Erik Greb

The prescription of positive airway pressure is associated with reduced all-cause mortality, according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.

The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.

To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.

All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.

In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.

A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.

Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.

One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.

These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.

The Sleep Heart Health Study was supported by grants from the National Institutes of Health.

[email protected]

SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.

The prescription of positive airway pressure is associated with reduced all-cause mortality, according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.

The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.

To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.

All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.

In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.

A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.

Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.

One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.

These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.

The Sleep Heart Health Study was supported by grants from the National Institutes of Health.

[email protected]

SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.

The prescription of positive airway pressure is associated with reduced all-cause mortality, according to the results of a cohort study published in JAMA Otolaryngology–Head & Neck Surgery.

The association becomes evident several years after positive airway pressure (PAP) initiation, according to the researchers. Obstructive sleep apnea (OSA) is among the top 10 modifiable cardiovascular risk factors, and is associated with increased risks of coronary artery disease, stroke, and death. PAP is the most effective treatment for OSA, but this treatment’s effect on all-cause and cardiovascular mortality is uncertain. Randomized trials have yielded inconclusive answers to this question, and evidence from observational studies has been weak.

To investigate the association between PAP prescription and mortality in patients with obesity and severe OSA, Quentin Lisan, MD, of the Paris Cardiovascular Research Center and his colleagues conducted a multicenter, population-based cohort study. The researchers examined data for 392 participants in the Sleep Heart Health Study, in which adult men and women age 40 years or older were recruited from nine population-based studies between 1995 and 1998 and followed for a mean of 11.1 years. With each participant who had been prescribed PAP, the investigators matched as many as four participants who had not been prescribed PAP, on the basis of age, sex, and apnea-hypopnea index. Of this sample, 81 patients were prescribed PAP, and 311 were not.

All participants had a clinic visit and underwent overnight polysomnography at baseline. At 2-3 years, participants had a follow-up visit or phone call, during which they were asked whether their physicians had prescribed PAP. Participants were monitored for cardiovascular and all-cause mortality.

In all, 319 of the 392 participants were men; the population’s mean age was 63 years. Patients who had received a PAP prescription had a higher body mass index and more education, compared with patients who had not received a prescription. Mean follow-up duration was 11.6 years in the PAP-prescribed group and 10.9 years in the nonprescribed group.

A total of 96 deaths occurred during follow-up: 12 in the PAP-prescribed group and 84 in the nonprescribed PAP group. The crude incidence rate of mortality was 24.7 deaths per 1,000 person-years in the nonprescribed group and 12.8 deaths per 1,000 person-years in the PAP-prescribed group. The difference in survival between the prescribed and nonprescribed groups was evident in survival curves after 6-7 years of follow-up. After adjustments for prevalent cardiovascular disease, hypertension, diabetes, body mass index, education level, smoking status, and alcohol consumption, the hazard ratio of all-cause mortality for the prescribed group was 0.38, compared with the nonprescribed group.

Dr. Lisan and his colleagues identified 27 deaths of cardiovascular origin, one of which occurred in the prescribed group. After adjusting for prevalent cardiovascular disease, the hazard ratio of cardiovascular mortality for the prescribed group was 0.06, compared with the nonprescribed group.

One reason that the reduction in mortality associated with PAP was not found in previous randomized, controlled trials could be that their mean length of follow-up was not long enough, the researchers wrote. For example, the mean length of follow-up in the SAVE trial was 3.7 years, but the survival benefit was not apparent in the present analysis until 6-7 years after treatment initiation.

These results are exploratory and require confirmation in future research, Dr. Lisan and his colleagues wrote. No information on adherence to PAP was available, and the researchers could not account for initiation and interruption of PAP therapy. Nevertheless, “prescribing PAP in patients with OSA should be pursued and encouraged, given its potential major public health implication,” they concluded.

The Sleep Heart Health Study was supported by grants from the National Institutes of Health.

[email protected]

SOURCE: Lisan Q et al. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. doi: 10.1001/jamaoto.2019.0281.

Adherence to a plant-based diet is inversely linked with the risk of incident heart failure, according to an analysis published online in the Journal of the American College of Cardiology.

Ron Chapple Studios/thinkstockphotos.com

Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.

Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.

Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.

The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.

The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.

After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.

After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.

One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.

SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.

Adherence to a plant-based diet is inversely linked with the risk of incident heart failure, according to an analysis published online in the Journal of the American College of Cardiology.

Ron Chapple Studios/thinkstockphotos.com

Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.

Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.

Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.

The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.

The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.

After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.

After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.

One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.

SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.

Adherence to a plant-based diet is inversely linked with the risk of incident heart failure, according to an analysis published online in the Journal of the American College of Cardiology.

Ron Chapple Studios/thinkstockphotos.com

Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.

Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.

Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.

The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.

The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.

After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.

After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.

One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.

SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Former National Football League players with cognitive, mood, and behavioral symptoms may have higher tau levels in the brain than asymptomatic people without a history of traumatic brain injury, according to research published online ahead of print April 10 in the New England Journal of Medicine. The distribution of tau in the players’ brains appears to be similar to that in persons with chronic traumatic encephalopathy (CTE).

CTE is a neurodegenerative disease that has been associated with a history of repetitive head impacts, such as those withstood in contact sports. The basis for the neuropathological diagnosis of CTE is a distinct pattern of tau deposition with minimal deposition of amyloid-beta. Paired helical filament tau aggregates are first observed in the frontal, temporal, and parietal cortices. They later spread throughout the cerebral cortex, medial temporal lobe, diencephalon, and brainstem. CTE is diagnosed only through post mortem neuropathological examinations.

To examine whether tau and amyloid deposition can be detected in the brains of living people at risk for CTE, Robert A. Stern, PhD, and his colleagues studied living former NFL players and asymptomatic controls with flortaucipir PET (to detect tau) and ¹⁸F-florbetapir PET (to detect amyloid-beta). Dr. Stern is director of clinical research at the CTE Center at Boston University. Eligible former players were male, aged 40-69 years, had played football in the NFL for at least 2 years, had had at least 12 years of total tackle football experience, and reported cognitive, behavioral, and mood symptoms through telephone screening. Eligible controls were male, aged 40-69 years, and had no cognitive symptoms or history of traumatic brain injury.

All subjects underwent flortaucipir PET, florbetapir PET, and T₁-weighted volumetric MRI of the head. Dr. Stern and his colleagues used automated image-analysis algorithms to compare the regional tau standardized uptake value ratio (SUVR) between the two patient groups and to evaluate potential associations between that ratio and symptom severity or years of football play.

