Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

Drug Stops Dangerous Bleeding in Patients Taking Factor Xa Inhibitors

The experimental drug andexanet is associated with control of serious bleeding in patients taking a common class of anticoagulants known as Factor Xa inhibitors, according to interim clinical trial results. Factor Xa inhibitors elevate the risk of serious bleeding. If approved by the FDA, andexanet would be the first agent available to directly reverse the effects of Factor Xa inhibition if bleeding occurs.

Factor Xa inhibitors, which inhibit a protein involved in the formation of blood clots, are commonly prescribed for patients who are at high risk for stroke and venous thrombosis. Because Factor Xa inhibitors and other anticoagulants reduce the body’s ability to form a blood clot, these drugs can also increase the risk of uncontrolled bleeding. When this happens, it can be challenging for doctors to stop the bleeding. About 25% of patients who experience bleeding in the brain while taking a Factor Xa inhibitor die.

“Unlike for some other anticoagulants, there is currently no approved reversal agent for Factor Xa inhibitors,” said Stuart Connolly, MD, Professor of Medicine at McMaster University in Hamilton, Ontario. “Factor Xa inhibitors are already widely used because of their excellent efficacy and safety profile. However, some physicians and patients may choose to use other anticoagulant drugs because they have a reversal agent, rather than using one of the Factor Xa inhibitors. Having a safe and effective reversal agent available will benefit patients with acute bleeding.”

About 2.9 million people in the United States currently take Factor Xa inhibitors. Of these people, most are older and have illnesses, such as heart failure, that put them at high risk for cardiovascular problems. Approximately 84,000 patients taking Factor Xa inhibitors are hospitalized for major bleeding each year, according to a recent analysis of the MarketScan Commercial and Medicare databases. The most common types of major bleeds include bleeding in the brain, sometimes resulting from a fall, and gastrointestinal bleeding.

Andexanet is a recombinant modified Factor Xa molecule designed to bind to and disable Factor Xa inhibitors, thereby allowing Factor Xa produced by the body to play its normal role in the formation of blood clots. In earlier trials performed in healthy volunteers, andexanet rapidly reversed the anticoagulant effect of Factor Xa inhibitors without causing any significant safety problems.

ANNEXA-4 is an ongoing clinical trial that uses andexanet to help treat patients experiencing major bleeding while taking Factor Xa inhibitors. The interim analysis includes data on safety outcomes for 227 patients and adjudicated efficacy outcomes for 132 patients enrolled at centers in the US, Canada, and Europe. All trial participants presented with acute major bleeding within 18 hours of taking one of four Factor Xa inhibitors (ie, apixaban, rivaroxaban, edoxaban, or enoxaparin). Patients received an injection of andexanet followed by a two-hour infusion of the drug, with the dosage determined based on the specific Factor Xa inhibitor the patient was taking and how long it had been since the last dose.

The trial assesses the drug’s efficacy in terms of the following two coprimary endpoints: reduction in anti-Factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. The interim results show that median anti-Factor Xa inhibitor activity was reduced by 88% for patients taking rivaroxaban, 91% for patients taking apixaban, and 75% for patients taking enoxaparin. Few patients in the study had received edoxaban. Excellent or good clinical hemostasis was achieved in 83% of patients overall.

Safety of andexanet was assessed in all 227 patients. At 30 days, 12% of patients had died, and 11% had a thrombotic event (ie, stroke, heart attack, or blood clot in the legs). These rates of adverse events are in line with what would be expected, given the underlying medical condition of the patients in the trial and the fact that many had not resumed anticoagulant treatment during the 30 days after receiving andexanet, Dr. Connolly said. The trial was funded by Portola Pharmaceuticals, maker of andexanet.

Low-Dose Triple Pill Lowers Blood Pressure More Than Usual Care

A pill combining low doses of three blood pressure–lowering medications significantly increased the number of patients reaching blood pressure targets, compared with usual care, said researchers. The combination therapy was not associated with a significant increase in adverse effects.

“Most people—70%—reached blood pressure targets with the triple pill. The benefits were seen straight away and maintained until six months, whereas with usual care, control rates were 55% at six months and even lower earlier in the trial,” said Ruth Webster, MBBS, Head of Research Programs at the George Institute for Global Health at the University of New South Wales in Sydney. “Based on our findings, we conclude that this new method of using blood pressure–lowering drugs was more effective and just as safe as current approaches.”

Despite the availability of effective blood pressure–lowering drugs, high blood pressure remains a major problem around the world, said Dr. Webster. Effectively treating high blood pressure can help to prevent strokes, heart attacks, and kidney problems. Globally, however, many people with high blood pressure receive no treatment, and only about a third of those who are treated achieve recommended reductions in blood pressure. Achieving desired reductions in blood pressure often requires treatment with more than one medication, which increases the complexity of treatment. Patients often have difficulty adhering to regimens that involve taking multiple pills every day.

This study was the first large trial designed to test the theory that starting treatment with low doses of three drugs could achieve better blood pressure control, compared with usual care, and that combining these drugs in a single pill would make it easier for doctors to prescribe treatment and for patients to adhere to it, said Dr. Webster.

The TRIUMPH trial, which was conducted in Sri Lanka, enrolled 700 patients (58% women) whose average age was 56. Trial participants had an average blood pressure of 154/90 mm Hg. Approximately 59% were receiving no treatment for high blood pressure before they enrolled in the trial. In addition to high blood pressure, 32% of participants had diabetes or chronic kidney disease.

Patients were randomly assigned to receive either the combination pill or usual care. The combination pill, or triple pill, consisted of the blood pressure medications telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (12.5 mg). These medications use different mechanisms to reduce blood pressure by relaxing the blood vessels. Usual care meant that patients received their doctors’ choice of blood pressure–lowering medication.

The trial’s primary end point was the proportion of patients who achieved a blood pressure target of 140/90 mm Hg or less (130/80 mm Hg or less in those with diabetes or chronic kidney disease) at six months.

Compared with patients receiving usual care, a significantly higher proportion of patients receiving the triple pill achieved their target blood pressure at six months. The average reduction in blood pressure was 8.7 mm Hg for participants receiving the triple pill and 4.5 mm Hg for those receiving usual care. At six months, 83% of participants in the triple pill group were still receiving the combination pill, and one-third of those in the usual-care group was receiving at least two blood pressure–lowering drugs.

The maximum difference between the two groups of patients was observed at six weeks after starting treatment, when 68% of those receiving the triple pill had achieved a blood pressure within their target range, compared with 44% of those receiving usual care. This result represented a 53% reduction in the risk for high blood pressure for patients receiving the triple pill, said Dr. Webster.

Rates of participants having to change treatment due to side effects were not significantly different between the two groups (6.6% for the triple pill and 6.8% for usual care). This finding should allay concerns that use of the three-drug combination pill could lead to an unacceptable increase in adverse medication side effects, said Dr. Webster.

Each of the drugs in the triple pill is highly effective in reducing blood pressure and preventing deaths and illness due to heart disease and strokes, she added. Each drug represents a different class of blood pressure medication, and previous studies have shown that combining such drugs results in synergistic effects.

“The most urgent need for innovative strategies to control blood pressure is in low- and middle-income countries,” said Dr. Webster.

The study’s findings are also important for high-income countries, she said. “A control rate of 70% would be a considerable improvement even in high-income settings. Most hypertension guidelines in these countries do not recommend combination blood pressure–lowering therapy for initial treatment in all people,” she said. “Our findings should prompt reconsideration of recommendations around the use of combination therapy.”

An inevitable consequence of a necessarily unblinded study is that doctors might manage patients differently, depending on the assigned treatment. It is important to note, however, that this trial was designed to evaluate a new strategy of care in a real-world setting, said Dr. Webster. To minimize the risk of bias in measuring the main outcomes, the number of patient visits was identical in both groups, and all outcomes were standardized and objectively documented, she said.

Metoprolol May Increase Postsurgical Risk of Stroke or Death

During the 12 months after undergoing noncardiac surgery, patients with heart disease or at risk for heart disease who are treated with the beta blocker metoprolol for 30 days are less likely than patients who receive a placebo to have a heart attack, but more likely to die or have a stroke, said researchers.

These follow-up findings confirm that an increased risk for death or stroke persists at one year post surgery in patients treated with metoprolol, said P. J. Devereaux, MD, PhD, Director of Cardiology at McMaster University in Hamilton, Ontario. Previously reported results from the same study at 30 days post surgery showed a similar pattern, with a reduction in heart attacks, but increases in deaths and strokes.

“Our results suggest at one year, for every 1,000 patients having noncardiac surgery, treatment with metoprolol would prevent heart attacks in 12 patients, but would result in an excess of 13 deaths and six strokes,” said Dr. Devereaux.

“While there is little doubt that some patients benefit from receiving beta blockers during the period immediately before and after noncardiac surgery, these data show that at least as many patients are seriously harmed,” he said. “These data tell us that we need to exercise caution when using beta blockers in this setting until we figure out how to mitigate the substantial risks and enable all patients to obtain the potential benefits of this intervention.”

Beta blockers work by slowing the heart rate and relaxing the blood vessels, which, in turn, reduces blood pressure. The problem is that during the period immediately after major noncardiac surgery (such as a hip or knee replacement, bowel resection, or abdominal aortic aneurysm repair), patients are usually treated with opioid medications to relieve pain, said Dr. Devereaux. The effects of those medications may mask drops in blood pressure or heart rate to dangerously low levels. “Hypotension is common in this setting and is a main contributor to the adverse effects resulting from perioperative beta blockers,” he said.

Patients who become hypotensive for whatever reason after surgery (eg, sepsis, bleeding, or heart failure) find their problem exacerbated when they are receiving a beta blocker, which further lowers blood pressure and makes treating hypotension more challenging.

