published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU to similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of tPA treatment did not begin until the patient reached a hospital. The German analysis showed that, in the observational Pre-hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference.¹ However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 1 or lower when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance

Dr Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90-day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at EDs operated by the Cleveland Clinic, a statistically significant difference.² However, this report included no data on clinical outcomes.

Running the Financial Numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality-adjusted life years. We calculated a cost of $35,000 per quality-adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

During his talk at the same session, Dr Grotta ran through the numbers for the Houston program. They spent $1.1 million to put their MSU into service in early 2014, and, based on the expenses accrued since then, he estimated an annual staffing cost of about $400,000 and an annual operating cost of about $100,000, for a total estimated 5-year cost of about $3.6 million. Staffing of the Houston MSU started with a registered nurse, CT technician, paramedic, and vascular neurologist, although, like most other US MSUs, the onboard neurologist has since been replaced by a second paramedic, and the neurological diagnostic consult is done via a telemedicine link.

Income from transport reimbursement, currently $500 per trip, and reimbursements of $17,000 above costs for administering tPA and of roughly $40,000 above costs for performing thrombectomy, are balancing these costs. Based on an estimated additional one thrombolysis case per month and one additional thrombectomy case per month, the MSU yields a potential incremental income to the hospital running the MSU of about $3.8 million over 5 years—enough to balance the operating cost, Dr Grotta said.

A key part of controlling costs is having the neurological consult done via a telemedicine link rather than by neurologist at the MSU. “Telemedicine reduces operational costs and improves efficiency,” noted M. Shazam Hussain, MD, interim director of the Cerebrovascular Center at the Cleveland Clinic. “Cost-effectiveness is a very important part of the concept” of MSUs, he said at the session.

The Houston group reported results from a study that directly compared the diagnostic performance of an onboard neurologist with that of a telemedicine neurologist linked-in remotely during MSU deployments for 174 patients. For these cases, the two neurologists each made an independent diagnosis that the researchers then compared. The two diagnoses concurred for 88% of the cases, Tzu-Ching Wu, MD, reported at the meeting. This rate of agreement matched the incidence of concordance between two neurologists who independently assessed the same patients at the hospital,³ said Dr Wu, a vascular neurologist and director of the telemedicine program at the University of Texas Health Science Center in Houston.

“The results support using telemedicine as the primary means of assessment on the MSU,” said Dr Wu. “This may enhance MSU efficiency and reduce costs.” His group’s next study of MSU telemedicine will compare the time needed to make a diagnostic decision using the two approaches, which Dr Wu reported was something not formally examined in the study.

However, telemedicine assessment of CT results gathered in an MSU has one major limitation: the time needed to transmit the huge amount of information from a CTA.

The MSU used by clinicians at the University of Tennessee, Memphis, incorporates an extremely powerful battery that enables “full CT scanner capability with a moving gantry,” said Andrei V. Alexandrov, MD, professor and chairman of neurology at the university. With this set up “we can do in-the-field multiphasic CT angiography from the aortic arch up within 4 minutes. The challenge of doing this is simple. It’s 1.7 gigabytes of data,” which would take a prohibitively long time to transmit from a remote site, he explained. As a result, the complete set of images from the field CTA is delivered on a memory stick to the attending hospital neurologist once the MSU returns.

Waiting for More Data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially nonsustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system, including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March.⁴ “Even if MSUs meet an acceptable societal threshold for cost-effectiveness, cost-efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD. They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 tPA treatments and 349 cancellations before arrival, noted Dr Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr Brandler, an emergency medicine physician at Stony Brook (NY) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost-effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of US patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver, Houston, and Memphis. Although currently designed to enroll 697 patients, Dr Grotta said he hopes to bring the number up to 1,000 patients.

“We are following the health care use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

References

1. Kunz A, Ebinger M, Geisler F, et al. Functional outcomes of pre-hospital thrombolysis in a mobile stroke treatment unit compared with conventional care: an observational registry study. Lancet Neurol. 2016;15(10):1035-1043. doi:10.1016/S1474-4422(16)30129-6.

2. Taqui A, Cerejo R, Itrat A, et al; Cleveland Pre-Hospital Acute Stroke Treatment (PHAST) Group. Reduction in time to treatment in prehospital telemedicine evaluation and thrombolysis. Neurology. 2017 March 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003786.

3. Ramadan AR, Denny MC, Vahidy F, et al. Agreement among stroke faculty and fellows in treating ischemic stroke patients with tissue-type plasminogen activator and thrombectomy. Stroke. 2017;48(1):222-224. doi:10.1161/STROKEAHA.116.015214.

4. Southerland AM, Brandler ES. The cost-efficiency of mobile stroke units: Where the rubber meets the road. Neurology. 2017 Mar 8. [Epub ahead of print]. doi:10.1212/WNL.0000000000003833.

Pulmonary Embolism Common in Patients With Acute Exacerbations of COPD

JIM KLING

FRONTLINE MEDICAL NEWS

About 16% of patients with unexplained acute exacerbations of chronic obstructive pulmonary disease (AECOPD) had an accompanying pulmonary embolism (PE), usually in regions that could be targeted with anticoagulants, according to a new systematic review and meta-analysis.

Approximately 70% of AECOPD cases develop in response to an infection, but about 30% of the time, an AE has no clear cause, the authors said in a report on their research. There is a known biological link between inflammation and coagulation, which suggests that patients experiencing AECOPD may be at increased risk of PE.

The researchers reviewed and analyzed seven studies, comprising 880 patients. Among the authors’ reasons for conducting this research was to update the pooled prevalence of PE in AECOPD from a previous systematic review published in Chest in 2009.

The meta-analysis revealed that 16.1% of patients with AECOPD were also diagnosed with PE (95% confidence interval [CI], 8.3%-25.8%). There was a wide range of variation between individual studies (prevalence 3.3%-29.1%). In six studies that reported on deep vein thrombosis (DVT), the pooled prevalence of DVT was 10.5% (95% CI, 4.3%-19.0%).

Five of the studies identified the PE location. An analysis of those studies showed that 35% were in the main pulmonary artery, and 31.7% were in the lobar and interlobar arteries. Such findings “[suggest] that the majority of these embolisms have important clinical consequences,” the authors wrote.

The researchers also looked at clinical markers that accompanied AECOPD and found a potential signal with respect to pleuritic chest pain. One study found a strong association between pleuritic chest pain and AECOPD patients with PE (81% vs 40% in those without PE). A second study showed a similar association (24% in PE vs 11.5% in non-PE patients), and a third study found no significant difference.

The presence of PE was also linked to hypotension, syncope, and acute right failure on ultrasonography, suggesting that PE may be associated with heart failure.

Patients with PE were less likely to have symptoms consistent with a respiratory tract infection. They also tended to have higher mortality rates and longer hospitalization rates compared with those without PE.

The meta-analysis had some limitations, including the heterogeneity of findings in the included studies, as well as the potential for publication bias, since reports showing unusually low or high rates may be more likely to be published, the researchers noted. There was also a high proportion of male subjects in the included studies.

Overall, the researchers concluded that PE is more likely in patients with pleuritic chest pain and signs of heart failure, and less likely in patients with signs of a respiratory infection. That information “might add to the clinical decision-making in patients with an AECOPD, because it would be undesirable to perform [CT pulmonary angiography] in every patient with an AECOPD,” the researchers wrote.

Aleva FE, Voets LW, Simons SO, de Mast Q, van der Ven AJ, Heijdra YF. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: A systematic review and meta-analysis. Chest. 2017;151(3):544-554. doi:10.1016/j.chest.2016.07.034.

Norepinephrine Shortage Linked to Mortality in Patients With Septic Shock

AMY KARON

FRONTLINE MEDICAL NEWS

A national shortage of norepinephrine in the United States was associated with higher rates of mortality among patients hospitalized with septic shock, investigators reported.