The investigators included 26 former players and 31 controls in their analysis. The group of former players had a higher percentage of black participants and a lower mean Mini-Mental State Examination score, compared with controls. The mean flortaucipir SUVR was higher among former players than among controls in the bilateral superior frontal (1.09 vs. 0.98), bilateral medial temporal (1.23 vs. 1.12), and left parietal (1.12 vs. 1.01) regions. Dr. Stern and his colleagues found no association between tau deposition in those regions and results on cognitive and neuropsychiatric tests. In a post hoc analysis, they calculated the correlation coefficients in the three brain regions between the SUVRs and years of play to be 0.58 in the bilateral superior frontal region, 0.45 in the bilateral medial temporal region, and 0.50 in the left parietal region. Mean cortical:cerebellar florbetapir SUVRs did not differ significantly between groups.

“These findings suggest that the cognitive difficulties reported by the former players were not related to Alzheimer’s disease amyloid-beta deposition,” said the authors. The study may have been insufficiently powered to detect associations between flortaucipir uptake and the clinical measures, they added. Also, paired helical filament tau pathology alone may not be associated with the former players’ neuropsychiatric symptoms and cognitive impairment. “Although this study showed between-group differences in flortaucipir PET measurements, our analyses do not pertain to detection of tau pathology in individual participants,” the authors concluded.

The study was supported by an investigator-initiated grant from Avid Radiopharmaceuticals. The National Institutes of Health, the state of Arizona, and the U.S. Department of Defense also supported the study.

[email protected]

SOURCE: Stern RA et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1900757 (Epub ahead of print).

Low LDL cholesterol levels and low triglyceride levels are associated with increased risk of hemorrhagic stroke among women, according to research published in Neurology.

“Women with very low LDL cholesterol or low triglycerides should be monitored by their doctors for other stroke risk factors that can be modified, like high blood pressure and smoking, in order to reduce their risk of hemorrhagic stroke,” said Pamela M. Rist, ScD, instructor in epidemiology at Harvard Medical School, Boston. “Additional research is needed to determine how to lower the risk of hemorrhagic stroke in women with very low LDL and low triglycerides.”
 

Several meta-analyses have indicated that LDL cholesterol levels are inversely associated with the risk of hemorrhagic stroke. Because lipid-lowering treatments are used to prevent cardiovascular disease, this potential association has implications for clinical practice. Most of the studies included in these meta-analyses had low numbers of events among women, which prevented researchers from stratifying their results by sex. Because women are at greater risk of stroke than men, Dr. Rist and her colleagues sought to evaluate the association between lipid levels and risk of hemorrhagic stroke.

An analysis of the Women’s Health Study

The investigators examined data from the Women’s Health Study, a randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer among female American health professionals aged 45 years or older. The study ended in March 2004, but follow-up is ongoing. At regular intervals, the women complete a questionnaire about disease outcomes, including stroke. Some participants agreed to provide a fasting venous blood sample before randomization. With the subjects’ permission, a committee of physicians examined medical records for women who reported a stroke on a follow-up questionnaire.

Dr. Rist and her colleagues analyzed 27,937 samples for levels of LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. They assigned each sample to one of five cholesterol level categories that were based on Adult Treatment Panel III guidelines. Cox proportional hazards models enabled the researchers to calculate the hazard ratio of incident hemorrhagic stroke events. They adjusted their results for covariates such as age, smoking status, menopausal status, body mass index, and alcohol consumption.

A U-shaped association

Women in the lowest category of LDL cholesterol level (less than 70 mg/dL) were younger, less likely to have a history of hypertension, and less likely to use cholesterol-lowering drugs than women in the reference group (100.0-129.9 mg/dL). Women with the lowest LDL cholesterol level were more likely to consume alcohol, have a normal weight, engage in physical activity, and be premenopausal than women in the reference group. The investigators confirmed 137 incident hemorrhagic stroke events during a mean 19.3 years of follow-up.

After data adjustment, the researchers found that women with the lowest level of LDL cholesterol had 2.17 times the risk of hemorrhagic stroke, compared with participants in the reference group. They found a trend toward increased risk among women with an LDL cholesterol level of 160 mg/dL or higher, but the result was not statistically significant. The highest risk for intracerebral hemorrhage (ICH) was among women with an LDL cholesterol level of less than 70 mg/dL (relative risk, 2.32), followed by women with a level of 160 mg/dL or higher (RR, 1.71).

In addition, after multivariable adjustment, women in the lowest quartile of triglycerides (less than or equal to 74 mg/dL for fasting and less than or equal to 85 mg/dL for nonfasting) had a significantly increased risk of hemorrhagic stroke, compared with women in the highest quartile (RR, 2.00). Low triglyceride levels were associated with an increased risk of subarachnoid hemorrhage, but not with an increased risk of ICH. Neither HDL cholesterol nor total cholesterol was associated with risk of hemorrhagic stroke, the researchers wrote.

Mechanism of increased risk unclear

The researchers do not yet know how low triglyceride and LDL cholesterol levels increase the risk of hemorrhagic stroke. One hypothesis is that low cholesterol promotes necrosis of the arterial medial layer’s smooth muscle cells. This impaired endothelium might be more susceptible to microaneurysms, which are common in patients with ICH, said the researchers.

The prospective design and the large sample size were two of the study’s strengths, but the study had important weaknesses as well, the researchers wrote. For example, few women were premenopausal at baseline, so the investigators could not evaluate whether menopausal status modifies the association between lipid levels and risk of hemorrhagic stroke. In addition, lipid levels were measured only at baseline, which prevented an analysis of whether change in lipid levels over time modifies the risk of hemorrhagic stroke.

Dr. Rist reported receiving a grant from the National Institutes of Health.

[email protected]

SOURCE: Rist PM et al. Neurology. 2019 April 10. doi: 10.1212/WNL.0000000000007454.

Low LDL cholesterol levels and low triglyceride levels are associated with increased risk of hemorrhagic stroke among women, according to research published in Neurology.

“Women with very low LDL cholesterol or low triglycerides should be monitored by their doctors for other stroke risk factors that can be modified, like high blood pressure and smoking, in order to reduce their risk of hemorrhagic stroke,” said Pamela M. Rist, ScD, instructor in epidemiology at Harvard Medical School, Boston. “Additional research is needed to determine how to lower the risk of hemorrhagic stroke in women with very low LDL and low triglycerides.”
 

Several meta-analyses have indicated that LDL cholesterol levels are inversely associated with the risk of hemorrhagic stroke. Because lipid-lowering treatments are used to prevent cardiovascular disease, this potential association has implications for clinical practice. Most of the studies included in these meta-analyses had low numbers of events among women, which prevented researchers from stratifying their results by sex. Because women are at greater risk of stroke than men, Dr. Rist and her colleagues sought to evaluate the association between lipid levels and risk of hemorrhagic stroke.