The PeriOperative Ischemic Eval­uation (POISE) trial enrolled 8,351 patients in 23 countries. Eligible patients were age 45 or older and had a history of heart disease, blood-vessel disease, stroke, congestive heart failure, or other health problems such as diabetes or impaired kidney function. Patients’ median age was 69, and 63% were men.

Patients were randomly assigned to receive metoprolol or a placebo, beginning a few hours before surgery and for 30 days afterward. Patients, health care providers, and research staff, except those analyzing data, were blinded to which group received metoprolol and which received a placebo. The study’s primary end point was a composite of the combined rate of death from heart disease, nonfatal heart attack, and nonfatal cardiac arrest after 30 days.

At one-year follow-up, fewer patients in the metoprolol group than in the placebo group had heart attacks (5% vs 6.2%), but more patients in the metoprolol group had died (9.8% vs 8.5%) or had a stroke (2% vs 1.4%).

These results followed the same pattern that had previously been seen at the 30-day follow-up: statistically fewer heart attacks in the metoprolol group (4.2% vs 5.7% in the placebo group), but statistically more deaths (3.1% vs 2.3% in the placebo group) and strokes (1% vs 0.5% in the placebo group).

Observers have suggested that the metoprolol dose in the POISE trial (200 mg/day) was too high and that a lower dose would have produced fewer adverse effects. But a lower dose might also have decreased the drug’s effectiveness in reducing heart attacks, said Dr. Devereaux, noting that the metoprolol dose in POISE only resulted in a 7-bpm lower heart rate, compared with placebo. More continuous monitoring “I believe the answer is more continuous patient monitoring during the immediate postsurgical period so that dangerous drops in heart rate or blood pressure are promptly identified and treated.”

Managing Blood Pressure in Barbershops Yields Improvements

African American men who received medical intervention aimed at controlling their high blood pressure while at the barber saw a marked drop in blood pressure in six months, according to researchers. Specifically, men who received frequent monitoring and medication management from a specially trained pharmacist who met them monthly in their barbershop lowered their systolic blood pressure by 21 mm Hg more, on average, compared with men who were encouraged by their barber to follow up with a doctor and to make healthy lifestyle choices.

While high blood pressure is a common problem among many American adults, African American men are more likely than other groups to have high blood pressure that is not adequately controlled and tend to have less contact with the health care system.

“By bringing state-of-the-art medicine directly to the people who need it on their home turf, in this case, in a barbershop, and making it both convenient and rigorous, blood pressure can be controlled just as well in African American men as in other groups,” said Ronald G. Victor, MD, Associate Director of the Smidt Heart Institute at Cedars-Sinai in Los Angeles. “If this model were scaled up and sustained, millions of lives could be saved, and many heart attacks and strokes could be prevented.”

Previous studies have shown that equipping barbers—who remain trusted, consistent, and convenient figures for many African American men—with health information can positively affect health. The new study is unique because it combined barbershop-based health outreach with the delivery of care by medical professionals at the barbershop and evaluated subsequent efficacy with a randomized trial.

The study recruited 319 men at 52 Los Angeles County barbershops. All the men had systolic blood pressure over 140 mm Hg, based on multiple measurements taken on two different days. The men ranged in age from 35 to 71 and, on average, had patronized their barbershop for more than a decade and had their hair cut twice a month.

In total, 303 men completed the study—representing a 95% cohort retention—and all received an intervention designed to help them lower their blood pressure.

A little over half of the men (171) were randomly assigned to receive health education from their barbers, who were trained to use a National Heart, Lung, and Blood Institute–developed script to encourage the men to visit their doctors and get their blood pressure under control.

The remaining men (132) were randomly assigned to receive regular monitoring (at least once per month) and active medication management by a pharmacist who met them at the barbershop. During each pharmacist visit, the men in this group received a blood pressure evaluation and a finger-stick blood test, which the pharmacist used to evaluate each man’s response to blood pressure medications and adjust prescriptions as needed. The pharmacists worked directly with the men under a collaborative care agreement with their primary care doctors.

On average, men who interacted only with their barber and were referred to their own doctor saw their systolic blood pressure decrease from 155 mm Hg at the start of the study to 145 mm Hg after six months. Diastolic blood pressured decreased by 4 mm Hg in this group. By contrast, men who interacted with their barber and a pharmacist saw their systolic blood pressure decrease from 153 mm Hg at the start of the study to 126 mm Hg after six months, along with a decrease in diastolic blood pressure of 18 mm Hg.

Under current American College of Cardiology–American Heart Association guidelines, blood pressure below 130/80 mm Hg is considered normal. At the end of six months, 64% of participants who saw a pharmacist had blood pressure in the normal range, compared with 12% of participants who were referred to their own doctor. “This is a large effect for a hypertension trial of any kind,” said Dr. Victor. “We are excited about the results.” Researchers are studying whether the effects can be sustained for an additional six months.

Drug Stops Dangerous Bleeding in Patients Taking Factor Xa Inhibitors

The experimental drug andexanet is associated with control of serious bleeding in patients taking a common class of anticoagulants known as Factor Xa inhibitors, according to interim clinical trial results. Factor Xa inhibitors elevate the risk of serious bleeding. If approved by the FDA, andexanet would be the first agent available to directly reverse the effects of Factor Xa inhibition if bleeding occurs.

Factor Xa inhibitors, which inhibit a protein involved in the formation of blood clots, are commonly prescribed for patients who are at high risk for stroke and venous thrombosis. Because Factor Xa inhibitors and other anticoagulants reduce the body’s ability to form a blood clot, these drugs can also increase the risk of uncontrolled bleeding. When this happens, it can be challenging for doctors to stop the bleeding. About 25% of patients who experience bleeding in the brain while taking a Factor Xa inhibitor die.

“Unlike for some other anticoagulants, there is currently no approved reversal agent for Factor Xa inhibitors,” said Stuart Connolly, MD, Professor of Medicine at McMaster University in Hamilton, Ontario. “Factor Xa inhibitors are already widely used because of their excellent efficacy and safety profile. However, some physicians and patients may choose to use other anticoagulant drugs because they have a reversal agent, rather than using one of the Factor Xa inhibitors. Having a safe and effective reversal agent available will benefit patients with acute bleeding.”

About 2.9 million people in the United States currently take Factor Xa inhibitors. Of these people, most are older and have illnesses, such as heart failure, that put them at high risk for cardiovascular problems. Approximately 84,000 patients taking Factor Xa inhibitors are hospitalized for major bleeding each year, according to a recent analysis of the MarketScan Commercial and Medicare databases. The most common types of major bleeds include bleeding in the brain, sometimes resulting from a fall, and gastrointestinal bleeding.

Andexanet is a recombinant modified Factor Xa molecule designed to bind to and disable Factor Xa inhibitors, thereby allowing Factor Xa produced by the body to play its normal role in the formation of blood clots. In earlier trials performed in healthy volunteers, andexanet rapidly reversed the anticoagulant effect of Factor Xa inhibitors without causing any significant safety problems.

ANNEXA-4 is an ongoing clinical trial that uses andexanet to help treat patients experiencing major bleeding while taking Factor Xa inhibitors. The interim analysis includes data on safety outcomes for 227 patients and adjudicated efficacy outcomes for 132 patients enrolled at centers in the US, Canada, and Europe. All trial participants presented with acute major bleeding within 18 hours of taking one of four Factor Xa inhibitors (ie, apixaban, rivaroxaban, edoxaban, or enoxaparin). Patients received an injection of andexanet followed by a two-hour infusion of the drug, with the dosage determined based on the specific Factor Xa inhibitor the patient was taking and how long it had been since the last dose.

The trial assesses the drug’s efficacy in terms of the following two coprimary endpoints: reduction in anti-Factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. The interim results show that median anti-Factor Xa inhibitor activity was reduced by 88% for patients taking rivaroxaban, 91% for patients taking apixaban, and 75% for patients taking enoxaparin. Few patients in the study had received edoxaban. Excellent or good clinical hemostasis was achieved in 83% of patients overall.

Safety of andexanet was assessed in all 227 patients. At 30 days, 12% of patients had died, and 11% had a thrombotic event (ie, stroke, heart attack, or blood clot in the legs). These rates of adverse events are in line with what would be expected, given the underlying medical condition of the patients in the trial and the fact that many had not resumed anticoagulant treatment during the 30 days after receiving andexanet, Dr. Connolly said. The trial was funded by Portola Pharmaceuticals, maker of andexanet.

Low-Dose Triple Pill Lowers Blood Pressure More Than Usual Care

A pill combining low doses of three blood pressure–lowering medications significantly increased the number of patients reaching blood pressure targets, compared with usual care, said researchers. The combination therapy was not associated with a significant increase in adverse effects.

“Most people—70%—reached blood pressure targets with the triple pill. The benefits were seen straight away and maintained until six months, whereas with usual care, control rates were 55% at six months and even lower earlier in the trial,” said Ruth Webster, MBBS, Head of Research Programs at the George Institute for Global Health at the University of New South Wales in Sydney. “Based on our findings, we conclude that this new method of using blood pressure–lowering drugs was more effective and just as safe as current approaches.”

Despite the availability of effective blood pressure–lowering drugs, high blood pressure remains a major problem around the world, said Dr. Webster. Effectively treating high blood pressure can help to prevent strokes, heart attacks, and kidney problems. Globally, however, many people with high blood pressure receive no treatment, and only about a third of those who are treated achieve recommended reductions in blood pressure. Achieving desired reductions in blood pressure often requires treatment with more than one medication, which increases the complexity of treatment. Patients often have difficulty adhering to regimens that involve taking multiple pills every day.