Rates of in-hospital mortality in 2011 were 40% during quarters when hospitals were facing shortages and 36% when they were not, Emily Vail, MD, and her associates said at the International Symposium on Intensive Care and Emergency Medicine. The report was published simultaneously in JAMA.

The link between norepinephrine shortage and death from septic shock persisted even after the researchers accounted for numerous clinical and demographic factors (adjusted odds ratio, 1.2; 95% CI, 1.01 to 1.30; P = .03), wrote Dr Vail of Columbia University, New York.

Drug shortages are common in the United States, but few studies have explored their effects on patient outcomes. Investigators compared mortality rates among affected patients during 3-month intervals when hospitals were and were not using at least 20% less norepinephrine than baseline. The researchers used Premier Healthcare Database, which includes both standard claims and detailed, dated logs of all services billed to patients or insurance, with minimal missing data.

A total of 77% patients admitted with septic shock received norepinephrine before the shortage. During the lowest point of the shortage, 56% of patients received it, the researchers reported. Clinicians most often used phenylephrine instead, prescribing it to up to 54% of patients during the worst time of the shortage. The absolute increase in mortality during the quarters of shortage was 3.7% (95% CI, 1.5%-6.0%).

Several factors might explain the link between norepinephrine shortage and mortality, the investigators said. The vasopressors chosen to replace norepinephrine might result directly in worse outcomes, but a decrease in norepinephrine use also might be a proxy for relevant variables such as delayed use of vasopressors, lack of knowledge of how to optimally dose vasopressors besides norepinephrine, or the absence of a pharmacist dedicated to helping optimize the use of limited supplies.

The study did not uncover a dose-response association between greater decreases in norepinephrine use and increased mortality, the researchers noted. “This may be due to a threshold effect of vasopressor shortage on mortality, or lack of power due to relatively few hospital quarters at the extreme levels of vasopressor shortage,” they wrote.

Because the deaths captured included only those that occurred in-hospital, “the results may have underestimated mortality, particularly for hospitals that tend to transfer patients early to other skilled care facilities,” the researchers noted.

The cohort of patients was limited to those who received vasopressors for 2 or more days and excluded patients who died on the first day of vasopressor treatment, the researchers said.

Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA.  21 March 2017. [Epub ahead of print]. doi:10.1001/jama.2017.2841.

The Food and Drug Administration has converted accelerated approval of osimertinib to full approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer (NSCLC), as detected by an FDA-approved test.

Also included in the indication, disease must have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy, the FDA said in a statement.

[email protected]

The Food and Drug Administration has converted accelerated approval of osimertinib to full approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer (NSCLC), as detected by an FDA-approved test.

Also included in the indication, disease must have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy, the FDA said in a statement.

[email protected]

The Food and Drug Administration has converted accelerated approval of osimertinib to full approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer (NSCLC), as detected by an FDA-approved test.

Also included in the indication, disease must have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy, the FDA said in a statement.

[email protected]

SAN DIEGO – Health care providers need to practice compassionate care to achieve the best results when managing patients who are dealing with opioid addiction, according to a panel of experts who spoke at the annual meeting of the American College of Physicians.

Caring “compassionately is not enabling, [it’s] doing the right thing by the patient,” explained Chwen-Yuen Angie Chen, MD, of Stanford (Calif.) University. “You can practice compassionate care if you have a knowledge base. Knowledge is extremely powerful and enables you to follow evidence-based medicine, which is truly compassionate care.”

Dr. Chen spoke at length about addiction medicine during a press conference outlining the ACP’s new position paper on preventing and treating substance abuse, where she was joined by ACP President Nitin S. Damle, MD, and ACP Board of Regents Chair Thomas G. Tape, MD. All three emphasized the need for decriminalization and destigmatization of opioid abuse, and they called on physicians to guide patients through resources and compassionate care to help them overcome the affliction.

“We know that we need to either taper, detoxify, or reduce opioid dosing. We know that we ought not to coprescribe with sedatives. We know that, if you need addiction treatment, you get referred, and you don’t just get cut off,” explained Dr. Chen.

In a video interview, Dr. Chen talked about the key take-home messages of the position paper, and she explained other aspects of substance abuse that requires provider’s awareness.

Dr. Chen did not report any relevant financial disclosures.

[email protected]

SAN DIEGO – Health care providers need to practice compassionate care to achieve the best results when managing patients who are dealing with opioid addiction, according to a panel of experts who spoke at the annual meeting of the American College of Physicians.

Caring “compassionately is not enabling, [it’s] doing the right thing by the patient,” explained Chwen-Yuen Angie Chen, MD, of Stanford (Calif.) University. “You can practice compassionate care if you have a knowledge base. Knowledge is extremely powerful and enables you to follow evidence-based medicine, which is truly compassionate care.”

Dr. Chen spoke at length about addiction medicine during a press conference outlining the ACP’s new position paper on preventing and treating substance abuse, where she was joined by ACP President Nitin S. Damle, MD, and ACP Board of Regents Chair Thomas G. Tape, MD. All three emphasized the need for decriminalization and destigmatization of opioid abuse, and they called on physicians to guide patients through resources and compassionate care to help them overcome the affliction.

“We know that we need to either taper, detoxify, or reduce opioid dosing. We know that we ought not to coprescribe with sedatives. We know that, if you need addiction treatment, you get referred, and you don’t just get cut off,” explained Dr. Chen.

In a video interview, Dr. Chen talked about the key take-home messages of the position paper, and she explained other aspects of substance abuse that requires provider’s awareness.

Dr. Chen did not report any relevant financial disclosures.

[email protected]

SAN DIEGO – Health care providers need to practice compassionate care to achieve the best results when managing patients who are dealing with opioid addiction, according to a panel of experts who spoke at the annual meeting of the American College of Physicians.

Caring “compassionately is not enabling, [it’s] doing the right thing by the patient,” explained Chwen-Yuen Angie Chen, MD, of Stanford (Calif.) University. “You can practice compassionate care if you have a knowledge base. Knowledge is extremely powerful and enables you to follow evidence-based medicine, which is truly compassionate care.”

Dr. Chen spoke at length about addiction medicine during a press conference outlining the ACP’s new position paper on preventing and treating substance abuse, where she was joined by ACP President Nitin S. Damle, MD, and ACP Board of Regents Chair Thomas G. Tape, MD. All three emphasized the need for decriminalization and destigmatization of opioid abuse, and they called on physicians to guide patients through resources and compassionate care to help them overcome the affliction.

“We know that we need to either taper, detoxify, or reduce opioid dosing. We know that we ought not to coprescribe with sedatives. We know that, if you need addiction treatment, you get referred, and you don’t just get cut off,” explained Dr. Chen.

In a video interview, Dr. Chen talked about the key take-home messages of the position paper, and she explained other aspects of substance abuse that requires provider’s awareness.

Dr. Chen did not report any relevant financial disclosures.

[email protected]

Psychotic symptoms in patients with borderline personality disorder (BPD) are common, distressing to patients, and challenging to treat. Issues of comorbidities and misdiagnoses in BPD patients further complicate matters and could lead to iatrogenic harm. The dissociation that patients with BPD experience could be confused with psychosis and exacerbate treatment and diagnostic confusion. Furthermore, BPD patients with unstable identity and who are sensitive to rejection could present in a bizarre, disorganized, or agitated manner when under stress.

Although pitfalls occur when managing psychotic symptoms in patients with BPD, there are trends and clues to help clinicians navigate diagnostic and treatment challenges. This article will review the literature, propose how to distinguish psychotic symptoms in BPD from those in primary psychotic disorders such as schizophrenia, and explore reasonable treatment options.

The scope of the problem

The DSM-5 criteria for BPD states that “during periods of extreme stress, transient paranoid ideation or dissociative symptoms may occur.”¹ The term “borderline” originated from the idea that symptoms bordered on the intersection of neurosis and psychosis.² However, psychotic symptoms in BPD are more varied and frequent than what DSM-5 criteria suggests.