An analysis of the Women’s Health Study

The investigators examined data from the Women’s Health Study, a randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer among female American health professionals aged 45 years or older. The study ended in March 2004, but follow-up is ongoing. At regular intervals, the women complete a questionnaire about disease outcomes, including stroke. Some participants agreed to provide a fasting venous blood sample before randomization. With the subjects’ permission, a committee of physicians examined medical records for women who reported a stroke on a follow-up questionnaire.

Dr. Rist and her colleagues analyzed 27,937 samples for levels of LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. They assigned each sample to one of five cholesterol level categories that were based on Adult Treatment Panel III guidelines. Cox proportional hazards models enabled the researchers to calculate the hazard ratio of incident hemorrhagic stroke events. They adjusted their results for covariates such as age, smoking status, menopausal status, body mass index, and alcohol consumption.

A U-shaped association

Women in the lowest category of LDL cholesterol level (less than 70 mg/dL) were younger, less likely to have a history of hypertension, and less likely to use cholesterol-lowering drugs than women in the reference group (100.0-129.9 mg/dL). Women with the lowest LDL cholesterol level were more likely to consume alcohol, have a normal weight, engage in physical activity, and be premenopausal than women in the reference group. The investigators confirmed 137 incident hemorrhagic stroke events during a mean 19.3 years of follow-up.

After data adjustment, the researchers found that women with the lowest level of LDL cholesterol had 2.17 times the risk of hemorrhagic stroke, compared with participants in the reference group. They found a trend toward increased risk among women with an LDL cholesterol level of 160 mg/dL or higher, but the result was not statistically significant. The highest risk for intracerebral hemorrhage (ICH) was among women with an LDL cholesterol level of less than 70 mg/dL (relative risk, 2.32), followed by women with a level of 160 mg/dL or higher (RR, 1.71).

In addition, after multivariable adjustment, women in the lowest quartile of triglycerides (less than or equal to 74 mg/dL for fasting and less than or equal to 85 mg/dL for nonfasting) had a significantly increased risk of hemorrhagic stroke, compared with women in the highest quartile (RR, 2.00). Low triglyceride levels were associated with an increased risk of subarachnoid hemorrhage, but not with an increased risk of ICH. Neither HDL cholesterol nor total cholesterol was associated with risk of hemorrhagic stroke, the researchers wrote.

Mechanism of increased risk unclear

The researchers do not yet know how low triglyceride and LDL cholesterol levels increase the risk of hemorrhagic stroke. One hypothesis is that low cholesterol promotes necrosis of the arterial medial layer’s smooth muscle cells. This impaired endothelium might be more susceptible to microaneurysms, which are common in patients with ICH, said the researchers.

The prospective design and the large sample size were two of the study’s strengths, but the study had important weaknesses as well, the researchers wrote. For example, few women were premenopausal at baseline, so the investigators could not evaluate whether menopausal status modifies the association between lipid levels and risk of hemorrhagic stroke. In addition, lipid levels were measured only at baseline, which prevented an analysis of whether change in lipid levels over time modifies the risk of hemorrhagic stroke.

Dr. Rist reported receiving a grant from the National Institutes of Health.

[email protected]

SOURCE: Rist PM et al. Neurology. 2019 April 10. doi: 10.1212/WNL.0000000000007454.

Low LDL cholesterol levels and low triglyceride levels are associated with increased risk of hemorrhagic stroke among women, according to research published in Neurology.

“Women with very low LDL cholesterol or low triglycerides should be monitored by their doctors for other stroke risk factors that can be modified, like high blood pressure and smoking, in order to reduce their risk of hemorrhagic stroke,” said Pamela M. Rist, ScD, instructor in epidemiology at Harvard Medical School, Boston. “Additional research is needed to determine how to lower the risk of hemorrhagic stroke in women with very low LDL and low triglycerides.”
 

Several meta-analyses have indicated that LDL cholesterol levels are inversely associated with the risk of hemorrhagic stroke. Because lipid-lowering treatments are used to prevent cardiovascular disease, this potential association has implications for clinical practice. Most of the studies included in these meta-analyses had low numbers of events among women, which prevented researchers from stratifying their results by sex. Because women are at greater risk of stroke than men, Dr. Rist and her colleagues sought to evaluate the association between lipid levels and risk of hemorrhagic stroke.

An analysis of the Women’s Health Study

The investigators examined data from the Women’s Health Study, a randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer among female American health professionals aged 45 years or older. The study ended in March 2004, but follow-up is ongoing. At regular intervals, the women complete a questionnaire about disease outcomes, including stroke. Some participants agreed to provide a fasting venous blood sample before randomization. With the subjects’ permission, a committee of physicians examined medical records for women who reported a stroke on a follow-up questionnaire.

Dr. Rist and her colleagues analyzed 27,937 samples for levels of LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. They assigned each sample to one of five cholesterol level categories that were based on Adult Treatment Panel III guidelines. Cox proportional hazards models enabled the researchers to calculate the hazard ratio of incident hemorrhagic stroke events. They adjusted their results for covariates such as age, smoking status, menopausal status, body mass index, and alcohol consumption.

A U-shaped association

Women in the lowest category of LDL cholesterol level (less than 70 mg/dL) were younger, less likely to have a history of hypertension, and less likely to use cholesterol-lowering drugs than women in the reference group (100.0-129.9 mg/dL). Women with the lowest LDL cholesterol level were more likely to consume alcohol, have a normal weight, engage in physical activity, and be premenopausal than women in the reference group. The investigators confirmed 137 incident hemorrhagic stroke events during a mean 19.3 years of follow-up.

After data adjustment, the researchers found that women with the lowest level of LDL cholesterol had 2.17 times the risk of hemorrhagic stroke, compared with participants in the reference group. They found a trend toward increased risk among women with an LDL cholesterol level of 160 mg/dL or higher, but the result was not statistically significant. The highest risk for intracerebral hemorrhage (ICH) was among women with an LDL cholesterol level of less than 70 mg/dL (relative risk, 2.32), followed by women with a level of 160 mg/dL or higher (RR, 1.71).

In addition, after multivariable adjustment, women in the lowest quartile of triglycerides (less than or equal to 74 mg/dL for fasting and less than or equal to 85 mg/dL for nonfasting) had a significantly increased risk of hemorrhagic stroke, compared with women in the highest quartile (RR, 2.00). Low triglyceride levels were associated with an increased risk of subarachnoid hemorrhage, but not with an increased risk of ICH. Neither HDL cholesterol nor total cholesterol was associated with risk of hemorrhagic stroke, the researchers wrote.

Mechanism of increased risk unclear

The researchers do not yet know how low triglyceride and LDL cholesterol levels increase the risk of hemorrhagic stroke. One hypothesis is that low cholesterol promotes necrosis of the arterial medial layer’s smooth muscle cells. This impaired endothelium might be more susceptible to microaneurysms, which are common in patients with ICH, said the researchers.