This study was the first large trial designed to test the theory that starting treatment with low doses of three drugs could achieve better blood pressure control, compared with usual care, and that combining these drugs in a single pill would make it easier for doctors to prescribe treatment and for patients to adhere to it, said Dr. Webster.

The TRIUMPH trial, which was conducted in Sri Lanka, enrolled 700 patients (58% women) whose average age was 56. Trial participants had an average blood pressure of 154/90 mm Hg. Approximately 59% were receiving no treatment for high blood pressure before they enrolled in the trial. In addition to high blood pressure, 32% of participants had diabetes or chronic kidney disease.

Patients were randomly assigned to receive either the combination pill or usual care. The combination pill, or triple pill, consisted of the blood pressure medications telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (12.5 mg). These medications use different mechanisms to reduce blood pressure by relaxing the blood vessels. Usual care meant that patients received their doctors’ choice of blood pressure–lowering medication.

The trial’s primary end point was the proportion of patients who achieved a blood pressure target of 140/90 mm Hg or less (130/80 mm Hg or less in those with diabetes or chronic kidney disease) at six months.

Compared with patients receiving usual care, a significantly higher proportion of patients receiving the triple pill achieved their target blood pressure at six months. The average reduction in blood pressure was 8.7 mm Hg for participants receiving the triple pill and 4.5 mm Hg for those receiving usual care. At six months, 83% of participants in the triple pill group were still receiving the combination pill, and one-third of those in the usual-care group was receiving at least two blood pressure–lowering drugs.

The maximum difference between the two groups of patients was observed at six weeks after starting treatment, when 68% of those receiving the triple pill had achieved a blood pressure within their target range, compared with 44% of those receiving usual care. This result represented a 53% reduction in the risk for high blood pressure for patients receiving the triple pill, said Dr. Webster.

Rates of participants having to change treatment due to side effects were not significantly different between the two groups (6.6% for the triple pill and 6.8% for usual care). This finding should allay concerns that use of the three-drug combination pill could lead to an unacceptable increase in adverse medication side effects, said Dr. Webster.

Each of the drugs in the triple pill is highly effective in reducing blood pressure and preventing deaths and illness due to heart disease and strokes, she added. Each drug represents a different class of blood pressure medication, and previous studies have shown that combining such drugs results in synergistic effects.

“The most urgent need for innovative strategies to control blood pressure is in low- and middle-income countries,” said Dr. Webster.

The study’s findings are also important for high-income countries, she said. “A control rate of 70% would be a considerable improvement even in high-income settings. Most hypertension guidelines in these countries do not recommend combination blood pressure–lowering therapy for initial treatment in all people,” she said. “Our findings should prompt reconsideration of recommendations around the use of combination therapy.”

An inevitable consequence of a necessarily unblinded study is that doctors might manage patients differently, depending on the assigned treatment. It is important to note, however, that this trial was designed to evaluate a new strategy of care in a real-world setting, said Dr. Webster. To minimize the risk of bias in measuring the main outcomes, the number of patient visits was identical in both groups, and all outcomes were standardized and objectively documented, she said.

Metoprolol May Increase Postsurgical Risk of Stroke or Death

During the 12 months after undergoing noncardiac surgery, patients with heart disease or at risk for heart disease who are treated with the beta blocker metoprolol for 30 days are less likely than patients who receive a placebo to have a heart attack, but more likely to die or have a stroke, said researchers.

These follow-up findings confirm that an increased risk for death or stroke persists at one year post surgery in patients treated with metoprolol, said P. J. Devereaux, MD, PhD, Director of Cardiology at McMaster University in Hamilton, Ontario. Previously reported results from the same study at 30 days post surgery showed a similar pattern, with a reduction in heart attacks, but increases in deaths and strokes.

“Our results suggest at one year, for every 1,000 patients having noncardiac surgery, treatment with metoprolol would prevent heart attacks in 12 patients, but would result in an excess of 13 deaths and six strokes,” said Dr. Devereaux.

“While there is little doubt that some patients benefit from receiving beta blockers during the period immediately before and after noncardiac surgery, these data show that at least as many patients are seriously harmed,” he said. “These data tell us that we need to exercise caution when using beta blockers in this setting until we figure out how to mitigate the substantial risks and enable all patients to obtain the potential benefits of this intervention.”

Beta blockers work by slowing the heart rate and relaxing the blood vessels, which, in turn, reduces blood pressure. The problem is that during the period immediately after major noncardiac surgery (such as a hip or knee replacement, bowel resection, or abdominal aortic aneurysm repair), patients are usually treated with opioid medications to relieve pain, said Dr. Devereaux. The effects of those medications may mask drops in blood pressure or heart rate to dangerously low levels. “Hypotension is common in this setting and is a main contributor to the adverse effects resulting from perioperative beta blockers,” he said.

Patients who become hypotensive for whatever reason after surgery (eg, sepsis, bleeding, or heart failure) find their problem exacerbated when they are receiving a beta blocker, which further lowers blood pressure and makes treating hypotension more challenging.

The PeriOperative Ischemic Eval­uation (POISE) trial enrolled 8,351 patients in 23 countries. Eligible patients were age 45 or older and had a history of heart disease, blood-vessel disease, stroke, congestive heart failure, or other health problems such as diabetes or impaired kidney function. Patients’ median age was 69, and 63% were men.

Patients were randomly assigned to receive metoprolol or a placebo, beginning a few hours before surgery and for 30 days afterward. Patients, health care providers, and research staff, except those analyzing data, were blinded to which group received metoprolol and which received a placebo. The study’s primary end point was a composite of the combined rate of death from heart disease, nonfatal heart attack, and nonfatal cardiac arrest after 30 days.

At one-year follow-up, fewer patients in the metoprolol group than in the placebo group had heart attacks (5% vs 6.2%), but more patients in the metoprolol group had died (9.8% vs 8.5%) or had a stroke (2% vs 1.4%).

These results followed the same pattern that had previously been seen at the 30-day follow-up: statistically fewer heart attacks in the metoprolol group (4.2% vs 5.7% in the placebo group), but statistically more deaths (3.1% vs 2.3% in the placebo group) and strokes (1% vs 0.5% in the placebo group).

Observers have suggested that the metoprolol dose in the POISE trial (200 mg/day) was too high and that a lower dose would have produced fewer adverse effects. But a lower dose might also have decreased the drug’s effectiveness in reducing heart attacks, said Dr. Devereaux, noting that the metoprolol dose in POISE only resulted in a 7-bpm lower heart rate, compared with placebo. More continuous monitoring “I believe the answer is more continuous patient monitoring during the immediate postsurgical period so that dangerous drops in heart rate or blood pressure are promptly identified and treated.”

Managing Blood Pressure in Barbershops Yields Improvements

African American men who received medical intervention aimed at controlling their high blood pressure while at the barber saw a marked drop in blood pressure in six months, according to researchers. Specifically, men who received frequent monitoring and medication management from a specially trained pharmacist who met them monthly in their barbershop lowered their systolic blood pressure by 21 mm Hg more, on average, compared with men who were encouraged by their barber to follow up with a doctor and to make healthy lifestyle choices.

While high blood pressure is a common problem among many American adults, African American men are more likely than other groups to have high blood pressure that is not adequately controlled and tend to have less contact with the health care system.

“By bringing state-of-the-art medicine directly to the people who need it on their home turf, in this case, in a barbershop, and making it both convenient and rigorous, blood pressure can be controlled just as well in African American men as in other groups,” said Ronald G. Victor, MD, Associate Director of the Smidt Heart Institute at Cedars-Sinai in Los Angeles. “If this model were scaled up and sustained, millions of lives could be saved, and many heart attacks and strokes could be prevented.”

Previous studies have shown that equipping barbers—who remain trusted, consistent, and convenient figures for many African American men—with health information can positively affect health. The new study is unique because it combined barbershop-based health outreach with the delivery of care by medical professionals at the barbershop and evaluated subsequent efficacy with a randomized trial.

The study recruited 319 men at 52 Los Angeles County barbershops. All the men had systolic blood pressure over 140 mm Hg, based on multiple measurements taken on two different days. The men ranged in age from 35 to 71 and, on average, had patronized their barbershop for more than a decade and had their hair cut twice a month.

In total, 303 men completed the study—representing a 95% cohort retention—and all received an intervention designed to help them lower their blood pressure.

A little over half of the men (171) were randomly assigned to receive health education from their barbers, who were trained to use a National Heart, Lung, and Blood Institute–developed script to encourage the men to visit their doctors and get their blood pressure under control.

The remaining men (132) were randomly assigned to receive regular monitoring (at least once per month) and active medication management by a pharmacist who met them at the barbershop. During each pharmacist visit, the men in this group received a blood pressure evaluation and a finger-stick blood test, which the pharmacist used to evaluate each man’s response to blood pressure medications and adjust prescriptions as needed. The pharmacists worked directly with the men under a collaborative care agreement with their primary care doctors.

On average, men who interacted only with their barber and were referred to their own doctor saw their systolic blood pressure decrease from 155 mm Hg at the start of the study to 145 mm Hg after six months. Diastolic blood pressured decreased by 4 mm Hg in this group. By contrast, men who interacted with their barber and a pharmacist saw their systolic blood pressure decrease from 153 mm Hg at the start of the study to 126 mm Hg after six months, along with a decrease in diastolic blood pressure of 18 mm Hg.

Under current American College of Cardiology–American Heart Association guidelines, blood pressure below 130/80 mm Hg is considered normal. At the end of six months, 64% of participants who saw a pharmacist had blood pressure in the normal range, compared with 12% of participants who were referred to their own doctor. “This is a large effect for a hypertension trial of any kind,” said Dr. Victor. “We are excited about the results.” Researchers are studying whether the effects can be sustained for an additional six months.