The prevalence of psychotic symptoms in patients with BPD has been estimated between 20% to 50%.³ There also is evidence of frequent auditory and visual hallucinations in patients with BPD, and a recent study using structured psychiatric interviews demonstrated that most BPD patients report at least 1 symptom of psychosis.⁴ Considering that psychiatric comorbidities are the rule rather than the exception in BPD, the presence of psychotic symptoms further complicates the diagnostic picture. Recognizing the symptoms of BPD is essential for understanding the course of the symptoms and predicting response to treatment.⁵

Treatment of BPD is strikingly different than that of a primary psychotic disorder. There is some evidence that low-dosage antipsychotics could ease mood instability and perceptual disturbances in patients with BPD.⁶ Antipsychotic dosages used to treat hallucinations and delusions in a primary psychotic disorder are unlikely to be as effective for a patient with BPD, and are associated with significant adverse effects. Furthermore, these adverse effects—such as weight gain, hyperlipidemia, and diabetes—could become new sources of distress. Clinicians also might miss an opportunity to engage a BPD patient in psychotherapy if the focus is on the anticipated effect of a medication. The mainstay treatment of BPD is an evidence-based psychotherapy, such as dialectical behavioral therapy, transference-focused psychotherapy, mentalization-based therapy, or good psychiatric management.⁷

CASE Hallucinations during times of stress

Ms. K, a 20-year-old single college student, presents to the psychiatric emergency room with worsening mood swings, anxiety, and hallucinations. Her mood swings are brief and intense, lasting minutes to hours. Anxiety often is triggered by feelings of emptiness and fear of abandonment. She describes herself as a “social chameleon” and notes that she changes how she behaves depending on who she spends time with.

She often hears the voice of her ex-boyfriend instructing her to kill herself and saying that she is a “terrible person.” Their relationship was intense, with many break-ups and reunions. She also reports feeling disconnected from herself at times as though she is being controlled by an outside entity. To relieve her emotional suffering, she cuts herself superficially. Although she has no family history of psychiatric illness, she fears that she may have schizophrenia.

Ms. K’s outpatient psychiatrist prescribes antipsychotics at escalating dosages over a few months (she now takes olanzapine, 40 mg/d, aripiprazole, 30 mg/d, clonazepam, 3 mg/d, and escitalopram, 30 mg/d), but the hallucinations remain. These symptoms worsen during stressful situations, and she notices that they almost are constant as she studies for final exams, prompting her psychiatrist to discuss a clozapine trial. Ms. K is not in psychotherapy, and recognizes that she does not deal with stress well. Despite her symptoms, she is organized in her thought process, has excellent grooming and hygiene, has many social connections, and performs well in school.

How does one approach a patient such as Ms. K?

A chief concern of hallucinations, particularly in a young adult at an age when psychotic disorders such as schizophrenia often emerge, can contribute to a diagnostic quandary. What evidence can guide the clinician? There are some key features to consider:

• Her “mood swings” are notable in their intensity and brevity, making a primary mood disorder with psychotic features less likely.
• Hallucinations are present in the absence of a prodromal period of functional decline or negative symptoms, making a primary psychotic disorder less likely.
• She does not have a family history of psychiatric illness, particularly a primary psychotic disorder.
• She maintains social connections, although her relationships are intense and tumultuous.
• Psychotic symptoms have not changed with higher dosages of antipsychotics.
• Complaints of feeling “disconnected from herself” and “empty” are common symptoms of BPD and necessitate further exploration.
• Psychotic symptoms are largely transient and stress-related, with an overwhelmingly negative tone.
• Techniques that individuals with schizophrenia use, such as distraction or trying to tune out voices, are not being employed. Instead, Ms. K attends to the voices and is anxiously focused on them.
• The relationship of her symptoms to interpersonal stress is key.

When evaluating a patient such as Ms. K, it is important to explore both the nature and timing of the psychotic symptoms and any other related psychiatric symptoms. This helps to determine a less ambiguous diagnosis and clearer treatment plan. Understanding the patient’s perspective about the psychotic symptoms also is useful to gauge the patient’s level of distress and her impression of what the symptoms mean.

Diagnostic considerations

BPD is characterized by a chaotic emotional climate with impulsivity and instability of self-image, affect, and relationships. Most BPD symptoms, including psychosis, often are exacerbated by the perception of abandonment or rejection and other interpersonal stressors.¹ Both BPD and schizophrenia are estimated to affect at least 1% of the general population.^8,9 Patients with BPD frequently meet criteria for comorbid mental illnesses, including major depressive disorder, substance use disorder, posttraumatic stress disorder, anxiety, and eating disorders.¹⁰ Because psychotic symptoms can present in some of these disorders, the context and time course of these symptoms are crucial to consider.

Misdiagnosis is common with BPD, and patients can receive the wrong treatment for years before BPD is considered, likely because of the stigma surrounding the diagnosis.⁵ One also must keep in mind that, although rare, a patient can have both BPD and a primary psychotic disorder.¹¹ Although a patient with schizophrenia could be prone to social isolation because of delusions or paranoia, BPD patients are more apt to experience intense interpersonal relationships driven by the need to avoid abandonment. Manipulation, anger, and neediness in relationships with both peers and health care providers are common—stark contrasts to typical negative symptoms, blunted affect, and a lack of social drive characteristic of schizophrenia.¹²

Distinguishing between psychosis in BPD and a psychotic disorder

Studies have sought to explore the quality of psychotic symptoms in BPD vs primary psychotic disorders, which can be challenging to differentiate (Table 1). Some have found that transient symptoms, such as non-delusional paranoia, are more prevalent in BPD, and “true” psychotic symptoms that are long-lasting and bizarre are indicative of schizophrenia.^13,14 Also, there is evidence that the lower levels of interpersonal functioning often found in BPD are predictive of psychotic symptoms in that disorder but not in schizophrenia.¹⁵

Auditory hallucinations in patients with BPD predominantly are negative and critical in tone.⁴ However, there is no consistent evidence that the quality of auditory hallucinations in BPD vs schizophrenia is different in any meaningful way.¹⁶ Because of the frequency of dissociative symptoms in BPD, it is likely that clinicians could misinterpret these symptoms to indicate disorganized behavior associated with a primary psychotic disorder. In one study, 50% of individuals with BPD experienced auditory hallucinations.¹¹ Differentiating between “internal” or “external” voices did not help to clarify the diagnosis, and paranoid delusions occurred in less than one-third of patients with BPD, but in approximately two-third of those with a diagnosis of schizophrenia.

The McLean Study of Adult Develop­ment, a longitudinal study of BPD patients, found that the prevalence of psychotic symptoms diminished over time. It is unclear whether this was due to the spontaneus remission rate of BPD symptoms in general or because of effective treatment.¹³

Psychotic symptoms in BPD seem to react to stress and increase in intensity when patients are in crisis.¹⁷ Nonetheless, because of the prevalence of psychosis in BPD patients and the distress it causes, clinicians should be cautioned against using terms that imply that the symptoms are not “true” or “real.”³

Treatment recommendations

When considering pharmacologic management of psychotic symptoms in BPD, aim to limit antipsychotic medications to low dosages because of adverse effects and the limited evidence that escalating dosages—and especially using >1 antipsychotic concurrently—are more effective.¹⁸ Educate patients that in BPD medications are, at best, considered adjunctive treatments. Blaming psychotic symptoms on a purely biological process in BPD, not only is harmful because medications are unlikely to significantly or consistently help, but also because they can undermine patient autonomy and reinforce the need for an outside entity (ie, medication) to fix their problems.