The prospective design and the large sample size were two of the study’s strengths, but the study had important weaknesses as well, the researchers wrote. For example, few women were premenopausal at baseline, so the investigators could not evaluate whether menopausal status modifies the association between lipid levels and risk of hemorrhagic stroke. In addition, lipid levels were measured only at baseline, which prevented an analysis of whether change in lipid levels over time modifies the risk of hemorrhagic stroke.

Dr. Rist reported receiving a grant from the National Institutes of Health.

[email protected]

SOURCE: Rist PM et al. Neurology. 2019 April 10. doi: 10.1212/WNL.0000000000007454.

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

[email protected]

WASHINGTON – Expenditures for combination acne products increased from $82 million in 1996 to $487 million in 2016, according to an analysis presented at the annual meeting of the American Academy of Dermatology.

During a late-breaking research session, David Li, a fourth-year medical student at Tufts University, Boston, presented the results of a retrospective cost analysis study, conducted to identify trends in overall spending for combination acne products. Spending measures were adjusted for inflation to 2016 U.S. dollars.

While spending on combination products for acne has increased significantly over the past 2 decades, comparative efficacy data for these products are limited, he noted. Combination products are more expensive than the sum of their component parts, and prescribing generic formulations of individual acne treatments could potentially reduce costs, but possible advantages of combination products for acne include improved patient adherence and increased efficacy.

Mr. Li, a research fellow in the department of dermatology at Brigham and Women’s Hospital in Boston, and his colleagues drafted a comprehensive list of available combination products (eight brand-name products and two generics). Most combine benzoyl peroxide with another common acne medication. To analyze trends in medication use, they performed a retrospective cost analysis using Medical Expenditure Panel Survey (MEPS) data from 1996 to 2016, searching for these combination medications to gather the annual number of prescriptions, number of users, expenditures, and aggregate demographics for each product. The data were weighted to represent national estimates.

They also used data from the National Average Drug Acquisition Cost (NADAC) database, used by the Centers for Medicare & Medicaid Services as a pricing benchmark, and calculated the difference between the unit price of each combination product and the sum of the prices of its generic components. They multiplied this difference by the median number of units prescribed annually for the given combination.

The researchers found that most users of combination acne products were younger than 18 years (23%), female (55%), and white (83%), and the most commonly prescribed combination product changed over time. From 1996 to 2002, Benzamycin (benzoyl peroxide and erythromycin) was the most frequently prescribed combination. Several years later, its place was taken by BenzaClin (benzoyl peroxide and clindamycin) from 2003 to 2010, followed by Ziana (clindamycin and tretinoin) in 2011 and Epiduo (adapalene and benzoyl peroxide) from 2012 to 2016.

“Spending has increased steadily from a little bit over $82 million in 1996 to nearly half a billion dollars in 2016,” Mr. Li said. “That’s a rise of more than 500% in the last 20 years. Based on the median pricing and utilization data that we derived from the NADAC database, we determined that substitution with component generics can provide median annual savings of at least a quarter billion dollars each year.”

Although the data indicate a trend toward increased use of and spending on new, branded combination products, the literature includes “minimal data to suggest whether one combination acne product is better than the next one, or how it compares to its component medications when used in combination,” he said. He and his colleagues found no comparative data apart from a 2001 study that examined Benzamycin and BenzaClin, which suggested that there was no difference in efficacy or tolerability between the products.

The present study is limited by reporting bias and recall bias because it relies partly on MEPS, a survey, and the NADAC pricing database had information only for 2013-2016. The researchers consequently used the most recent prices to calculate potential savings.

“Until we have more meaningful data to suggest otherwise, we’re in a state of equipoise,” said Mr. Li.

The research was funded by the National Center for Advancing Translational Sciences, part of the National Institutes of Health.
 

[email protected]

SOURCE: Li D et al. AAD 2019, Abstract 11333.

WASHINGTON – Expenditures for combination acne products increased from $82 million in 1996 to $487 million in 2016, according to an analysis presented at the annual meeting of the American Academy of Dermatology.

During a late-breaking research session, David Li, a fourth-year medical student at Tufts University, Boston, presented the results of a retrospective cost analysis study, conducted to identify trends in overall spending for combination acne products. Spending measures were adjusted for inflation to 2016 U.S. dollars.

While spending on combination products for acne has increased significantly over the past 2 decades, comparative efficacy data for these products are limited, he noted. Combination products are more expensive than the sum of their component parts, and prescribing generic formulations of individual acne treatments could potentially reduce costs, but possible advantages of combination products for acne include improved patient adherence and increased efficacy.

Mr. Li, a research fellow in the department of dermatology at Brigham and Women’s Hospital in Boston, and his colleagues drafted a comprehensive list of available combination products (eight brand-name products and two generics). Most combine benzoyl peroxide with another common acne medication. To analyze trends in medication use, they performed a retrospective cost analysis using Medical Expenditure Panel Survey (MEPS) data from 1996 to 2016, searching for these combination medications to gather the annual number of prescriptions, number of users, expenditures, and aggregate demographics for each product. The data were weighted to represent national estimates.

They also used data from the National Average Drug Acquisition Cost (NADAC) database, used by the Centers for Medicare & Medicaid Services as a pricing benchmark, and calculated the difference between the unit price of each combination product and the sum of the prices of its generic components. They multiplied this difference by the median number of units prescribed annually for the given combination.

The researchers found that most users of combination acne products were younger than 18 years (23%), female (55%), and white (83%), and the most commonly prescribed combination product changed over time. From 1996 to 2002, Benzamycin (benzoyl peroxide and erythromycin) was the most frequently prescribed combination. Several years later, its place was taken by BenzaClin (benzoyl peroxide and clindamycin) from 2003 to 2010, followed by Ziana (clindamycin and tretinoin) in 2011 and Epiduo (adapalene and benzoyl peroxide) from 2012 to 2016.

“Spending has increased steadily from a little bit over $82 million in 1996 to nearly half a billion dollars in 2016,” Mr. Li said. “That’s a rise of more than 500% in the last 20 years. Based on the median pricing and utilization data that we derived from the NADAC database, we determined that substitution with component generics can provide median annual savings of at least a quarter billion dollars each year.”

Although the data indicate a trend toward increased use of and spending on new, branded combination products, the literature includes “minimal data to suggest whether one combination acne product is better than the next one, or how it compares to its component medications when used in combination,” he said. He and his colleagues found no comparative data apart from a 2001 study that examined Benzamycin and BenzaClin, which suggested that there was no difference in efficacy or tolerability between the products.

The present study is limited by reporting bias and recall bias because it relies partly on MEPS, a survey, and the NADAC pricing database had information only for 2013-2016. The researchers consequently used the most recent prices to calculate potential savings.