Drug Stops Dangerous Bleeding in Patients Taking Factor Xa Inhibitors

The experimental drug andexanet is associated with control of serious bleeding in patients taking a common class of anticoagulants known as Factor Xa inhibitors, according to interim clinical trial results. Factor Xa inhibitors elevate the risk of serious bleeding. If approved by the FDA, andexanet would be the first agent available to directly reverse the effects of Factor Xa inhibition if bleeding occurs.

Factor Xa inhibitors, which inhibit a protein involved in the formation of blood clots, are commonly prescribed for patients who are at high risk for stroke and venous thrombosis. Because Factor Xa inhibitors and other anticoagulants reduce the body’s ability to form a blood clot, these drugs can also increase the risk of uncontrolled bleeding. When this happens, it can be challenging for doctors to stop the bleeding. About 25% of patients who experience bleeding in the brain while taking a Factor Xa inhibitor die.

“Unlike for some other anticoagulants, there is currently no approved reversal agent for Factor Xa inhibitors,” said Stuart Connolly, MD, Professor of Medicine at McMaster University in Hamilton, Ontario. “Factor Xa inhibitors are already widely used because of their excellent efficacy and safety profile. However, some physicians and patients may choose to use other anticoagulant drugs because they have a reversal agent, rather than using one of the Factor Xa inhibitors. Having a safe and effective reversal agent available will benefit patients with acute bleeding.”

About 2.9 million people in the United States currently take Factor Xa inhibitors. Of these people, most are older and have illnesses, such as heart failure, that put them at high risk for cardiovascular problems. Approximately 84,000 patients taking Factor Xa inhibitors are hospitalized for major bleeding each year, according to a recent analysis of the MarketScan Commercial and Medicare databases. The most common types of major bleeds include bleeding in the brain, sometimes resulting from a fall, and gastrointestinal bleeding.

Andexanet is a recombinant modified Factor Xa molecule designed to bind to and disable Factor Xa inhibitors, thereby allowing Factor Xa produced by the body to play its normal role in the formation of blood clots. In earlier trials performed in healthy volunteers, andexanet rapidly reversed the anticoagulant effect of Factor Xa inhibitors without causing any significant safety problems.

ANNEXA-4 is an ongoing clinical trial that uses andexanet to help treat patients experiencing major bleeding while taking Factor Xa inhibitors. The interim analysis includes data on safety outcomes for 227 patients and adjudicated efficacy outcomes for 132 patients enrolled at centers in the US, Canada, and Europe. All trial participants presented with acute major bleeding within 18 hours of taking one of four Factor Xa inhibitors (ie, apixaban, rivaroxaban, edoxaban, or enoxaparin). Patients received an injection of andexanet followed by a two-hour infusion of the drug, with the dosage determined based on the specific Factor Xa inhibitor the patient was taking and how long it had been since the last dose.

The trial assesses the drug’s efficacy in terms of the following two coprimary endpoints: reduction in anti-Factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. The interim results show that median anti-Factor Xa inhibitor activity was reduced by 88% for patients taking rivaroxaban, 91% for patients taking apixaban, and 75% for patients taking enoxaparin. Few patients in the study had received edoxaban. Excellent or good clinical hemostasis was achieved in 83% of patients overall.

Safety of andexanet was assessed in all 227 patients. At 30 days, 12% of patients had died, and 11% had a thrombotic event (ie, stroke, heart attack, or blood clot in the legs). These rates of adverse events are in line with what would be expected, given the underlying medical condition of the patients in the trial and the fact that many had not resumed anticoagulant treatment during the 30 days after receiving andexanet, Dr. Connolly said. The trial was funded by Portola Pharmaceuticals, maker of andexanet.

Low-Dose Triple Pill Lowers Blood Pressure More Than Usual Care

A pill combining low doses of three blood pressure–lowering medications significantly increased the number of patients reaching blood pressure targets, compared with usual care, said researchers. The combination therapy was not associated with a significant increase in adverse effects.

“Most people—70%—reached blood pressure targets with the triple pill. The benefits were seen straight away and maintained until six months, whereas with usual care, control rates were 55% at six months and even lower earlier in the trial,” said Ruth Webster, MBBS, Head of Research Programs at the George Institute for Global Health at the University of New South Wales in Sydney. “Based on our findings, we conclude that this new method of using blood pressure–lowering drugs was more effective and just as safe as current approaches.”

Despite the availability of effective blood pressure–lowering drugs, high blood pressure remains a major problem around the world, said Dr. Webster. Effectively treating high blood pressure can help to prevent strokes, heart attacks, and kidney problems. Globally, however, many people with high blood pressure receive no treatment, and only about a third of those who are treated achieve recommended reductions in blood pressure. Achieving desired reductions in blood pressure often requires treatment with more than one medication, which increases the complexity of treatment. Patients often have difficulty adhering to regimens that involve taking multiple pills every day.

This study was the first large trial designed to test the theory that starting treatment with low doses of three drugs could achieve better blood pressure control, compared with usual care, and that combining these drugs in a single pill would make it easier for doctors to prescribe treatment and for patients to adhere to it, said Dr. Webster.

The TRIUMPH trial, which was conducted in Sri Lanka, enrolled 700 patients (58% women) whose average age was 56. Trial participants had an average blood pressure of 154/90 mm Hg. Approximately 59% were receiving no treatment for high blood pressure before they enrolled in the trial. In addition to high blood pressure, 32% of participants had diabetes or chronic kidney disease.

Patients were randomly assigned to receive either the combination pill or usual care. The combination pill, or triple pill, consisted of the blood pressure medications telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (12.5 mg). These medications use different mechanisms to reduce blood pressure by relaxing the blood vessels. Usual care meant that patients received their doctors’ choice of blood pressure–lowering medication.

The trial’s primary end point was the proportion of patients who achieved a blood pressure target of 140/90 mm Hg or less (130/80 mm Hg or less in those with diabetes or chronic kidney disease) at six months.

Compared with patients receiving usual care, a significantly higher proportion of patients receiving the triple pill achieved their target blood pressure at six months. The average reduction in blood pressure was 8.7 mm Hg for participants receiving the triple pill and 4.5 mm Hg for those receiving usual care. At six months, 83% of participants in the triple pill group were still receiving the combination pill, and one-third of those in the usual-care group was receiving at least two blood pressure–lowering drugs.

The maximum difference between the two groups of patients was observed at six weeks after starting treatment, when 68% of those receiving the triple pill had achieved a blood pressure within their target range, compared with 44% of those receiving usual care. This result represented a 53% reduction in the risk for high blood pressure for patients receiving the triple pill, said Dr. Webster.

Rates of participants having to change treatment due to side effects were not significantly different between the two groups (6.6% for the triple pill and 6.8% for usual care). This finding should allay concerns that use of the three-drug combination pill could lead to an unacceptable increase in adverse medication side effects, said Dr. Webster.

Each of the drugs in the triple pill is highly effective in reducing blood pressure and preventing deaths and illness due to heart disease and strokes, she added. Each drug represents a different class of blood pressure medication, and previous studies have shown that combining such drugs results in synergistic effects.

“The most urgent need for innovative strategies to control blood pressure is in low- and middle-income countries,” said Dr. Webster.

The study’s findings are also important for high-income countries, she said. “A control rate of 70% would be a considerable improvement even in high-income settings. Most hypertension guidelines in these countries do not recommend combination blood pressure–lowering therapy for initial treatment in all people,” she said. “Our findings should prompt reconsideration of recommendations around the use of combination therapy.”

An inevitable consequence of a necessarily unblinded study is that doctors might manage patients differently, depending on the assigned treatment. It is important to note, however, that this trial was designed to evaluate a new strategy of care in a real-world setting, said Dr. Webster. To minimize the risk of bias in measuring the main outcomes, the number of patient visits was identical in both groups, and all outcomes were standardized and objectively documented, she said.

Metoprolol May Increase Postsurgical Risk of Stroke or Death

During the 12 months after undergoing noncardiac surgery, patients with heart disease or at risk for heart disease who are treated with the beta blocker metoprolol for 30 days are less likely than patients who receive a placebo to have a heart attack, but more likely to die or have a stroke, said researchers.

These follow-up findings confirm that an increased risk for death or stroke persists at one year post surgery in patients treated with metoprolol, said P. J. Devereaux, MD, PhD, Director of Cardiology at McMaster University in Hamilton, Ontario. Previously reported results from the same study at 30 days post surgery showed a similar pattern, with a reduction in heart attacks, but increases in deaths and strokes.

“Our results suggest at one year, for every 1,000 patients having noncardiac surgery, treatment with metoprolol would prevent heart attacks in 12 patients, but would result in an excess of 13 deaths and six strokes,” said Dr. Devereaux.

“While there is little doubt that some patients benefit from receiving beta blockers during the period immediately before and after noncardiac surgery, these data show that at least as many patients are seriously harmed,” he said. “These data tell us that we need to exercise caution when using beta blockers in this setting until we figure out how to mitigate the substantial risks and enable all patients to obtain the potential benefits of this intervention.”

Beta blockers work by slowing the heart rate and relaxing the blood vessels, which, in turn, reduces blood pressure. The problem is that during the period immediately after major noncardiac surgery (such as a hip or knee replacement, bowel resection, or abdominal aortic aneurysm repair), patients are usually treated with opioid medications to relieve pain, said Dr. Devereaux. The effects of those medications may mask drops in blood pressure or heart rate to dangerously low levels. “Hypotension is common in this setting and is a main contributor to the adverse effects resulting from perioperative beta blockers,” he said.