When treatment is ineffective and symptoms do not improve, a patient with BPD likely will experience mounting distress. This, in turn, could exacerbate impulsive, suicidal, and self-injurious behaviors. Emphasize psychotherapy, particularly for those whose psychotic symptoms are transient, stress-related, and present during acute crises (Table 2). With evidence-based psychotherapy, BPD patients can become active participants in treatment, coupling developing insight with concrete skills and teachable principles. This leads to increased interpersonal effectiveness and resilience during times of stress. Challenging the patient’s psychotic symptoms as false or “made up” rarely is helpful and usually harmful, leading to the possible severance of the therapeutic alliance.³

Bottom Line

Psychotic symptoms in patients with borderline personality disorder (BPD) could look similar to those in primary psychotic disorders. Factors suggesting BPD include a pattern of worsening psychotic symptoms during stress, long-term symptom instability, lack of delusions, presence of dissociation, and nonresponse to antipsychotics. Although low-dosage antipsychotics could provide some relief of psychotic symptoms in a patient with BPD, they often are not consistently effective and frequently lead to adverse effects. Emphasize evidence-based psychotherapies.

Psychotic symptoms in patients with borderline personality disorder (BPD) are common, distressing to patients, and challenging to treat. Issues of comorbidities and misdiagnoses in BPD patients further complicate matters and could lead to iatrogenic harm. The dissociation that patients with BPD experience could be confused with psychosis and exacerbate treatment and diagnostic confusion. Furthermore, BPD patients with unstable identity and who are sensitive to rejection could present in a bizarre, disorganized, or agitated manner when under stress.

Although pitfalls occur when managing psychotic symptoms in patients with BPD, there are trends and clues to help clinicians navigate diagnostic and treatment challenges. This article will review the literature, propose how to distinguish psychotic symptoms in BPD from those in primary psychotic disorders such as schizophrenia, and explore reasonable treatment options.

The scope of the problem

The DSM-5 criteria for BPD states that “during periods of extreme stress, transient paranoid ideation or dissociative symptoms may occur.”¹ The term “borderline” originated from the idea that symptoms bordered on the intersection of neurosis and psychosis.² However, psychotic symptoms in BPD are more varied and frequent than what DSM-5 criteria suggests.

The prevalence of psychotic symptoms in patients with BPD has been estimated between 20% to 50%.³ There also is evidence of frequent auditory and visual hallucinations in patients with BPD, and a recent study using structured psychiatric interviews demonstrated that most BPD patients report at least 1 symptom of psychosis.⁴ Considering that psychiatric comorbidities are the rule rather than the exception in BPD, the presence of psychotic symptoms further complicates the diagnostic picture. Recognizing the symptoms of BPD is essential for understanding the course of the symptoms and predicting response to treatment.⁵

Treatment of BPD is strikingly different than that of a primary psychotic disorder. There is some evidence that low-dosage antipsychotics could ease mood instability and perceptual disturbances in patients with BPD.⁶ Antipsychotic dosages used to treat hallucinations and delusions in a primary psychotic disorder are unlikely to be as effective for a patient with BPD, and are associated with significant adverse effects. Furthermore, these adverse effects—such as weight gain, hyperlipidemia, and diabetes—could become new sources of distress. Clinicians also might miss an opportunity to engage a BPD patient in psychotherapy if the focus is on the anticipated effect of a medication. The mainstay treatment of BPD is an evidence-based psychotherapy, such as dialectical behavioral therapy, transference-focused psychotherapy, mentalization-based therapy, or good psychiatric management.⁷

CASE Hallucinations during times of stress

Ms. K, a 20-year-old single college student, presents to the psychiatric emergency room with worsening mood swings, anxiety, and hallucinations. Her mood swings are brief and intense, lasting minutes to hours. Anxiety often is triggered by feelings of emptiness and fear of abandonment. She describes herself as a “social chameleon” and notes that she changes how she behaves depending on who she spends time with.

She often hears the voice of her ex-boyfriend instructing her to kill herself and saying that she is a “terrible person.” Their relationship was intense, with many break-ups and reunions. She also reports feeling disconnected from herself at times as though she is being controlled by an outside entity. To relieve her emotional suffering, she cuts herself superficially. Although she has no family history of psychiatric illness, she fears that she may have schizophrenia.

Ms. K’s outpatient psychiatrist prescribes antipsychotics at escalating dosages over a few months (she now takes olanzapine, 40 mg/d, aripiprazole, 30 mg/d, clonazepam, 3 mg/d, and escitalopram, 30 mg/d), but the hallucinations remain. These symptoms worsen during stressful situations, and she notices that they almost are constant as she studies for final exams, prompting her psychiatrist to discuss a clozapine trial. Ms. K is not in psychotherapy, and recognizes that she does not deal with stress well. Despite her symptoms, she is organized in her thought process, has excellent grooming and hygiene, has many social connections, and performs well in school.

How does one approach a patient such as Ms. K?

A chief concern of hallucinations, particularly in a young adult at an age when psychotic disorders such as schizophrenia often emerge, can contribute to a diagnostic quandary. What evidence can guide the clinician? There are some key features to consider:

• Her “mood swings” are notable in their intensity and brevity, making a primary mood disorder with psychotic features less likely.
• Hallucinations are present in the absence of a prodromal period of functional decline or negative symptoms, making a primary psychotic disorder less likely.
• She does not have a family history of psychiatric illness, particularly a primary psychotic disorder.
• She maintains social connections, although her relationships are intense and tumultuous.
• Psychotic symptoms have not changed with higher dosages of antipsychotics.
• Complaints of feeling “disconnected from herself” and “empty” are common symptoms of BPD and necessitate further exploration.
• Psychotic symptoms are largely transient and stress-related, with an overwhelmingly negative tone.
• Techniques that individuals with schizophrenia use, such as distraction or trying to tune out voices, are not being employed. Instead, Ms. K attends to the voices and is anxiously focused on them.
• The relationship of her symptoms to interpersonal stress is key.

When evaluating a patient such as Ms. K, it is important to explore both the nature and timing of the psychotic symptoms and any other related psychiatric symptoms. This helps to determine a less ambiguous diagnosis and clearer treatment plan. Understanding the patient’s perspective about the psychotic symptoms also is useful to gauge the patient’s level of distress and her impression of what the symptoms mean.

Diagnostic considerations

BPD is characterized by a chaotic emotional climate with impulsivity and instability of self-image, affect, and relationships. Most BPD symptoms, including psychosis, often are exacerbated by the perception of abandonment or rejection and other interpersonal stressors.¹ Both BPD and schizophrenia are estimated to affect at least 1% of the general population.^8,9 Patients with BPD frequently meet criteria for comorbid mental illnesses, including major depressive disorder, substance use disorder, posttraumatic stress disorder, anxiety, and eating disorders.¹⁰ Because psychotic symptoms can present in some of these disorders, the context and time course of these symptoms are crucial to consider.

Misdiagnosis is common with BPD, and patients can receive the wrong treatment for years before BPD is considered, likely because of the stigma surrounding the diagnosis.⁵ One also must keep in mind that, although rare, a patient can have both BPD and a primary psychotic disorder.¹¹ Although a patient with schizophrenia could be prone to social isolation because of delusions or paranoia, BPD patients are more apt to experience intense interpersonal relationships driven by the need to avoid abandonment. Manipulation, anger, and neediness in relationships with both peers and health care providers are common—stark contrasts to typical negative symptoms, blunted affect, and a lack of social drive characteristic of schizophrenia.¹²

Distinguishing between psychosis in BPD and a psychotic disorder

Studies have sought to explore the quality of psychotic symptoms in BPD vs primary psychotic disorders, which can be challenging to differentiate (Table 1). Some have found that transient symptoms, such as non-delusional paranoia, are more prevalent in BPD, and “true” psychotic symptoms that are long-lasting and bizarre are indicative of schizophrenia.^13,14 Also, there is evidence that the lower levels of interpersonal functioning often found in BPD are predictive of psychotic symptoms in that disorder but not in schizophrenia.¹⁵

Auditory hallucinations in patients with BPD predominantly are negative and critical in tone.⁴ However, there is no consistent evidence that the quality of auditory hallucinations in BPD vs schizophrenia is different in any meaningful way.¹⁶ Because of the frequency of dissociative symptoms in BPD, it is likely that clinicians could misinterpret these symptoms to indicate disorganized behavior associated with a primary psychotic disorder. In one study, 50% of individuals with BPD experienced auditory hallucinations.¹¹ Differentiating between “internal” or “external” voices did not help to clarify the diagnosis, and paranoid delusions occurred in less than one-third of patients with BPD, but in approximately two-third of those with a diagnosis of schizophrenia.