“Until we have more meaningful data to suggest otherwise, we’re in a state of equipoise,” said Mr. Li.

The research was funded by the National Center for Advancing Translational Sciences, part of the National Institutes of Health.
 

[email protected]

SOURCE: Li D et al. AAD 2019, Abstract 11333.

WASHINGTON – Expenditures for combination acne products increased from $82 million in 1996 to $487 million in 2016, according to an analysis presented at the annual meeting of the American Academy of Dermatology.

During a late-breaking research session, David Li, a fourth-year medical student at Tufts University, Boston, presented the results of a retrospective cost analysis study, conducted to identify trends in overall spending for combination acne products. Spending measures were adjusted for inflation to 2016 U.S. dollars.

While spending on combination products for acne has increased significantly over the past 2 decades, comparative efficacy data for these products are limited, he noted. Combination products are more expensive than the sum of their component parts, and prescribing generic formulations of individual acne treatments could potentially reduce costs, but possible advantages of combination products for acne include improved patient adherence and increased efficacy.

Mr. Li, a research fellow in the department of dermatology at Brigham and Women’s Hospital in Boston, and his colleagues drafted a comprehensive list of available combination products (eight brand-name products and two generics). Most combine benzoyl peroxide with another common acne medication. To analyze trends in medication use, they performed a retrospective cost analysis using Medical Expenditure Panel Survey (MEPS) data from 1996 to 2016, searching for these combination medications to gather the annual number of prescriptions, number of users, expenditures, and aggregate demographics for each product. The data were weighted to represent national estimates.

They also used data from the National Average Drug Acquisition Cost (NADAC) database, used by the Centers for Medicare & Medicaid Services as a pricing benchmark, and calculated the difference between the unit price of each combination product and the sum of the prices of its generic components. They multiplied this difference by the median number of units prescribed annually for the given combination.

The researchers found that most users of combination acne products were younger than 18 years (23%), female (55%), and white (83%), and the most commonly prescribed combination product changed over time. From 1996 to 2002, Benzamycin (benzoyl peroxide and erythromycin) was the most frequently prescribed combination. Several years later, its place was taken by BenzaClin (benzoyl peroxide and clindamycin) from 2003 to 2010, followed by Ziana (clindamycin and tretinoin) in 2011 and Epiduo (adapalene and benzoyl peroxide) from 2012 to 2016.

“Spending has increased steadily from a little bit over $82 million in 1996 to nearly half a billion dollars in 2016,” Mr. Li said. “That’s a rise of more than 500% in the last 20 years. Based on the median pricing and utilization data that we derived from the NADAC database, we determined that substitution with component generics can provide median annual savings of at least a quarter billion dollars each year.”

Although the data indicate a trend toward increased use of and spending on new, branded combination products, the literature includes “minimal data to suggest whether one combination acne product is better than the next one, or how it compares to its component medications when used in combination,” he said. He and his colleagues found no comparative data apart from a 2001 study that examined Benzamycin and BenzaClin, which suggested that there was no difference in efficacy or tolerability between the products.

The present study is limited by reporting bias and recall bias because it relies partly on MEPS, a survey, and the NADAC pricing database had information only for 2013-2016. The researchers consequently used the most recent prices to calculate potential savings.

“Until we have more meaningful data to suggest otherwise, we’re in a state of equipoise,” said Mr. Li.

The research was funded by the National Center for Advancing Translational Sciences, part of the National Institutes of Health.
 

[email protected]

SOURCE: Li D et al. AAD 2019, Abstract 11333.

HONOLULU – Telerehabilitation is as effective as in-clinic rehabilitation for improving arm function after stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association. Telerehabilitation also provides patient education as effectively as in-clinic rehabilitation, said Steven C. Cramer, MD, professor of neurology at the University of California, Irvine.

Stroke is a leading cause of disability, and more than 80% of patients with stroke have motor deficits when they present to the ED. Research indicates that high doses of rehabilitation therapy improve brain and motor function. However, many patients get low amounts of rehabilitation because of obstacles such as travel difficulties and shortages of therapy providers. “We reasoned that telerehabilitation is ideally suited to efficiently provide a large dose of useful, high-quality rehab therapy after stroke,” Dr. Cramer said.

Participants received supervised and unsupervised therapy

He and his colleagues enrolled patients who had experienced a stroke during the previous 4-36 weeks and who had arm motor deficits into their study. Eligible participants were adults, had experienced ischemic stroke or intracerebral hemorrhage, and had an arm Fugl-Meyer score between 22 and 56 out of 66.

Dr. Cramer’s group randomized 124 participants at 11 National Institutes of Health StrokeNet sites to 6 weeks of intensive arm rehabilitation therapy, plus stroke education, delivered in clinic or at home by a telehealth system. For both groups, treatment included 36 sessions that each lasted for 70 minutes. Half of the sessions were supervised and half were not. All sessions included at least 15 minutes of arm exercises and at least 15 minutes of functional training. Unsupervised sessions also included at least 5 minutes of stroke education on topics such as prevention, risk factors, recognition, and treatment. Participants in the in-clinic group worked with therapists in the clinic on supervised days and at home with a personalized booklet on unsupervised days. Participants in the telerehabilitation group played specially designed and individually tailored computer games at home on all days and had video conferences with therapists on supervised days. The treatment groups included approximately equal numbers of patients; treatment duration, intensity, and frequency were matched between groups.

The investigators hypothesized that telerehabilitation was not inferior to in-clinic rehabilitation. The study’s primary endpoint was change in Fugl-Meyer score from baseline to 30 days after the end of therapy. Secondary end points included Box and Blocks score (that is, a measure of arm function), Stroke Impact Scale–hand, and gains in stroke knowledge. The researchers defined the noninferiority margin as 30% of the gains of the in-clinic group. End points were evaluated by blinded assessors.

Patients had clinically meaningful gains

Participants’ average age was 61 years; the mean baseline arm Fugl-Meyer score was 42. Stroke onset had occurred at a mean of 4.5 months previously, and most strokes were ischemic. In all, 10 participants dropped out of the study. The rate of compliance was 98.3% in the telerehabilitation group and 93.0% in the in-clinic group.

The change in Fugl-Meyer score from baseline to 30 days post therapy was 8.36 points in the in-clinic group and 7.86 points in the telerehabilitation group. The changes in this score were higher than the minimal clinically important difference. The difference between groups, adjusted for covariance, was approximately 0. In addition, the 95% confidence interval for the change in score in the telerehabilitation group was within the noninferiority margin. “We can say that telerehabilitation is not inferior” to in-clinic therapy, said Dr. Cramer.

Telerehabilitation also was noninferior to in-clinic rehabilitation on the Box and Blocks score, and gains in stroke knowledge were significant and comparable in both groups. “Interestingly, the arm motor gains did not differ whether the subjects had aphasia or not,” said Dr. Cramer.