Patients who become hypotensive for whatever reason after surgery (eg, sepsis, bleeding, or heart failure) find their problem exacerbated when they are receiving a beta blocker, which further lowers blood pressure and makes treating hypotension more challenging.

The PeriOperative Ischemic Eval­uation (POISE) trial enrolled 8,351 patients in 23 countries. Eligible patients were age 45 or older and had a history of heart disease, blood-vessel disease, stroke, congestive heart failure, or other health problems such as diabetes or impaired kidney function. Patients’ median age was 69, and 63% were men.

Patients were randomly assigned to receive metoprolol or a placebo, beginning a few hours before surgery and for 30 days afterward. Patients, health care providers, and research staff, except those analyzing data, were blinded to which group received metoprolol and which received a placebo. The study’s primary end point was a composite of the combined rate of death from heart disease, nonfatal heart attack, and nonfatal cardiac arrest after 30 days.

At one-year follow-up, fewer patients in the metoprolol group than in the placebo group had heart attacks (5% vs 6.2%), but more patients in the metoprolol group had died (9.8% vs 8.5%) or had a stroke (2% vs 1.4%).

These results followed the same pattern that had previously been seen at the 30-day follow-up: statistically fewer heart attacks in the metoprolol group (4.2% vs 5.7% in the placebo group), but statistically more deaths (3.1% vs 2.3% in the placebo group) and strokes (1% vs 0.5% in the placebo group).

Observers have suggested that the metoprolol dose in the POISE trial (200 mg/day) was too high and that a lower dose would have produced fewer adverse effects. But a lower dose might also have decreased the drug’s effectiveness in reducing heart attacks, said Dr. Devereaux, noting that the metoprolol dose in POISE only resulted in a 7-bpm lower heart rate, compared with placebo. More continuous monitoring “I believe the answer is more continuous patient monitoring during the immediate postsurgical period so that dangerous drops in heart rate or blood pressure are promptly identified and treated.”

Managing Blood Pressure in Barbershops Yields Improvements

African American men who received medical intervention aimed at controlling their high blood pressure while at the barber saw a marked drop in blood pressure in six months, according to researchers. Specifically, men who received frequent monitoring and medication management from a specially trained pharmacist who met them monthly in their barbershop lowered their systolic blood pressure by 21 mm Hg more, on average, compared with men who were encouraged by their barber to follow up with a doctor and to make healthy lifestyle choices.

While high blood pressure is a common problem among many American adults, African American men are more likely than other groups to have high blood pressure that is not adequately controlled and tend to have less contact with the health care system.

“By bringing state-of-the-art medicine directly to the people who need it on their home turf, in this case, in a barbershop, and making it both convenient and rigorous, blood pressure can be controlled just as well in African American men as in other groups,” said Ronald G. Victor, MD, Associate Director of the Smidt Heart Institute at Cedars-Sinai in Los Angeles. “If this model were scaled up and sustained, millions of lives could be saved, and many heart attacks and strokes could be prevented.”

Previous studies have shown that equipping barbers—who remain trusted, consistent, and convenient figures for many African American men—with health information can positively affect health. The new study is unique because it combined barbershop-based health outreach with the delivery of care by medical professionals at the barbershop and evaluated subsequent efficacy with a randomized trial.

The study recruited 319 men at 52 Los Angeles County barbershops. All the men had systolic blood pressure over 140 mm Hg, based on multiple measurements taken on two different days. The men ranged in age from 35 to 71 and, on average, had patronized their barbershop for more than a decade and had their hair cut twice a month.

In total, 303 men completed the study—representing a 95% cohort retention—and all received an intervention designed to help them lower their blood pressure.

A little over half of the men (171) were randomly assigned to receive health education from their barbers, who were trained to use a National Heart, Lung, and Blood Institute–developed script to encourage the men to visit their doctors and get their blood pressure under control.

The remaining men (132) were randomly assigned to receive regular monitoring (at least once per month) and active medication management by a pharmacist who met them at the barbershop. During each pharmacist visit, the men in this group received a blood pressure evaluation and a finger-stick blood test, which the pharmacist used to evaluate each man’s response to blood pressure medications and adjust prescriptions as needed. The pharmacists worked directly with the men under a collaborative care agreement with their primary care doctors.

On average, men who interacted only with their barber and were referred to their own doctor saw their systolic blood pressure decrease from 155 mm Hg at the start of the study to 145 mm Hg after six months. Diastolic blood pressured decreased by 4 mm Hg in this group. By contrast, men who interacted with their barber and a pharmacist saw their systolic blood pressure decrease from 153 mm Hg at the start of the study to 126 mm Hg after six months, along with a decrease in diastolic blood pressure of 18 mm Hg.

Under current American College of Cardiology–American Heart Association guidelines, blood pressure below 130/80 mm Hg is considered normal. At the end of six months, 64% of participants who saw a pharmacist had blood pressure in the normal range, compared with 12% of participants who were referred to their own doctor. “This is a large effect for a hypertension trial of any kind,” said Dr. Victor. “We are excited about the results.” Researchers are studying whether the effects can be sustained for an additional six months.

Deborah I. Friedman, MD, MPH

Dr. Friedman is a Professor in the Departments of Neurology and Ophthalmology at the University of Texas Southwestern Medical Center in Dallas.

Neuro-ophthalmology is a small subspecialty that had its origins in ophthalmology but has always included neurologists. National neuro-ophthalmology meetings in North America began with the Rocky Mountain Neuro-Ophthalmology Course in 1975, which led to the formation of the Rocky Mountain Neuro-Ophthalmology Society in 1980. By 1986, it had 240 members and changed its name to the North American Neuro-Ophthalmology Society (NANOS). Already existing was the 1.5-day annual Frank Walsh Society meeting with its clinical-pathological correlation format, which originated at Johns Hopkins Medical School. The two societies merged in 1992. Currently, NANOS has grown to more than 650 members and is the premier organization for neuro-ophthalmology worldwide. The society’s journal, the Journal of Neuro-Ophthalmology, commenced publication in 1994, one year after the inaugural issue of Neurology Reviews.

Overcoming an early reputation for “admiring” disease, neuro-ophthalmology has evolved considerably over the past 25 years, with advances in neuroimaging, genomics, proteomics, office-based technologies, and immunology. The first multicenter, randomized trial in neuro-ophthalmology—the Optic Neuritis Treatment Trial (ONTT),¹ published 25 years ago—showed that intravenous methylprednisolone 250 mg QID for three days followed by an 11-day prednisone taper was superior to either oral prednisone (1 mg/kg for 14 days) or oral placebo (14 days), speeding the recovery of vision with slightly better vision at six months. There was a higher rate of relapse in the group assigned to receive oral prednisone. The ONTT was a pivotal event for neuro-ophthalmology, heralding a paradigm shift from observational reporting to randomized clinical trials.

Three years later, the Ischemic Optic Neuropathy Decompression Trial (IONDT)² showed that optic nerve sheath fenestration surgery, performed within 14 days of symptom onset for acute non-arteritic ischemic optic neuropathy or within 30 days in participants with a progressive course, did not improve visual acuity or visual field compared to careful follow-up and medical management at six months. Enrollees randomized to undergo surgery had a lower rate of improvement and were more likely to lose three or more lines of vision than the control group.

With this momentum, the Neuro-Ophthalmology Research Disease Investigators Consortium was formed to create infrastructure for future clinical trials of neuro-ophthalmic disorders. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)³ studied patients with idiopathic intracranial hypertension and mild visual field loss. IIHTT confirmed that acetazolamide (500 mg BID, increasing to a maximum dose of 4 grams daily) was superior to placebo treatment when combined with a supervised weight loss program, resulting in improved visual field loss, papilledema grade, weight reduction, lumbar puncture opening pressure, and quality of life. Ongoing research efforts are investigating treatments for Leber hereditary optic neuropathy, non-arteritic ischemic optic neuropathy, thyroid eye disease, rehabilitation for poststroke homonymous hemianopia and giant cell arteritis in adults, and idiopathic intracranial hypertension and optic nerve gliomas in children.

Attendance at the NANOS annual meeting continues to grow, emphasizing scientific as well as clinical neuro-ophthalmic topics. Vibrant and active neuro-ophthalmology societies in other parts of the world (eg, Europe, Japan, Australia, British Isles) contribute to the camaraderie, collegiality, collaboration, and discovery that advance our field.

Happy 25th anniversary to Neurology Reviews! The next 25 years will likely transform the field of neuro-ophthalmology as we better understand the molecular and genetic basis of neuro-ophthalmic disorders. No longer “diagnose and adios,” we anticipate significant therapeutic advancements—and perhaps cures—for individuals with severe, sight-impairing, neuro-ophthalmic conditions.

References

1. Beck RW, Clearly PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581-588.

2. The Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273(8):625-632.

3. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss. JAMA. 2014;311(16):1641-1651.

Deborah I. Friedman, MD, MPH

Dr. Friedman is a Professor in the Departments of Neurology and Ophthalmology at the University of Texas Southwestern Medical Center in Dallas.

Neuro-ophthalmology is a small subspecialty that had its origins in ophthalmology but has always included neurologists. National neuro-ophthalmology meetings in North America began with the Rocky Mountain Neuro-Ophthalmology Course in 1975, which led to the formation of the Rocky Mountain Neuro-Ophthalmology Society in 1980. By 1986, it had 240 members and changed its name to the North American Neuro-Ophthalmology Society (NANOS). Already existing was the 1.5-day annual Frank Walsh Society meeting with its clinical-pathological correlation format, which originated at Johns Hopkins Medical School. The two societies merged in 1992. Currently, NANOS has grown to more than 650 members and is the premier organization for neuro-ophthalmology worldwide. The society’s journal, the Journal of Neuro-Ophthalmology, commenced publication in 1994, one year after the inaugural issue of Neurology Reviews.