The McLean Study of Adult Develop­ment, a longitudinal study of BPD patients, found that the prevalence of psychotic symptoms diminished over time. It is unclear whether this was due to the spontaneus remission rate of BPD symptoms in general or because of effective treatment.¹³

Psychotic symptoms in BPD seem to react to stress and increase in intensity when patients are in crisis.¹⁷ Nonetheless, because of the prevalence of psychosis in BPD patients and the distress it causes, clinicians should be cautioned against using terms that imply that the symptoms are not “true” or “real.”³

Treatment recommendations

When considering pharmacologic management of psychotic symptoms in BPD, aim to limit antipsychotic medications to low dosages because of adverse effects and the limited evidence that escalating dosages—and especially using >1 antipsychotic concurrently—are more effective.¹⁸ Educate patients that in BPD medications are, at best, considered adjunctive treatments. Blaming psychotic symptoms on a purely biological process in BPD, not only is harmful because medications are unlikely to significantly or consistently help, but also because they can undermine patient autonomy and reinforce the need for an outside entity (ie, medication) to fix their problems.

When treatment is ineffective and symptoms do not improve, a patient with BPD likely will experience mounting distress. This, in turn, could exacerbate impulsive, suicidal, and self-injurious behaviors. Emphasize psychotherapy, particularly for those whose psychotic symptoms are transient, stress-related, and present during acute crises (Table 2). With evidence-based psychotherapy, BPD patients can become active participants in treatment, coupling developing insight with concrete skills and teachable principles. This leads to increased interpersonal effectiveness and resilience during times of stress. Challenging the patient’s psychotic symptoms as false or “made up” rarely is helpful and usually harmful, leading to the possible severance of the therapeutic alliance.³

Bottom Line

Psychotic symptoms in patients with borderline personality disorder (BPD) could look similar to those in primary psychotic disorders. Factors suggesting BPD include a pattern of worsening psychotic symptoms during stress, long-term symptom instability, lack of delusions, presence of dissociation, and nonresponse to antipsychotics. Although low-dosage antipsychotics could provide some relief of psychotic symptoms in a patient with BPD, they often are not consistently effective and frequently lead to adverse effects. Emphasize evidence-based psychotherapies.

Psychotic symptoms in patients with borderline personality disorder (BPD) are common, distressing to patients, and challenging to treat. Issues of comorbidities and misdiagnoses in BPD patients further complicate matters and could lead to iatrogenic harm. The dissociation that patients with BPD experience could be confused with psychosis and exacerbate treatment and diagnostic confusion. Furthermore, BPD patients with unstable identity and who are sensitive to rejection could present in a bizarre, disorganized, or agitated manner when under stress.

Although pitfalls occur when managing psychotic symptoms in patients with BPD, there are trends and clues to help clinicians navigate diagnostic and treatment challenges. This article will review the literature, propose how to distinguish psychotic symptoms in BPD from those in primary psychotic disorders such as schizophrenia, and explore reasonable treatment options.

The scope of the problem

The DSM-5 criteria for BPD states that “during periods of extreme stress, transient paranoid ideation or dissociative symptoms may occur.”¹ The term “borderline” originated from the idea that symptoms bordered on the intersection of neurosis and psychosis.² However, psychotic symptoms in BPD are more varied and frequent than what DSM-5 criteria suggests.

The prevalence of psychotic symptoms in patients with BPD has been estimated between 20% to 50%.³ There also is evidence of frequent auditory and visual hallucinations in patients with BPD, and a recent study using structured psychiatric interviews demonstrated that most BPD patients report at least 1 symptom of psychosis.⁴ Considering that psychiatric comorbidities are the rule rather than the exception in BPD, the presence of psychotic symptoms further complicates the diagnostic picture. Recognizing the symptoms of BPD is essential for understanding the course of the symptoms and predicting response to treatment.⁵

Treatment of BPD is strikingly different than that of a primary psychotic disorder. There is some evidence that low-dosage antipsychotics could ease mood instability and perceptual disturbances in patients with BPD.⁶ Antipsychotic dosages used to treat hallucinations and delusions in a primary psychotic disorder are unlikely to be as effective for a patient with BPD, and are associated with significant adverse effects. Furthermore, these adverse effects—such as weight gain, hyperlipidemia, and diabetes—could become new sources of distress. Clinicians also might miss an opportunity to engage a BPD patient in psychotherapy if the focus is on the anticipated effect of a medication. The mainstay treatment of BPD is an evidence-based psychotherapy, such as dialectical behavioral therapy, transference-focused psychotherapy, mentalization-based therapy, or good psychiatric management.⁷

CASE Hallucinations during times of stress

Ms. K, a 20-year-old single college student, presents to the psychiatric emergency room with worsening mood swings, anxiety, and hallucinations. Her mood swings are brief and intense, lasting minutes to hours. Anxiety often is triggered by feelings of emptiness and fear of abandonment. She describes herself as a “social chameleon” and notes that she changes how she behaves depending on who she spends time with.

She often hears the voice of her ex-boyfriend instructing her to kill herself and saying that she is a “terrible person.” Their relationship was intense, with many break-ups and reunions. She also reports feeling disconnected from herself at times as though she is being controlled by an outside entity. To relieve her emotional suffering, she cuts herself superficially. Although she has no family history of psychiatric illness, she fears that she may have schizophrenia.

Ms. K’s outpatient psychiatrist prescribes antipsychotics at escalating dosages over a few months (she now takes olanzapine, 40 mg/d, aripiprazole, 30 mg/d, clonazepam, 3 mg/d, and escitalopram, 30 mg/d), but the hallucinations remain. These symptoms worsen during stressful situations, and she notices that they almost are constant as she studies for final exams, prompting her psychiatrist to discuss a clozapine trial. Ms. K is not in psychotherapy, and recognizes that she does not deal with stress well. Despite her symptoms, she is organized in her thought process, has excellent grooming and hygiene, has many social connections, and performs well in school.

How does one approach a patient such as Ms. K?

A chief concern of hallucinations, particularly in a young adult at an age when psychotic disorders such as schizophrenia often emerge, can contribute to a diagnostic quandary. What evidence can guide the clinician? There are some key features to consider:

• Her “mood swings” are notable in their intensity and brevity, making a primary mood disorder with psychotic features less likely.
• Hallucinations are present in the absence of a prodromal period of functional decline or negative symptoms, making a primary psychotic disorder less likely.
• She does not have a family history of psychiatric illness, particularly a primary psychotic disorder.
• She maintains social connections, although her relationships are intense and tumultuous.
• Psychotic symptoms have not changed with higher dosages of antipsychotics.
• Complaints of feeling “disconnected from herself” and “empty” are common symptoms of BPD and necessitate further exploration.
• Psychotic symptoms are largely transient and stress-related, with an overwhelmingly negative tone.
• Techniques that individuals with schizophrenia use, such as distraction or trying to tune out voices, are not being employed. Instead, Ms. K attends to the voices and is anxiously focused on them.
• The relationship of her symptoms to interpersonal stress is key.

When evaluating a patient such as Ms. K, it is important to explore both the nature and timing of the psychotic symptoms and any other related psychiatric symptoms. This helps to determine a less ambiguous diagnosis and clearer treatment plan. Understanding the patient’s perspective about the psychotic symptoms also is useful to gauge the patient’s level of distress and her impression of what the symptoms mean.