The investigators measured activity-inherent motivation (that is, how much a patient likes rehabilitation) using the Physical Activity Enjoyment Scale. Scores were higher in the in-clinic group, compared with the telerehabilitation group. “People like going to sit with a live human, and they like the longer time with the live human. This is something for us to study further and understand,” said Dr. Cramer.

Dr. Cramer and colleagues observed six serious adverse events in the in-clinic group and one in the telerehabilitation group, such as pneumonia or palpitations, all of which were deemed unrelated to therapy. Adverse events related to therapy (for example, shoulder pain and fatigue) were equally distributed between the two groups.

“What we were trying to do with home-based telehealth does not compete with or replace traditional rehab medicine. It is expanding tools for occupational and physical therapists, for nurses and physicians,” said Dr. Cramer.

Future studies could examine the efficacy of telerehabilitation in the treatment of language deficits, leg weakness, micturition, and dysphagia. “We might also study telehealth such as this to see how we can improve access and lower the cost of poststroke rehab care,” he concluded.

The study was funded by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development and several grants from the National Institute of Neurological Disorders and Stroke. Dr. Cramer has an ownership interest in TRCare, a company that plans to market a telerehabilitation system and was not involved in the study. In addition, he is a consultant or advisor for MicroTransponder, Dart Neuroscience, Neurolutions, Regenera, Abbvie, SanBio, and TRCare.

[email protected]

SOURCE: Cramer SC et al. ISC 2019, Abstract LB23.

HONOLULU – Telerehabilitation is as effective as in-clinic rehabilitation for improving arm function after stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association. Telerehabilitation also provides patient education as effectively as in-clinic rehabilitation, said Steven C. Cramer, MD, professor of neurology at the University of California, Irvine.

Stroke is a leading cause of disability, and more than 80% of patients with stroke have motor deficits when they present to the ED. Research indicates that high doses of rehabilitation therapy improve brain and motor function. However, many patients get low amounts of rehabilitation because of obstacles such as travel difficulties and shortages of therapy providers. “We reasoned that telerehabilitation is ideally suited to efficiently provide a large dose of useful, high-quality rehab therapy after stroke,” Dr. Cramer said.

Participants received supervised and unsupervised therapy

He and his colleagues enrolled patients who had experienced a stroke during the previous 4-36 weeks and who had arm motor deficits into their study. Eligible participants were adults, had experienced ischemic stroke or intracerebral hemorrhage, and had an arm Fugl-Meyer score between 22 and 56 out of 66.

Dr. Cramer’s group randomized 124 participants at 11 National Institutes of Health StrokeNet sites to 6 weeks of intensive arm rehabilitation therapy, plus stroke education, delivered in clinic or at home by a telehealth system. For both groups, treatment included 36 sessions that each lasted for 70 minutes. Half of the sessions were supervised and half were not. All sessions included at least 15 minutes of arm exercises and at least 15 minutes of functional training. Unsupervised sessions also included at least 5 minutes of stroke education on topics such as prevention, risk factors, recognition, and treatment. Participants in the in-clinic group worked with therapists in the clinic on supervised days and at home with a personalized booklet on unsupervised days. Participants in the telerehabilitation group played specially designed and individually tailored computer games at home on all days and had video conferences with therapists on supervised days. The treatment groups included approximately equal numbers of patients; treatment duration, intensity, and frequency were matched between groups.

The investigators hypothesized that telerehabilitation was not inferior to in-clinic rehabilitation. The study’s primary endpoint was change in Fugl-Meyer score from baseline to 30 days after the end of therapy. Secondary end points included Box and Blocks score (that is, a measure of arm function), Stroke Impact Scale–hand, and gains in stroke knowledge. The researchers defined the noninferiority margin as 30% of the gains of the in-clinic group. End points were evaluated by blinded assessors.

Patients had clinically meaningful gains

Participants’ average age was 61 years; the mean baseline arm Fugl-Meyer score was 42. Stroke onset had occurred at a mean of 4.5 months previously, and most strokes were ischemic. In all, 10 participants dropped out of the study. The rate of compliance was 98.3% in the telerehabilitation group and 93.0% in the in-clinic group.

The change in Fugl-Meyer score from baseline to 30 days post therapy was 8.36 points in the in-clinic group and 7.86 points in the telerehabilitation group. The changes in this score were higher than the minimal clinically important difference. The difference between groups, adjusted for covariance, was approximately 0. In addition, the 95% confidence interval for the change in score in the telerehabilitation group was within the noninferiority margin. “We can say that telerehabilitation is not inferior” to in-clinic therapy, said Dr. Cramer.

Telerehabilitation also was noninferior to in-clinic rehabilitation on the Box and Blocks score, and gains in stroke knowledge were significant and comparable in both groups. “Interestingly, the arm motor gains did not differ whether the subjects had aphasia or not,” said Dr. Cramer.

The investigators measured activity-inherent motivation (that is, how much a patient likes rehabilitation) using the Physical Activity Enjoyment Scale. Scores were higher in the in-clinic group, compared with the telerehabilitation group. “People like going to sit with a live human, and they like the longer time with the live human. This is something for us to study further and understand,” said Dr. Cramer.

Dr. Cramer and colleagues observed six serious adverse events in the in-clinic group and one in the telerehabilitation group, such as pneumonia or palpitations, all of which were deemed unrelated to therapy. Adverse events related to therapy (for example, shoulder pain and fatigue) were equally distributed between the two groups.

“What we were trying to do with home-based telehealth does not compete with or replace traditional rehab medicine. It is expanding tools for occupational and physical therapists, for nurses and physicians,” said Dr. Cramer.

Future studies could examine the efficacy of telerehabilitation in the treatment of language deficits, leg weakness, micturition, and dysphagia. “We might also study telehealth such as this to see how we can improve access and lower the cost of poststroke rehab care,” he concluded.

The study was funded by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development and several grants from the National Institute of Neurological Disorders and Stroke. Dr. Cramer has an ownership interest in TRCare, a company that plans to market a telerehabilitation system and was not involved in the study. In addition, he is a consultant or advisor for MicroTransponder, Dart Neuroscience, Neurolutions, Regenera, Abbvie, SanBio, and TRCare.

[email protected]

SOURCE: Cramer SC et al. ISC 2019, Abstract LB23.

HONOLULU – Telerehabilitation is as effective as in-clinic rehabilitation for improving arm function after stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association. Telerehabilitation also provides patient education as effectively as in-clinic rehabilitation, said Steven C. Cramer, MD, professor of neurology at the University of California, Irvine.