Overcoming an early reputation for “admiring” disease, neuro-ophthalmology has evolved considerably over the past 25 years, with advances in neuroimaging, genomics, proteomics, office-based technologies, and immunology. The first multicenter, randomized trial in neuro-ophthalmology—the Optic Neuritis Treatment Trial (ONTT),¹ published 25 years ago—showed that intravenous methylprednisolone 250 mg QID for three days followed by an 11-day prednisone taper was superior to either oral prednisone (1 mg/kg for 14 days) or oral placebo (14 days), speeding the recovery of vision with slightly better vision at six months. There was a higher rate of relapse in the group assigned to receive oral prednisone. The ONTT was a pivotal event for neuro-ophthalmology, heralding a paradigm shift from observational reporting to randomized clinical trials.

Three years later, the Ischemic Optic Neuropathy Decompression Trial (IONDT)² showed that optic nerve sheath fenestration surgery, performed within 14 days of symptom onset for acute non-arteritic ischemic optic neuropathy or within 30 days in participants with a progressive course, did not improve visual acuity or visual field compared to careful follow-up and medical management at six months. Enrollees randomized to undergo surgery had a lower rate of improvement and were more likely to lose three or more lines of vision than the control group.

With this momentum, the Neuro-Ophthalmology Research Disease Investigators Consortium was formed to create infrastructure for future clinical trials of neuro-ophthalmic disorders. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)³ studied patients with idiopathic intracranial hypertension and mild visual field loss. IIHTT confirmed that acetazolamide (500 mg BID, increasing to a maximum dose of 4 grams daily) was superior to placebo treatment when combined with a supervised weight loss program, resulting in improved visual field loss, papilledema grade, weight reduction, lumbar puncture opening pressure, and quality of life. Ongoing research efforts are investigating treatments for Leber hereditary optic neuropathy, non-arteritic ischemic optic neuropathy, thyroid eye disease, rehabilitation for poststroke homonymous hemianopia and giant cell arteritis in adults, and idiopathic intracranial hypertension and optic nerve gliomas in children.

Attendance at the NANOS annual meeting continues to grow, emphasizing scientific as well as clinical neuro-ophthalmic topics. Vibrant and active neuro-ophthalmology societies in other parts of the world (eg, Europe, Japan, Australia, British Isles) contribute to the camaraderie, collegiality, collaboration, and discovery that advance our field.

Happy 25th anniversary to Neurology Reviews! The next 25 years will likely transform the field of neuro-ophthalmology as we better understand the molecular and genetic basis of neuro-ophthalmic disorders. No longer “diagnose and adios,” we anticipate significant therapeutic advancements—and perhaps cures—for individuals with severe, sight-impairing, neuro-ophthalmic conditions.

References

1. Beck RW, Clearly PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581-588.

2. The Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273(8):625-632.

3. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss. JAMA. 2014;311(16):1641-1651.

Deborah I. Friedman, MD, MPH

Dr. Friedman is a Professor in the Departments of Neurology and Ophthalmology at the University of Texas Southwestern Medical Center in Dallas.

Neuro-ophthalmology is a small subspecialty that had its origins in ophthalmology but has always included neurologists. National neuro-ophthalmology meetings in North America began with the Rocky Mountain Neuro-Ophthalmology Course in 1975, which led to the formation of the Rocky Mountain Neuro-Ophthalmology Society in 1980. By 1986, it had 240 members and changed its name to the North American Neuro-Ophthalmology Society (NANOS). Already existing was the 1.5-day annual Frank Walsh Society meeting with its clinical-pathological correlation format, which originated at Johns Hopkins Medical School. The two societies merged in 1992. Currently, NANOS has grown to more than 650 members and is the premier organization for neuro-ophthalmology worldwide. The society’s journal, the Journal of Neuro-Ophthalmology, commenced publication in 1994, one year after the inaugural issue of Neurology Reviews.

Overcoming an early reputation for “admiring” disease, neuro-ophthalmology has evolved considerably over the past 25 years, with advances in neuroimaging, genomics, proteomics, office-based technologies, and immunology. The first multicenter, randomized trial in neuro-ophthalmology—the Optic Neuritis Treatment Trial (ONTT),¹ published 25 years ago—showed that intravenous methylprednisolone 250 mg QID for three days followed by an 11-day prednisone taper was superior to either oral prednisone (1 mg/kg for 14 days) or oral placebo (14 days), speeding the recovery of vision with slightly better vision at six months. There was a higher rate of relapse in the group assigned to receive oral prednisone. The ONTT was a pivotal event for neuro-ophthalmology, heralding a paradigm shift from observational reporting to randomized clinical trials.

Three years later, the Ischemic Optic Neuropathy Decompression Trial (IONDT)² showed that optic nerve sheath fenestration surgery, performed within 14 days of symptom onset for acute non-arteritic ischemic optic neuropathy or within 30 days in participants with a progressive course, did not improve visual acuity or visual field compared to careful follow-up and medical management at six months. Enrollees randomized to undergo surgery had a lower rate of improvement and were more likely to lose three or more lines of vision than the control group.

With this momentum, the Neuro-Ophthalmology Research Disease Investigators Consortium was formed to create infrastructure for future clinical trials of neuro-ophthalmic disorders. The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)³ studied patients with idiopathic intracranial hypertension and mild visual field loss. IIHTT confirmed that acetazolamide (500 mg BID, increasing to a maximum dose of 4 grams daily) was superior to placebo treatment when combined with a supervised weight loss program, resulting in improved visual field loss, papilledema grade, weight reduction, lumbar puncture opening pressure, and quality of life. Ongoing research efforts are investigating treatments for Leber hereditary optic neuropathy, non-arteritic ischemic optic neuropathy, thyroid eye disease, rehabilitation for poststroke homonymous hemianopia and giant cell arteritis in adults, and idiopathic intracranial hypertension and optic nerve gliomas in children.

Attendance at the NANOS annual meeting continues to grow, emphasizing scientific as well as clinical neuro-ophthalmic topics. Vibrant and active neuro-ophthalmology societies in other parts of the world (eg, Europe, Japan, Australia, British Isles) contribute to the camaraderie, collegiality, collaboration, and discovery that advance our field.

Happy 25th anniversary to Neurology Reviews! The next 25 years will likely transform the field of neuro-ophthalmology as we better understand the molecular and genetic basis of neuro-ophthalmic disorders. No longer “diagnose and adios,” we anticipate significant therapeutic advancements—and perhaps cures—for individuals with severe, sight-impairing, neuro-ophthalmic conditions.

References

1. Beck RW, Clearly PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581-588.

2. The Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273(8):625-632.

3. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss. JAMA. 2014;311(16):1641-1651.

Background: Increased saturation of hospital capacity compromises patient outcomes. This creates additional challenges for the provision of appropriate specialized care. In some hospitals, patients are “bed-spaced,” or admitted to non–internal medicine service locations, such as a surgical ward, in order to free up space in the emergency department. Whether bed-spacing reduces quality of care or patient outcomes has not been previously studied.

Study design: Retrospective cohort study.

Setting: Large tertiary care academic hospital in Canada, during Jan. 1, 2015-Jan. 1, 2016.

Synopsis: There were 3,243 patients included in the analysis, of which 1,125 (35%) were bed-spaced to the off-service wards. The remaining 2,118 patients (65%) were admitted to the assigned internal medicine units. In the first week of hospitalization, in-hospital mortality among bed-spaced patients was approximately three times that of patients admitted to the assigned internal medicine wards. Upon admission, in-hospital mortality for the bed-spaced patients had a hazard ratio of 3.42 (95% confidence interval, 2.23-5.26; P less than .0001) with subsequent decrease by 0.97 (95% CI, 0.94-0.99; P = .0133) per day in the hospital. By the third week of hospitalization, the mortality risks had equalized. Sensitivity analyses revealed similar results.

Bottom line: This retrospective study is based on a single center; however, the observed increased mortality among the bed-spaced patients merits further investigation. Assessment of study generalizability and formulation of strategies for improving patient safety are needed.

Citation: Bai AD et al. Mortality of hospitalised internal medicine patients bed-spaced to non–internal medicine inpatient units: Retrospective cohort study. BMJ Qual Saf. 2018 Jan;27(1):11-20. doi: 10.1136/bmjqs-2017-006925.

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

Background: Increased saturation of hospital capacity compromises patient outcomes. This creates additional challenges for the provision of appropriate specialized care. In some hospitals, patients are “bed-spaced,” or admitted to non–internal medicine service locations, such as a surgical ward, in order to free up space in the emergency department. Whether bed-spacing reduces quality of care or patient outcomes has not been previously studied.

Study design: Retrospective cohort study.

Setting: Large tertiary care academic hospital in Canada, during Jan. 1, 2015-Jan. 1, 2016.

Synopsis: There were 3,243 patients included in the analysis, of which 1,125 (35%) were bed-spaced to the off-service wards. The remaining 2,118 patients (65%) were admitted to the assigned internal medicine units. In the first week of hospitalization, in-hospital mortality among bed-spaced patients was approximately three times that of patients admitted to the assigned internal medicine wards. Upon admission, in-hospital mortality for the bed-spaced patients had a hazard ratio of 3.42 (95% confidence interval, 2.23-5.26; P less than .0001) with subsequent decrease by 0.97 (95% CI, 0.94-0.99; P = .0133) per day in the hospital. By the third week of hospitalization, the mortality risks had equalized. Sensitivity analyses revealed similar results.

Bottom line: This retrospective study is based on a single center; however, the observed increased mortality among the bed-spaced patients merits further investigation. Assessment of study generalizability and formulation of strategies for improving patient safety are needed.