Diagnostic considerations

BPD is characterized by a chaotic emotional climate with impulsivity and instability of self-image, affect, and relationships. Most BPD symptoms, including psychosis, often are exacerbated by the perception of abandonment or rejection and other interpersonal stressors.¹ Both BPD and schizophrenia are estimated to affect at least 1% of the general population.^8,9 Patients with BPD frequently meet criteria for comorbid mental illnesses, including major depressive disorder, substance use disorder, posttraumatic stress disorder, anxiety, and eating disorders.¹⁰ Because psychotic symptoms can present in some of these disorders, the context and time course of these symptoms are crucial to consider.

Misdiagnosis is common with BPD, and patients can receive the wrong treatment for years before BPD is considered, likely because of the stigma surrounding the diagnosis.⁵ One also must keep in mind that, although rare, a patient can have both BPD and a primary psychotic disorder.¹¹ Although a patient with schizophrenia could be prone to social isolation because of delusions or paranoia, BPD patients are more apt to experience intense interpersonal relationships driven by the need to avoid abandonment. Manipulation, anger, and neediness in relationships with both peers and health care providers are common—stark contrasts to typical negative symptoms, blunted affect, and a lack of social drive characteristic of schizophrenia.¹²

Distinguishing between psychosis in BPD and a psychotic disorder

Studies have sought to explore the quality of psychotic symptoms in BPD vs primary psychotic disorders, which can be challenging to differentiate (Table 1). Some have found that transient symptoms, such as non-delusional paranoia, are more prevalent in BPD, and “true” psychotic symptoms that are long-lasting and bizarre are indicative of schizophrenia.^13,14 Also, there is evidence that the lower levels of interpersonal functioning often found in BPD are predictive of psychotic symptoms in that disorder but not in schizophrenia.¹⁵

Auditory hallucinations in patients with BPD predominantly are negative and critical in tone.⁴ However, there is no consistent evidence that the quality of auditory hallucinations in BPD vs schizophrenia is different in any meaningful way.¹⁶ Because of the frequency of dissociative symptoms in BPD, it is likely that clinicians could misinterpret these symptoms to indicate disorganized behavior associated with a primary psychotic disorder. In one study, 50% of individuals with BPD experienced auditory hallucinations.¹¹ Differentiating between “internal” or “external” voices did not help to clarify the diagnosis, and paranoid delusions occurred in less than one-third of patients with BPD, but in approximately two-third of those with a diagnosis of schizophrenia.

The McLean Study of Adult Develop­ment, a longitudinal study of BPD patients, found that the prevalence of psychotic symptoms diminished over time. It is unclear whether this was due to the spontaneus remission rate of BPD symptoms in general or because of effective treatment.¹³

Psychotic symptoms in BPD seem to react to stress and increase in intensity when patients are in crisis.¹⁷ Nonetheless, because of the prevalence of psychosis in BPD patients and the distress it causes, clinicians should be cautioned against using terms that imply that the symptoms are not “true” or “real.”³

Treatment recommendations

When considering pharmacologic management of psychotic symptoms in BPD, aim to limit antipsychotic medications to low dosages because of adverse effects and the limited evidence that escalating dosages—and especially using >1 antipsychotic concurrently—are more effective.¹⁸ Educate patients that in BPD medications are, at best, considered adjunctive treatments. Blaming psychotic symptoms on a purely biological process in BPD, not only is harmful because medications are unlikely to significantly or consistently help, but also because they can undermine patient autonomy and reinforce the need for an outside entity (ie, medication) to fix their problems.

When treatment is ineffective and symptoms do not improve, a patient with BPD likely will experience mounting distress. This, in turn, could exacerbate impulsive, suicidal, and self-injurious behaviors. Emphasize psychotherapy, particularly for those whose psychotic symptoms are transient, stress-related, and present during acute crises (Table 2). With evidence-based psychotherapy, BPD patients can become active participants in treatment, coupling developing insight with concrete skills and teachable principles. This leads to increased interpersonal effectiveness and resilience during times of stress. Challenging the patient’s psychotic symptoms as false or “made up” rarely is helpful and usually harmful, leading to the possible severance of the therapeutic alliance.³

Bottom Line

Psychotic symptoms in patients with borderline personality disorder (BPD) could look similar to those in primary psychotic disorders. Factors suggesting BPD include a pattern of worsening psychotic symptoms during stress, long-term symptom instability, lack of delusions, presence of dissociation, and nonresponse to antipsychotics. Although low-dosage antipsychotics could provide some relief of psychotic symptoms in a patient with BPD, they often are not consistently effective and frequently lead to adverse effects. Emphasize evidence-based psychotherapies.

Take-Home Points

• Adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome following pediatric spine surgery.
• Must recognize nonspecific symptoms such as abdominal pain, tenderness, distention, bilious or projectile vomiting, hypoactive bowel sounds, and anorexia postoperatively.
• Complications of SMA syndrome can potentially lead to aspiration pneumonia, acute gastric rupture, or cardiovascular collapse and death.

Superior mesenteric artery (SMA) syndrome resulting from surgical treatment of scoliosis has been recognized in the medical literature since 1752.¹ Throughout the literature, SMA syndrome variably has been referred to as cast syndrome, Wilkie syndrome, arteriomesenteric duodenal obstruction, and chronic duodenal ileus.² We now recognize numerous etiologies of SMA syndrome, as several sources can externally compress the duodenum. Classic acute symptoms of bowel obstruction include bilious vomiting, nausea, and epigastric pain. Chronic manifestations of SMA syndrome may include weight loss and decreased appetite. Our literature review revealed that adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome after pediatric spine surgery.

We report the case of a 14-year-old boy who developed SMA syndrome after undergoing scoliosis surgery. The patient and his mother provided written informed consent for print and electronic publication of this case report.

Case Report

A 14-year-old boy with a history of idiopathic scoliosis presented to Cohen Children’s Hospital (Long Island Jewish Medical Center) with bilious vomiting that had persisted for 7 days after posterior T9–L4 fusion with instrumentation.

Discussion

SMA syndrome is attributed to the anatomical orientation of the third part of the duodenum, which passes between the aorta and the SMA (Figure 4).

Adolescents are particularly vulnerable to this condition. Faster adolescent bone growth relative to visceral growth is accompanied by a decrease in SMA angle.³ Occasionally, body casts are used after surgery to immobilize the vertebrae and augment healing. Cast syndrome occurs when pressure from a body cast causes a bowel obstruction secondary to spinal hyperextension and amplified spinal lordosis.² This finding, dating to the 19th century, was reported by Willet⁴ when a patient died 48 hours after application of a body cast. In 1950, the term cast syndrome was coined after a motorcyclist’s injuries were treated with a hip spica cast and the patient died of cardiovascular collapse secondary to persistent vomiting.⁵

Table 1 summarizes various evaluation, diagnosis, and treatment algorithms designed to optimize nutrition and weight in patients developing signs and symptoms of SMA syndrome after posterior spinal instrumentation and fusion for adolescent idiopathic scoliosis (AIS).

Take-Home Points

• Adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome following pediatric spine surgery.
• Must recognize nonspecific symptoms such as abdominal pain, tenderness, distention, bilious or projectile vomiting, hypoactive bowel sounds, and anorexia postoperatively.
• Complications of SMA syndrome can potentially lead to aspiration pneumonia, acute gastric rupture, or cardiovascular collapse and death.

Superior mesenteric artery (SMA) syndrome resulting from surgical treatment of scoliosis has been recognized in the medical literature since 1752.¹ Throughout the literature, SMA syndrome variably has been referred to as cast syndrome, Wilkie syndrome, arteriomesenteric duodenal obstruction, and chronic duodenal ileus.² We now recognize numerous etiologies of SMA syndrome, as several sources can externally compress the duodenum. Classic acute symptoms of bowel obstruction include bilious vomiting, nausea, and epigastric pain. Chronic manifestations of SMA syndrome may include weight loss and decreased appetite. Our literature review revealed that adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome after pediatric spine surgery.