Stroke is a leading cause of disability, and more than 80% of patients with stroke have motor deficits when they present to the ED. Research indicates that high doses of rehabilitation therapy improve brain and motor function. However, many patients get low amounts of rehabilitation because of obstacles such as travel difficulties and shortages of therapy providers. “We reasoned that telerehabilitation is ideally suited to efficiently provide a large dose of useful, high-quality rehab therapy after stroke,” Dr. Cramer said.

Participants received supervised and unsupervised therapy

He and his colleagues enrolled patients who had experienced a stroke during the previous 4-36 weeks and who had arm motor deficits into their study. Eligible participants were adults, had experienced ischemic stroke or intracerebral hemorrhage, and had an arm Fugl-Meyer score between 22 and 56 out of 66.

Dr. Cramer’s group randomized 124 participants at 11 National Institutes of Health StrokeNet sites to 6 weeks of intensive arm rehabilitation therapy, plus stroke education, delivered in clinic or at home by a telehealth system. For both groups, treatment included 36 sessions that each lasted for 70 minutes. Half of the sessions were supervised and half were not. All sessions included at least 15 minutes of arm exercises and at least 15 minutes of functional training. Unsupervised sessions also included at least 5 minutes of stroke education on topics such as prevention, risk factors, recognition, and treatment. Participants in the in-clinic group worked with therapists in the clinic on supervised days and at home with a personalized booklet on unsupervised days. Participants in the telerehabilitation group played specially designed and individually tailored computer games at home on all days and had video conferences with therapists on supervised days. The treatment groups included approximately equal numbers of patients; treatment duration, intensity, and frequency were matched between groups.

The investigators hypothesized that telerehabilitation was not inferior to in-clinic rehabilitation. The study’s primary endpoint was change in Fugl-Meyer score from baseline to 30 days after the end of therapy. Secondary end points included Box and Blocks score (that is, a measure of arm function), Stroke Impact Scale–hand, and gains in stroke knowledge. The researchers defined the noninferiority margin as 30% of the gains of the in-clinic group. End points were evaluated by blinded assessors.

Patients had clinically meaningful gains

Participants’ average age was 61 years; the mean baseline arm Fugl-Meyer score was 42. Stroke onset had occurred at a mean of 4.5 months previously, and most strokes were ischemic. In all, 10 participants dropped out of the study. The rate of compliance was 98.3% in the telerehabilitation group and 93.0% in the in-clinic group.

The change in Fugl-Meyer score from baseline to 30 days post therapy was 8.36 points in the in-clinic group and 7.86 points in the telerehabilitation group. The changes in this score were higher than the minimal clinically important difference. The difference between groups, adjusted for covariance, was approximately 0. In addition, the 95% confidence interval for the change in score in the telerehabilitation group was within the noninferiority margin. “We can say that telerehabilitation is not inferior” to in-clinic therapy, said Dr. Cramer.

Telerehabilitation also was noninferior to in-clinic rehabilitation on the Box and Blocks score, and gains in stroke knowledge were significant and comparable in both groups. “Interestingly, the arm motor gains did not differ whether the subjects had aphasia or not,” said Dr. Cramer.

The investigators measured activity-inherent motivation (that is, how much a patient likes rehabilitation) using the Physical Activity Enjoyment Scale. Scores were higher in the in-clinic group, compared with the telerehabilitation group. “People like going to sit with a live human, and they like the longer time with the live human. This is something for us to study further and understand,” said Dr. Cramer.

Dr. Cramer and colleagues observed six serious adverse events in the in-clinic group and one in the telerehabilitation group, such as pneumonia or palpitations, all of which were deemed unrelated to therapy. Adverse events related to therapy (for example, shoulder pain and fatigue) were equally distributed between the two groups.

“What we were trying to do with home-based telehealth does not compete with or replace traditional rehab medicine. It is expanding tools for occupational and physical therapists, for nurses and physicians,” said Dr. Cramer.

Future studies could examine the efficacy of telerehabilitation in the treatment of language deficits, leg weakness, micturition, and dysphagia. “We might also study telehealth such as this to see how we can improve access and lower the cost of poststroke rehab care,” he concluded.

The study was funded by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development and several grants from the National Institute of Neurological Disorders and Stroke. Dr. Cramer has an ownership interest in TRCare, a company that plans to market a telerehabilitation system and was not involved in the study. In addition, he is a consultant or advisor for MicroTransponder, Dart Neuroscience, Neurolutions, Regenera, Abbvie, SanBio, and TRCare.

[email protected]

SOURCE: Cramer SC et al. ISC 2019, Abstract LB23.

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

HONOLULU – Compared with standard treatment, intensive blood pressure reduction does not significantly reduce the risk of recurrent stroke, according to research presented at the International Stroke Conference sponsored by the American Heart Association.

Combined with data from previous trials, these results support a target systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg for secondary stroke prevention, said Kazuo Kitagawa, MD, PhD.

Lowering blood pressure reduces the risk of recurrent stroke, but investigators have not identified the best target blood pressure for this indication. The Secondary Prevention of Small Subcortical Strokes Trial (SPS3) examined the efficacy of intensive blood pressure treatment for secondary stroke prevention. The investigators randomized more than 3,000 patients with recent lacunar stroke to intensive or standard blood pressure treatment. Intensive treatment (a target systolic blood pressure of less than 130 mm Hg) conferred a nonsignificant reduction of the risk of recurrent stroke. A 2018 meta-analysis of SPS3 and two smaller randomized controlled trials also showed that intensive treatment did not significantly reduce the risk of recurrent stroke.
 

A new multicenter trial

Dr. Kitagawa, of Tokyo Women’s Medical University, and colleagues conducted a new trial to evaluate whether intensive blood pressure reduction significantly reduced the risk of recurrent stroke, compared with standard treatment (a systolic target of less than 140 mm Hg and a diastolic target of less than 90 mm Hg). Between 2010 and 2016, they enrolled patients with a history of stroke within the previous 3 years at 140 hospitals in Japan. Participants were randomized to standard blood pressure treatment or intensive blood pressure treatment (defined in this study as a systolic target of less than 120 mm Hg and a diastolic target of less than 80 mm Hg). The primary end point was recurrent stroke.

Both treatment regimens were based on stepwise multidrug rationing. Step 1 was an angiotensin II receptor blockade (ARB), step 2 was the addition of diuretics, step 3 was the addition of calcium channel blockers, step 4 was an increase of the ARB, step 5 was increase of the calcium channel blocker, and step 6 was the addition of spironolactone.

This trial was stopped at the end of 2016 because of slow recruitment and funding cessation. Investigators randomized 1,280 patients out of a planned 2,000. Seventeen patients were excluded from analysis. At baseline, participants’ mean age was 67 years, and mean systolic blood pressure was 145 mm Hg. The qualifying event was ischemic stroke for 85% of patients and intracerebral hemorrhage for 15%. Mean follow-up duration was 3.9 years.
 