Citation: Bai AD et al. Mortality of hospitalised internal medicine patients bed-spaced to non–internal medicine inpatient units: Retrospective cohort study. BMJ Qual Saf. 2018 Jan;27(1):11-20. doi: 10.1136/bmjqs-2017-006925.

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

Background: Increased saturation of hospital capacity compromises patient outcomes. This creates additional challenges for the provision of appropriate specialized care. In some hospitals, patients are “bed-spaced,” or admitted to non–internal medicine service locations, such as a surgical ward, in order to free up space in the emergency department. Whether bed-spacing reduces quality of care or patient outcomes has not been previously studied.

Study design: Retrospective cohort study.

Setting: Large tertiary care academic hospital in Canada, during Jan. 1, 2015-Jan. 1, 2016.

Synopsis: There were 3,243 patients included in the analysis, of which 1,125 (35%) were bed-spaced to the off-service wards. The remaining 2,118 patients (65%) were admitted to the assigned internal medicine units. In the first week of hospitalization, in-hospital mortality among bed-spaced patients was approximately three times that of patients admitted to the assigned internal medicine wards. Upon admission, in-hospital mortality for the bed-spaced patients had a hazard ratio of 3.42 (95% confidence interval, 2.23-5.26; P less than .0001) with subsequent decrease by 0.97 (95% CI, 0.94-0.99; P = .0133) per day in the hospital. By the third week of hospitalization, the mortality risks had equalized. Sensitivity analyses revealed similar results.

Bottom line: This retrospective study is based on a single center; however, the observed increased mortality among the bed-spaced patients merits further investigation. Assessment of study generalizability and formulation of strategies for improving patient safety are needed.

Citation: Bai AD et al. Mortality of hospitalised internal medicine patients bed-spaced to non–internal medicine inpatient units: Retrospective cohort study. BMJ Qual Saf. 2018 Jan;27(1):11-20. doi: 10.1136/bmjqs-2017-006925.

Dr. Burklin is assistant professor of medicine in the division of hospital medicine, Emory University, Atlanta.

CHICAGO – Clinical guidelines recommend 12 lymph nodes or more are needed to achieve adequate sampling in colon cancer, but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.

Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.

“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”

Dr. Dehal and his coauthors reported having no financial disclosures.

SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.

*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type

CHICAGO – Clinical guidelines recommend 12 lymph nodes or more are needed to achieve adequate sampling in colon cancer, but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.

Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.

“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”

Dr. Dehal and his coauthors reported having no financial disclosures.

SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.

*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type

CHICAGO – Clinical guidelines recommend 12 lymph nodes or more are needed to achieve adequate sampling in colon cancer, but those guidelines may need to be revised to take into account which side the cancer is on to accurately stage a subset of patients with colon cancer, according to results of a prospective, multicenter clinical trial presented at the Society of Surgical Oncology Annual Cancer Symposium.

Ahmed Dehal, MD, of John Wayne Canter Institute in Santa Monica, Calif., presented results of the trial that compared nodal staging in right-sided vs. left-sided colon cancer in two cohorts with T3N0 colon cancer who had at least one lymph node examined: a group of 370 patients from the randomized, multicenter prospective trial; and a sampling of 153,945 patients in the National Cancer Database (NCDB). The latter was used to validate findings in the trial group.

“Current guidelines regarding the minimum number of nodes needed to accurately stage patients with node-negative T3 colon cancer may need to be reevaluated given that the decision to give those patients chemotherapy is largely based on the nodal status,” he said. “More studies are needed to improve our understanding of the impact of sidedness on nodal staging in the colon cancer.”

Dr. Dehal and his coauthors reported having no financial disclosures.

SOURCE: Dehal A et al. Society of Surgical Oncology Annual Cancer Symposium. Abstract #23: Accuracy of nodal staging is influenced by sidedness in colon cancer: Results of a multicenter prospective trial.

*CORRECTION, 4/4/2018; a previous version of this story misidentified the cancer type

New Genetic Risk Factors for Stroke Determined

New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.

Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].

MS Medication Withdrawn Because of Safety Concerns

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Many Elderly Patients With Epilepsy Receive Interacting Treatments

Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.

Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.

Are Physically Fit Women at Reduced Risk for Dementia?

High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.

Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].

Data on Geriatric TBI May Be Inadequate

Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.

Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].

TDCS Improves Gait in Parkinson’s Disease

Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.

Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].

Patients With Major Stroke Need Realistic Planning

Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.

Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.

Dengue Fever Is Associated With Increased Risk of Stroke

Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.

Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.

Do Survivors of Stroke Need Additional Help Taking Medication?

More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.

Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.

Sun Exposure Associated With Reduced Risk of MS

Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.

Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].

New Blood Pressure Guidelines May Not Benefit Everyone

The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.

Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].

—Kimberly Williams

New Genetic Risk Factors for Stroke Determined

New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.

Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].

MS Medication Withdrawn Because of Safety Concerns

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Many Elderly Patients With Epilepsy Receive Interacting Treatments

Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.

Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.

Are Physically Fit Women at Reduced Risk for Dementia?

High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.

Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].

Data on Geriatric TBI May Be Inadequate

Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.

Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].

TDCS Improves Gait in Parkinson’s Disease

Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.

Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].

Patients With Major Stroke Need Realistic Planning

Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.

Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.

Dengue Fever Is Associated With Increased Risk of Stroke

Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.

Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.

Do Survivors of Stroke Need Additional Help Taking Medication?

More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.

Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.

Sun Exposure Associated With Reduced Risk of MS

Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.

Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].

New Blood Pressure Guidelines May Not Benefit Everyone

The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.

Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].

—Kimberly Williams

New Genetic Risk Factors for Stroke Determined

New genetic risk factors for stroke have been identified, thereby tripling the number of gene regions known to affect stroke risk, according to a study published online ahead of print March 12 in Nature Genetics. Researchers conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 with stroke) and discovered 22 new stroke risk loci, bringing the total to 32. In addition, the investigators found shared genetic variation with related vascular traits (eg, blood pressure, cardiac traits, and venous thromboembolism) at individual loci and using genetic risk scores and linkage-disequilibrium-score regression. Several loci had distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology. The researchers prioritized risk variants and genes through bioinformatics analyses using functional datasets.

Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Mar 12 [Epub ahead of print].

MS Medication Withdrawn Because of Safety Concerns

Citing concerns about safety, Biogen and AbbVie announced March 2 that they will be withdrawing daclizumab (Zinbryta) from worldwide markets. Daclizumab has known risks, so it was usually prescribed only for people with relapsing multiple sclerosis who had tried two or more other medications that had not worked well enough. Reports of inflammatory encephalitis and meningoencephalitis led the European Medicines Agency to initiate an Article 20 referral procedure. In such referrals, a medicine or class of medicines are scientifically assessed because of concerns over safety or quality. However, Biogen and AbbVie concluded that, because of the complex nature of these reports and how few patients were taking daclizumab, it would be difficult to characterize the nature of the medication’s harms and benefits, so the companies instead have decided to withdraw the medication from the market.

Many Elderly Patients With Epilepsy Receive Interacting Treatments

Many elderly patients with epilepsy receive combinations of nonepilepsy drugs (NEDs) and antiepileptic drugs (AEDs) that could interact, according to a study published February 7 in Epilepsia. Researchers retrospectively analyzed 2008–2010 Medicare claims for a random sample of beneficiaries age 67 and older. Prevalent cases had a diagnosis of epilepsy and took one or more AEDs. Incident cases had no seizure or epilepsy claim codes or AEDs in the preceding 365 days. Interacting pairs of AEDs and NEDs were identified by literature review. Logistic regression models were used to examine factors affecting the likelihood of interaction risk. Interacting drug pairs affected NED efficacy in 24.5% of incident cases and 39% of prevalent cases. Combinations affected AED efficacy in 20.4% of incident cases and 29.3% of prevalent cases.

Faught E, Szaflarski JP, Richman J, et al. Risk of pharmacokinetic interactions between antiepileptic and other drugs in older persons and factors associated with risk. Epilepsia. 2018;59(3):715-723.

Are Physically Fit Women at Reduced Risk for Dementia?

High cardiovascular fitness in midlife is associated with decreased risk of subsequent dementia, according to a study published online ahead of print March 14 in Neurology. Physicians examined a population-based sample of 1,462 women ages 38 to 60 in 1968. A subsample of 191 women with an average age of 50 took a maximal ergometer cycling test to measure their peak cardiovascular capacity. Over the following 44 years, participants were tested for dementia six times. By 2012, 44 of the women developed dementia. Approximately 5% of the highly fit women developed dementia, compared with 25% of moderately fit women, and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.

Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology. 2018 Mar 14 [Epub ahead of print].

Data on Geriatric TBI May Be Inadequate

Many older adults with traumatic brain injury (TBI) respond well to aggressive management and rehabilitation, which suggests that age and TBI severity alone are inadequate prognostic markers, according to a study published online ahead of print February 15 in the Journal of Neurotrauma. Researchers reviewed the literature on incident TBI sustained in older adulthood. They found few geriatric-specific TBI guidelines to assist with complex management decisions and concluded that TBI prognostic models do not perform optimally in this population. Major barriers in management of geriatric TBI include underrepresentation of older adults in TBI research, lack of systematic measurement of preinjury health that may predict outcome and response to treatment, and lack of geriatric-specific TBI common data elements. Investigators need to develop more age-inclusive TBI research protocols, said the authors.

Gardner RC, Dams-O’Connor K, Morrissey MR, Manley GT. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018 Feb 15 [Epub ahead of print].