We report the case of a 14-year-old boy who developed SMA syndrome after undergoing scoliosis surgery. The patient and his mother provided written informed consent for print and electronic publication of this case report.

Case Report

A 14-year-old boy with a history of idiopathic scoliosis presented to Cohen Children’s Hospital (Long Island Jewish Medical Center) with bilious vomiting that had persisted for 7 days after posterior T9–L4 fusion with instrumentation.

Discussion

SMA syndrome is attributed to the anatomical orientation of the third part of the duodenum, which passes between the aorta and the SMA (Figure 4).

Adolescents are particularly vulnerable to this condition. Faster adolescent bone growth relative to visceral growth is accompanied by a decrease in SMA angle.³ Occasionally, body casts are used after surgery to immobilize the vertebrae and augment healing. Cast syndrome occurs when pressure from a body cast causes a bowel obstruction secondary to spinal hyperextension and amplified spinal lordosis.² This finding, dating to the 19th century, was reported by Willet⁴ when a patient died 48 hours after application of a body cast. In 1950, the term cast syndrome was coined after a motorcyclist’s injuries were treated with a hip spica cast and the patient died of cardiovascular collapse secondary to persistent vomiting.⁵

Table 1 summarizes various evaluation, diagnosis, and treatment algorithms designed to optimize nutrition and weight in patients developing signs and symptoms of SMA syndrome after posterior spinal instrumentation and fusion for adolescent idiopathic scoliosis (AIS).

Take-Home Points

• Adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome following pediatric spine surgery.
• Must recognize nonspecific symptoms such as abdominal pain, tenderness, distention, bilious or projectile vomiting, hypoactive bowel sounds, and anorexia postoperatively.
• Complications of SMA syndrome can potentially lead to aspiration pneumonia, acute gastric rupture, or cardiovascular collapse and death.

Superior mesenteric artery (SMA) syndrome resulting from surgical treatment of scoliosis has been recognized in the medical literature since 1752.¹ Throughout the literature, SMA syndrome variably has been referred to as cast syndrome, Wilkie syndrome, arteriomesenteric duodenal obstruction, and chronic duodenal ileus.² We now recognize numerous etiologies of SMA syndrome, as several sources can externally compress the duodenum. Classic acute symptoms of bowel obstruction include bilious vomiting, nausea, and epigastric pain. Chronic manifestations of SMA syndrome may include weight loss and decreased appetite. Our literature review revealed that adolescent growth spurt, height-to-weight ratio, and perioperative weight loss are risk factors associated with SMA syndrome after pediatric spine surgery.

We report the case of a 14-year-old boy who developed SMA syndrome after undergoing scoliosis surgery. The patient and his mother provided written informed consent for print and electronic publication of this case report.

Case Report

A 14-year-old boy with a history of idiopathic scoliosis presented to Cohen Children’s Hospital (Long Island Jewish Medical Center) with bilious vomiting that had persisted for 7 days after posterior T9–L4 fusion with instrumentation.

Discussion

SMA syndrome is attributed to the anatomical orientation of the third part of the duodenum, which passes between the aorta and the SMA (Figure 4).

Adolescents are particularly vulnerable to this condition. Faster adolescent bone growth relative to visceral growth is accompanied by a decrease in SMA angle.³ Occasionally, body casts are used after surgery to immobilize the vertebrae and augment healing. Cast syndrome occurs when pressure from a body cast causes a bowel obstruction secondary to spinal hyperextension and amplified spinal lordosis.² This finding, dating to the 19th century, was reported by Willet⁴ when a patient died 48 hours after application of a body cast. In 1950, the term cast syndrome was coined after a motorcyclist’s injuries were treated with a hip spica cast and the patient died of cardiovascular collapse secondary to persistent vomiting.⁵

Table 1 summarizes various evaluation, diagnosis, and treatment algorithms designed to optimize nutrition and weight in patients developing signs and symptoms of SMA syndrome after posterior spinal instrumentation and fusion for adolescent idiopathic scoliosis (AIS).

SAN DIEGO – Reflecting on his 33-year career as director of the National Institute of Allergy and Infectious Diseases, Anthony S. Fauci, MD, can say one thing for certain: Emerging and re-emerging infectious diseases in the continental United States are here to stay.

In an article that he and his colleagues published in the Lancet in 2008, they used the term “perpetual challenge” to describe emerging infections, a descriptor that resonates with him to this day.

[email protected]

SAN DIEGO – Reflecting on his 33-year career as director of the National Institute of Allergy and Infectious Diseases, Anthony S. Fauci, MD, can say one thing for certain: Emerging and re-emerging infectious diseases in the continental United States are here to stay.

In an article that he and his colleagues published in the Lancet in 2008, they used the term “perpetual challenge” to describe emerging infections, a descriptor that resonates with him to this day.

[email protected]

SAN DIEGO – Reflecting on his 33-year career as director of the National Institute of Allergy and Infectious Diseases, Anthony S. Fauci, MD, can say one thing for certain: Emerging and re-emerging infectious diseases in the continental United States are here to stay.

In an article that he and his colleagues published in the Lancet in 2008, they used the term “perpetual challenge” to describe emerging infections, a descriptor that resonates with him to this day.

[email protected]

Editor’s note: Each month, SHM puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Umesh Sharma, MD, MBA, FHM, chair of the division of community hospital medicine at Mayo Clinic. Umesh became a Fellow in Hospital Medicine in 2016 and has found great value in attending the annual meeting each year.

What inspired you to join SHM, and what prompted you to apply for the Fellow in Hospital Medicine designation?

How did you use SHM resources to help you in your pathway to Fellowship in Hospital Medicine?

There are specific eligibility requirements for the Fellow in Hospital Medicine designation, including a minimum of 5 years as a practicing hospitalist and 3 years as an SHM member, endorsements from two active members, regular meeting attendance and more. SHM provides a checklist for Fellow applicants online and an FAQ page to make the application process as user-friendly as possible. A friend of mine, Dr. Deepak Pahuja, is a Fellow, and he mentored me throughout the process.
 

How else has SHM contributed to your professional growth and provided you with tools you need to lead hospitalists at Mayo Clinic?

There are many resources that SHM provides to help with professional growth both online and at in-person meetings. I referenced the Key Principles and Characteristics of an Effective Hospital Medicine Group, an online assessment guide, in my role as department chair in La Crosse, Wisc., to resurrect a hospital medicine group, secure resources, hire career hospitalists, and create a well-functioning, well-managed, efficient, effective group with zero turnover during a span of 4 years.

By focusing on the leadership track at annual meetings, I have been able to gain knowledge on proven leadership strategies and enhance my skills, which I have applied on many occasions in my practice. Being able to talk to multisite hospital medicine group colleagues in person helped me to learn best practices in how to successfully manage the integration of 14 hospital medicine community hospital sites across Mayo Midwest. I was able to get ideas on effectively understanding and managing challenges, like recruitment retention, staffing to workloads, and scope of practice, among others. SHM promotes peer-to-peer learning and has helped me share and learn best practices as it relates to the clinical and nonclinical aspect of the practice of hospital medicine.
 

What one piece of advice would you give fellow hospitalists during this transformational time in health care?

This is an exciting time in health care, especially for hospital medicine professionals, who are at the forefront of providing value-based care. Every change is an opportunity to improve and innovate; the best way to handle change is to embrace and lead it.

Ms. Steele is SHM’s communications coordinator.

To apply for the Fellow in Hospital Medicine designation, visit www.hospitalmedicine.org/fellows.




 

Editor’s note: Each month, SHM puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Umesh Sharma, MD, MBA, FHM, chair of the division of community hospital medicine at Mayo Clinic. Umesh became a Fellow in Hospital Medicine in 2016 and has found great value in attending the annual meeting each year.

What inspired you to join SHM, and what prompted you to apply for the Fellow in Hospital Medicine designation?