Intensive treatment reduced blood pressure

At 1 year, the mean systolic blood pressure was 132.0 mm Hg in the standard-treatment group and 123.7 mm Hg in the intensive-treatment group. Mean diastolic blood pressure was 77.5 mm Hg in the standard-treatment group and 72.8 mm Hg in the intensive-treatment group. The investigators observed a significant difference in blood pressure between the groups throughout the study period.

The annual rate of stroke recurrence was 2.26% in the standard-treatment group and 1.65% in the intensive-treatment group. Intensive treatment tended to reduce stroke recurrence (hazard ratio, 0.73), but the result was not statistically significant. “The nonsignificant finding might be due to early termination or the modest difference in blood pressure level [between groups],” said Dr. Kitagawa.

Subgroup analyses did not indicate any interaction between treatment group and age, sex, qualifying event, mean systolic blood pressure at baseline, or diabetes. The rate of ischemic stroke was similar between the two groups, but the rate of intracerebral hemorrhage was lower in the intensive treatment group than in the standard treatment group. The rate of serious adverse events was similar between treatment groups.

When Dr. Kitagawa and colleagues pooled their data with those examined in the 2018 meta-analysis, they found that intensive treatment significantly reduced the risk of recurrent stroke (hazard ratio, 0.68), compared with standard treatment.

This study was sponsored by Biomedis International.

[email protected]

SOURCE: Kitagawa K et al. ISC 2019, Abstract LB10.

HONOLULU – Andexanet alfa rapidly reverses factor Xa inhibition and effectively establishes hemostasis in patients with acute major bleeding, according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.

Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
 

A single-cohort study

Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.

The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
 

Hemostasis was sustained for 12 hours

The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).

The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.

Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.

To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.

The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.

The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.

Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.

[email protected]

SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.

HONOLULU – Andexanet alfa rapidly reverses factor Xa inhibition and effectively establishes hemostasis in patients with acute major bleeding, according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.

Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
 

A single-cohort study

Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.

The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
 

Hemostasis was sustained for 12 hours

The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).

The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.

Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.

To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.

The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.

The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.

Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.

[email protected]

SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.

HONOLULU – Andexanet alfa rapidly reverses factor Xa inhibition and effectively establishes hemostasis in patients with acute major bleeding, according to a study presented at the International Stroke Conference sponsored by the American Heart Association. The medication is associated with a low rate of mortality resulting from intracerebral hemorrhage (ICH), compared with the general population of patients with ICH receiving anticoagulation.

Factor Xa inhibitors such as apixaban and rivaroxaban effectively prevent thromboembolic events but may cause or exacerbate acute major bleeding. Andexanet alfa, a modified, recombinant, inactive form of human factor Xa, was developed and approved as a reversal agent for factor Xa inhibitors. In a 2015 study, andexanet rapidly and safely reversed anti–factor Xa activity in large cohorts of patients without bleeding.
 

A single-cohort study

Truman John Milling Jr., MD, an emergency medicine physician at Dell Seton Medical Center at the University of Texas in Austin, and his colleagues conducted the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study to evaluate the drug’s safety and efficacy in patients with acute major bleeding associated with treatment with a factor Xa inhibitor. For participants to be eligible, their bleeding had to be life threatening with signs of hemodynamic compromise, be associated with a decrease in hemoglobin level of at least 2 g/dL, or occur in a critical organ such as the brain. An independent academic committee determined whether patients met these criteria.

The trial’s primary efficacy outcomes were change from baseline in anti–factor Xa activity and the percentage of patients with excellent or good hemostatic efficacy at 12 hours. The primary safety endpoints were death, thrombotic events, and the development of neutralizing antibodies to andexanet or to native factor X and factor Xa. The efficacy population included patients with major bleeding and baseline anti–factor Xa activity of at least 75 ng/mL. The safety population included all patients who received a dose of andexanet. The independent committee adjudicated the efficacy and safety outcomes.
 

Hemostasis was sustained for 12 hours

The investigators enrolled 352 participants into the study, all of whom received andexanet and were followed for at least 30 days or until death. The population’s mean age was 77 years. “These were older and sicker patients with a significant amount of comorbid disease,” said Dr. Milling. The primary indication for anticoagulation was atrial fibrillation in 80% of patients. The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26% of patients. The remaining 10% of patients had bleeding affecting other areas (such as pericardial or intramuscular bleeding).

The investigators included 254 patients in the efficacy population. At the end of the administration of the andexanet bolus, the median value for anti–factor Xa activity decreased by 92% among participants receiving apixaban, 92% among participants receiving rivaroxaban, and 75% among patients receiving enoxaparin. Among patients receiving apixaban, the median value for anti–factor Xa activity was decreased by 32% at 4 hours, 34% at 8 hours, and 38% at 12 hours. Among patients receiving rivaroxaban, the median value for anti–factor Xa activity was decreased by 42% at 4 hours, 48% at 8 hours, and 62% at 12 hours.

Dr. Milling and his colleagues assessed hemostatic efficacy in 249 patients. Of this group, 82% achieved good or excellent hemostasis. Among participants with good or excellent hemostasis, 84% had excellent results, and 16% had good results. Subanalysis by factor Xa inhibitor, type of bleed, age, and dose of andexanet did not alter the findings significantly.

To determine whether hemostasis had been sustained sufficiently to prevent clinical deterioration, the investigators examined 71 patients with ICH and a single-compartment bleed. From 1 hour to 12 hours, one patient’s outcome changed from excellent/good to poor/none, and one patient’s outcome changed from excellent to good. For the majority of these patients, however, good hemostasis was sustained from 1 to 12 hours.

The rate of thromboembolic events was 9.7%, which is in the expected range for this population, said Dr. Milling. These events were distributed evenly among the 4 weeks of the study. Stroke and deep vein thrombosis accounted for most of these events, and pulmonary emboli and heart attacks occurred as well. “Once we restarted oral anticoagulation ... there were no more thrombotic events,” said Dr. Milling. No patient developed neutralizing antibodies to factor X or factor Xa, nor did any patient develop neutralizing antibodies to andexanet.

The overall mortality rate was 13.9%. The rate of mortality resulting from ICH was 15%, and the rate of mortality resulting from gastrointestinal bleeding was 11%. These results are impressive, considering that patients had received anticoagulants, said Dr. Milling.

Portola Pharmaceuticals, the maker of andexanet alfa, funded the study. Dr. Milling reported receiving funding and honoraria from the Population Health Research Institute at McMasters University, Janssen, CSL Behring, and Octapharma. He also received a small research payment from Portola Pharmaceuticals. Several of the investigators reported receiving funding from Portola Pharmaceuticals.

[email protected]

SOURCE: Milling TJ et al. ISC 2019, Abstract LB7.