TDCS Improves Gait in Parkinson’s Disease

Transcranial direct-current stimulation (TDCS) reduces freezing of gait and improves executive function and mobility, according to a study published online ahead of print February 13 in Movement Disorders. Researchers examined 20 patients with Parkinson’s disease and freezing of gait. The patients received 20 minutes of TDCS or sham treatment during three separate visits. TDCS targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously or primary motor cortex only. Participants completed the Timed Up and Go and Stroop tests before and after each stimulation session. Performance on the Timed Up and Go and Stroop tests improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after stimulation of the primary motor cortex alone or sham stimulation.

Dagan M, Herman T, Harrison R, et al. Multitarget transcranial direct current stimulation for freezing of gait in Parkinson’s disease. Mov Disord. 2018 Feb 13 [Epub ahead of print].

Patients With Major Stroke Need Realistic Planning

Doctors who care for patients with severe stroke should plan with patients and caregivers and discuss the possibility of death or survival with disability, according to a study published March 5 in the Canadian Medical Association Journal. Researchers recruited a purposive sample of people with total anterior circulation stroke at three stroke services and conducted serial, qualitative interviews with participants and their caregivers at six weeks, six months, and one year. Investigators also conducted a data-linkage study of all patients with anterior circulation stroke admitted to the three services over six months. About 57% of patients died within six months. Patients experienced immediate and persistent emotional distress and poor quality of life. Physicians should practice palliative care for these patients, but avoid using that term, said the authors.

Kendall M, Cowey E, Mead G, et al. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ. 2018;190(9):E238-E246.

Dengue Fever Is Associated With Increased Risk of Stroke

Dengue fever is associated with an increased risk of stroke in the first few months after diagnosis, according to a study published March 12 in Canadian Medical Association Journal. Using data from the Taiwan National Health Insurance Research Database, researchers examined 13,787 patients diagnosed with dengue fever between 2000 and 2012. The control cohort consisted of patients matched by demographic characteristics and stroke-related comorbidities who did not have dengue fever. The overall incidence rate of stroke was 5.33 per 1,000 person-years in the dengue fever cohort and 3.72 per 1,000 person-years in the control cohort. The adjusted hazard ratio of stroke was 1.16 in patients with dengue fever. The risk of stroke was 2.49 times higher in patients with dengue fever during the first two months after diagnosis, compared with controls.

Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ. 2018;190(10):E285-E290.

Do Survivors of Stroke Need Additional Help Taking Medication?

More than half of patients with stroke need help taking medication, according to a study published March 11 in BMJ Open. Approximately 600 community-dwelling patients with stroke responded to a five-item questionnaire about practical support that they need and receive. Approximately 56% of respondents got help with taking medication, and 11% needed additional help, including help with prescriptions and collection of medicines, getting medicines out of the packaging, and being reminded to take medicines. Being dependent on others was associated with experiencing more unmet needs with daily medicine taking. About 35% of respondents said that they had missed taking medicine in the previous 30 days. Younger patients with stroke were more likely to miss their medicines, possibly because they were less likely to receive help from a caregiver.

Jamison J, Ayerbe L, Di Tanna GL, et al. Evaluating practical support stroke survivors get with medicines and unmet needs in primary care: a survey. BMJ Open. 2018;8(3):e019874.

Sun Exposure Associated With Reduced Risk of MS

Living in areas with high ambient levels of ultraviolet-B light during childhood and the years before multiple sclerosis (MS) onset is associated with a lower MS risk, according to a study published online ahead of print March 7 in Neurology. Researchers identified 151 women with MS and 235 age-matched controls. The average age at MS onset was 40. All participants completed questionnaires about summer, winter, and lifetime sun exposure. Researchers separated the women into three groups representing low, moderate, and high ultraviolet-B ray exposure, based on their residence. Women who lived in sunnier climates with the highest exposure to ultraviolet-B rays had a 45% reduced risk of developing MS across all pre-MS onset age groups, when compared with participants living in areas with the lowest ultraviolet-B ray exposure.

Tremlett H, Zhu F, Ascherio A, Munger KL. Sun exposure over the life course and associations with multiple sclerosis. Neurology. 2018 Mar 7 [Epub ahead of print].

New Blood Pressure Guidelines May Not Benefit Everyone

The new blood pressure guidelines could harm certain patients, according to a study published online ahead of print March 2 in the Journal of the American College of Cardiology. Investigators examined the effect of 10-year cardiovascular disease (CVD) risk on primary outcome events and serious adverse events in the Systolic Pressure Intervention Trial, which was a basis for the new guidelines. They stratified patients by quartiles of risk and used Cox proportional hazards models to examine associations. From the first to fourth quartiles, the number needed to treat to prevent primary outcomes decreased from 91 to 38. The number needed to harm for all-cause serious adverse events increased from 62 to 250. Classifying patients by future risk could identify patients who would benefit from intensive treatment, said the authors.

Phillips RA, Xu J, Peterson LE, et al. Impact of cardiovascular risk on the relative benefit and harm of intensive treatment of hypertension. J Am Coll Cardiol. 2018 Mar 2 [Epub ahead of print].

—Kimberly Williams

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

The oral immunomodulatory drug lenalidomide is active and may provide prolonged responses in certain patients with a rare and aggressive subtype of primary cutaneous lymphoma, according to results of a phase 2 study.

In the study, which comprised 19 patients with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), 5 patients (26.3%) had a response at 6 months, and there were still 3 patients in response at 12 months. The findings were reported in the Journal of Investigative Dermatology.

In an exploratory analysis, reducing the dose of lenalidomide was associated with prolonged response and improved survival, noted lead author Marie Beylot-Barry, MD, of the dermatology department, Hôpital Saint-André, CHU Bordeaux, France, and her colleagues.

“Lenalidomide at reduced doses may allow prolonged responses in few patients, and represents a therapeutic option in relapsing/refractory PCDLBCL, LT,” the researchers wrote.

Found mostly on the lower limbs of elderly patients, PCDLBCL, LT exhibits aggressive behavior and is associated with a high rate of skin recurrences. First-line therapy for the cutaneous lymphoma is typically rituximab and chemotherapy, regardless of clinical stage or patient age, the researchers wrote, though primary resistance or recurrence after treatment occurs in about half of patients. “In such relapsing or refractory cases, no treatment has demonstrated a sustained benefit thus far,” they noted.

Lenalidomide has already demonstrated efficacy in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and it induces inhibition of cell signaling, engaging NF-kappaB signaling. PCDLBCL, LT is marked by genetic alterations leading to the NF-kappaB pathway, which represents a therapeutic target.

Dr. Beylot-Barry and her colleagues initiated a multicenter, single-arm, phase 2 trial of 19 patients refractory/relapsing PCDLBCL, LT. Median progression-free survival in the trial was 4.9 months. The 6-month overall response rate – the primary endpoint of the trial – was 26.3%, which was not significantly superior to a prespecified 20% minimal response rate, according to the researchers.

SOURCE: Beylot-Barry M et al. J Invest Dermatol. 2018 Mar 26. doi: 10.1016/j.jid.2018.03.1516.

Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.¹ In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.² Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. Rosacea may be divided into four subtypes, and more than one subtype may be simultaneously present in an individual at one time. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.

Courtesy Dr. Laurence F. Eichenfield

Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.

References

1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.

2. Cutis. 2016 Jul;98(1):49-53.

3. J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1732-8.

4. J Fr Ophtalmol. 2011 Dec;34(10):703-10.

5. J Am Acad Dermatol. 2015 May;72(5):749-58.

6. Indian J Dermatol. 2011 Jan;56(1):30-2.

7. Cutis, 2004. 74(2):99-103.

8. Pediatr Dermatol. 1992 Mar;9(1):22-6.

9. Pediatr Dermatol. 2015 Jul-Aug;32(4):e136-9.

10. Br J Dermatol. 2005 Dec;153(6):1176-81.

11. J Am Acad Dermatol. 2015 May;72(5):761-70.

Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.¹ In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.² Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. Rosacea may be divided into four subtypes, and more than one subtype may be simultaneously present in an individual at one time. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.

Courtesy Dr. Laurence F. Eichenfield

Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.

References

1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.

2. Cutis. 2016 Jul;98(1):49-53.

3. J Eur Acad Dermatol Venereol. 2017 Oct;31(10):1732-8.

4. J Fr Ophtalmol. 2011 Dec;34(10):703-10.

5. J Am Acad Dermatol. 2015 May;72(5):749-58.

6. Indian J Dermatol. 2011 Jan;56(1):30-2.

7. Cutis, 2004. 74(2):99-103.

8. Pediatr Dermatol. 1992 Mar;9(1):22-6.

9. Pediatr Dermatol. 2015 Jul-Aug;32(4):e136-9.

10. Br J Dermatol. 2005 Dec;153(6):1176-81.

11. J Am Acad Dermatol. 2015 May;72(5):761-70.

Rosacea is a chronic inflammatory skin disorder characterized by flushing, telangiectasia, erythema, papules, and pustules, most classically of the central face. Fair-skinned individuals and women are more commonly affected than are men, with age of onset typically around 30 years and older.¹ In children and adolescents, rosacea is rare, especially among prepubertal children, so other papulopustular disorders should be considered when a rosacealike picture is present.² Recurrent chalazia are seen with ocular rosacea and may be a clue to the diagnosis of acne rosacea. Rosacea may be divided into four subtypes, and more than one subtype may be simultaneously present in an individual at one time. An individual’s subtype of rosacea also may transform with time to a different or an additional subtype.

Courtesy Dr. Laurence F. Eichenfield

Allison Han is a medical student at the University of California, San Diego. Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. There are no conflicts of interest or financial disclosures for Ms. Han or Dr. Eichenfield.

References

1. J Am Acad Dermatol. 2018 Jan;78(1):148-55.

2. Cutis. 2016 Jul;98(1):49-53.

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