How did you use SHM resources to help you in your pathway to Fellowship in Hospital Medicine?

There are specific eligibility requirements for the Fellow in Hospital Medicine designation, including a minimum of 5 years as a practicing hospitalist and 3 years as an SHM member, endorsements from two active members, regular meeting attendance and more. SHM provides a checklist for Fellow applicants online and an FAQ page to make the application process as user-friendly as possible. A friend of mine, Dr. Deepak Pahuja, is a Fellow, and he mentored me throughout the process.
 

How else has SHM contributed to your professional growth and provided you with tools you need to lead hospitalists at Mayo Clinic?

There are many resources that SHM provides to help with professional growth both online and at in-person meetings. I referenced the Key Principles and Characteristics of an Effective Hospital Medicine Group, an online assessment guide, in my role as department chair in La Crosse, Wisc., to resurrect a hospital medicine group, secure resources, hire career hospitalists, and create a well-functioning, well-managed, efficient, effective group with zero turnover during a span of 4 years.

By focusing on the leadership track at annual meetings, I have been able to gain knowledge on proven leadership strategies and enhance my skills, which I have applied on many occasions in my practice. Being able to talk to multisite hospital medicine group colleagues in person helped me to learn best practices in how to successfully manage the integration of 14 hospital medicine community hospital sites across Mayo Midwest. I was able to get ideas on effectively understanding and managing challenges, like recruitment retention, staffing to workloads, and scope of practice, among others. SHM promotes peer-to-peer learning and has helped me share and learn best practices as it relates to the clinical and nonclinical aspect of the practice of hospital medicine.
 

What one piece of advice would you give fellow hospitalists during this transformational time in health care?

This is an exciting time in health care, especially for hospital medicine professionals, who are at the forefront of providing value-based care. Every change is an opportunity to improve and innovate; the best way to handle change is to embrace and lead it.

Ms. Steele is SHM’s communications coordinator.

To apply for the Fellow in Hospital Medicine designation, visit www.hospitalmedicine.org/fellows.




 

Editor’s note: Each month, SHM puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Umesh Sharma, MD, MBA, FHM, chair of the division of community hospital medicine at Mayo Clinic. Umesh became a Fellow in Hospital Medicine in 2016 and has found great value in attending the annual meeting each year.

What inspired you to join SHM, and what prompted you to apply for the Fellow in Hospital Medicine designation?

How did you use SHM resources to help you in your pathway to Fellowship in Hospital Medicine?

There are specific eligibility requirements for the Fellow in Hospital Medicine designation, including a minimum of 5 years as a practicing hospitalist and 3 years as an SHM member, endorsements from two active members, regular meeting attendance and more. SHM provides a checklist for Fellow applicants online and an FAQ page to make the application process as user-friendly as possible. A friend of mine, Dr. Deepak Pahuja, is a Fellow, and he mentored me throughout the process.
 

How else has SHM contributed to your professional growth and provided you with tools you need to lead hospitalists at Mayo Clinic?

There are many resources that SHM provides to help with professional growth both online and at in-person meetings. I referenced the Key Principles and Characteristics of an Effective Hospital Medicine Group, an online assessment guide, in my role as department chair in La Crosse, Wisc., to resurrect a hospital medicine group, secure resources, hire career hospitalists, and create a well-functioning, well-managed, efficient, effective group with zero turnover during a span of 4 years.

By focusing on the leadership track at annual meetings, I have been able to gain knowledge on proven leadership strategies and enhance my skills, which I have applied on many occasions in my practice. Being able to talk to multisite hospital medicine group colleagues in person helped me to learn best practices in how to successfully manage the integration of 14 hospital medicine community hospital sites across Mayo Midwest. I was able to get ideas on effectively understanding and managing challenges, like recruitment retention, staffing to workloads, and scope of practice, among others. SHM promotes peer-to-peer learning and has helped me share and learn best practices as it relates to the clinical and nonclinical aspect of the practice of hospital medicine.
 

What one piece of advice would you give fellow hospitalists during this transformational time in health care?

This is an exciting time in health care, especially for hospital medicine professionals, who are at the forefront of providing value-based care. Every change is an opportunity to improve and innovate; the best way to handle change is to embrace and lead it.

Ms. Steele is SHM’s communications coordinator.

To apply for the Fellow in Hospital Medicine designation, visit www.hospitalmedicine.org/fellows.




 

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

B-cell precursor ALL

Blinatumomab has demonstrated activity in high-risk patients with Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP-ALL), according to research published in the Journal of Clinical Oncology.

This phase 2 trial enrolled patients with relapsed or refractory Ph+ BCP-ALL who had failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blinatumomab produced a complete response (CR) in 31% of these patients, the median relapse-free survival was 6.7 months, and the median overall survival was 7.1 months.

The most common adverse events (AEs) were pyrexia, neurologic events, febrile neutropenia, and headache.

“Patients with Ph+ relapsed or refractory B-cell precursor ALL typically have lower remission rates, poor long-term prognosis, and shorter duration of remission than patients with Philadelphia chromosome-negative disease, and are especially in need of new treatment options beyond TKIs,” said study author Anthony Stein, MD, of City of Hope in Duarte, California.

“Results from this phase 2 study showed blinatumomab induced complete remission in these high-risk patients, regardless of prior TKI therapy or mutational status . . . .”

This study was supported by Amgen, the company developing and marketing blinatumomab.

The trial enrolled 45 patients with relapsed or refractory Ph+ BCP-ALL. Fifty-nine percent of patients had additional cytogenetic abnormalities. Forty-six percent had ABL1 kinase domain mutations, and 27% had the T315I mutation.

The patients’ median age was 55 (range, 23-78), and 55% were male. The median baseline bone marrow blast percentage was 80% (range, 6% to 98%).

Eighty-four percent of patients had received at least 2 prior TKIs. All patients were refractory to (56%), had relapsed on (33%), or progressed after (11%) TKI therapy. Forty-four percent of patients had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT).

The patients received blinatumomab in 28-day cycles by continuous intravenous infusion. The median number of cycles received was 2 (range, 1-5).

Efficacy

Thirty-six percent of patients (n=16) had a CR or CR with partial hematologic recovery (CRh) during the first 2 cycles of treatment. For 31% of patients (n=14), their best response was a CR.

Eighty-eight percent of patients who achieved a CR/CRh (n=14) achieved minimal residual disease (MRD) negativity.

Forty percent of patients with a T315I mutation had a CR/CRh (4/10), and all of these responders were MRD negative.

Seven responders (44%) went on to allo-HSCT, 6 of whom were transplant-naïve.

Eight of the 16 responders (50%) ultimately relapsed. Their median time to relapse was 6.7 months. Three patients relapsed during treatment, 2 relapsed without undergoing allo-HSCT, and 3 relapsed after allo-HSCT.

Seven responders (44%) were still alive and had not relapsed at last follow-up. The remaining responder died in CR after allo-HSCT.

The median relapse-free survival was 6.7 months, with or without censoring for allo-HSCT. And the median overall survival was 7.1 months, with or without censoring for allo-HSCT.

Safety

The most common AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Nearly half of patients (47%) had neurologic events.

Eighty-two percent of patients had grade 3 or higher treatment-emergent AEs. The most common were febrile neutropenia (27%), thrombocytopenia (22%), and anemia (16%).

Forty-four percent of patients had grade 3 or higher AEs that were considered possibly related to blinatumomab. The most common were febrile neutropenia and increased levels of alanine aminotransferase (11% each).

Five patients had fatal AEs—multiorgan failure, sepsis, septic shock, cerebral hemorrhage, and respiratory failure. The case of septic shock was considered related to treatment with blinatumomab.

Three patients developed cytokine release syndrome (all grade 1 or 2), but none of them had their treatment interrupted or discontinued as a result.

Three patients had grade 3 neurologic events, and 1 of these events (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL). 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL). 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL).