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Spinal cord stimulation restores poststroke arm, hand function in two patients
The results provide “promising, albeit preliminary, evidence that spinal cord stimulation could be an assistive as well as a restorative approach for upper-limb recovery after stroke,” wrote first author Marc P. Powell, PhD, of Reach Neuro Inc., Pittsburgh, and colleagues.
The findings were published online in Nature Medicine.
Top cause of paralysis
“Stroke is the largest cause of paralysis in the world,” with nearly three-quarters of patients with stroke experiencing lasting deficits in motor control of their arm and hand, co–senior study author Marco Capogrosso, PhD, assistant professor of neurological surgery at the University of Pittsburgh, said during a press briefing.
Stroke can disrupt communication between the brain and the spinal cord, leading to motor deficits in the arm and hand. However, below the lesion, the spinal circuits that control movement remain intact and could be targeted to restore function, Dr. Capogrosso noted.
Spinal cord stimulation has shown promise in promoting long-lasting recovery of leg motor function in patients with spinal cord injury; but until now, it’s been largely unexplored for upper-limb recovery.
In this “first-in-human” study, the investigators percutaneously implanted two linear leads in the dorsolateral epidural space targeting neural circuits that control arm and hand muscles in two patients.
One of the patients was a woman (age, 31 years) who had experienced a right thalamic hemorrhagic stroke secondary to a cavernous malformation 9 years before enrolling in the pilot study.
The other patient was a woman (age, 47 years) who experienced a right ischemic middle cerebral artery (MCA) stroke secondary to a right carotid dissection, resulting in a large MCA territory infarct 3 years before entering the study.
In both patients, continuous stimulation of the targeted neural circuits led to significant and immediate improvement in arm and hand strength and dexterity. This enabled the patients to perform movements that they couldn’t perform without spinal cord stimulation.
The process also enabled fine motor skills, such as opening a lock and using utensils to eat independently – tasks that the younger woman had not been able to do for 9 years.
“Perhaps even more interesting, we found that after a few weeks of use, some of these improvements endure when the stimulation is switched off, indicating exciting avenues for the future of stroke therapies,” Dr. Capogrosso said in a news release.
No serious adverse events were reported.
‘Easily translated’
Dr. Capogrosso said that, thanks to years of preclinical research, the investigators have developed a practical, easy-to-use stimulation protocol adapting existing clinical technologies that “could be easily translated to the hospital and quickly moved from the lab to the clinic.”
The researchers noted, however, that further studies in larger cohorts will be required to validate the safety and efficacy of this approach.
They are currently working with more patients with stroke to fine-tune placement of the leads and stimulation protocol, as well as determine which patients are best suited for the approach.
“Creating effective neurorehabilitation solutions for people affected by movement impairment after stroke is becoming ever more urgent,” co–senior author Elvira Pirondini, PhD, assistant professor of physical medicine and rehabilitation at the University of Pittsburgh, said in the release.
“Even mild deficits resulting from a stroke can isolate people from social and professional lives and become very debilitating, with motor impairments in the arm and hand being especially taxing and impeding simple daily activities, such as writing, eating, and getting dressed,” she added.
This research was funded by the National Institutes of Health BRAIN Initiative, with additional research support provided by the Department of Neurological Surgery and the Department of Physical Medicine and Rehabilitation at Pitt, and the Department of Mechanical Engineering and the Neuroscience Institute at Carnegie Mellon University. Three investigators have financial interests in Reach Neuro, which has an interest in the technology being evaluated in this study.
A version of this article first appeared on Medscape.com.
The results provide “promising, albeit preliminary, evidence that spinal cord stimulation could be an assistive as well as a restorative approach for upper-limb recovery after stroke,” wrote first author Marc P. Powell, PhD, of Reach Neuro Inc., Pittsburgh, and colleagues.
The findings were published online in Nature Medicine.
Top cause of paralysis
“Stroke is the largest cause of paralysis in the world,” with nearly three-quarters of patients with stroke experiencing lasting deficits in motor control of their arm and hand, co–senior study author Marco Capogrosso, PhD, assistant professor of neurological surgery at the University of Pittsburgh, said during a press briefing.
Stroke can disrupt communication between the brain and the spinal cord, leading to motor deficits in the arm and hand. However, below the lesion, the spinal circuits that control movement remain intact and could be targeted to restore function, Dr. Capogrosso noted.
Spinal cord stimulation has shown promise in promoting long-lasting recovery of leg motor function in patients with spinal cord injury; but until now, it’s been largely unexplored for upper-limb recovery.
In this “first-in-human” study, the investigators percutaneously implanted two linear leads in the dorsolateral epidural space targeting neural circuits that control arm and hand muscles in two patients.
One of the patients was a woman (age, 31 years) who had experienced a right thalamic hemorrhagic stroke secondary to a cavernous malformation 9 years before enrolling in the pilot study.
The other patient was a woman (age, 47 years) who experienced a right ischemic middle cerebral artery (MCA) stroke secondary to a right carotid dissection, resulting in a large MCA territory infarct 3 years before entering the study.
In both patients, continuous stimulation of the targeted neural circuits led to significant and immediate improvement in arm and hand strength and dexterity. This enabled the patients to perform movements that they couldn’t perform without spinal cord stimulation.
The process also enabled fine motor skills, such as opening a lock and using utensils to eat independently – tasks that the younger woman had not been able to do for 9 years.
“Perhaps even more interesting, we found that after a few weeks of use, some of these improvements endure when the stimulation is switched off, indicating exciting avenues for the future of stroke therapies,” Dr. Capogrosso said in a news release.
No serious adverse events were reported.
‘Easily translated’
Dr. Capogrosso said that, thanks to years of preclinical research, the investigators have developed a practical, easy-to-use stimulation protocol adapting existing clinical technologies that “could be easily translated to the hospital and quickly moved from the lab to the clinic.”
The researchers noted, however, that further studies in larger cohorts will be required to validate the safety and efficacy of this approach.
They are currently working with more patients with stroke to fine-tune placement of the leads and stimulation protocol, as well as determine which patients are best suited for the approach.
“Creating effective neurorehabilitation solutions for people affected by movement impairment after stroke is becoming ever more urgent,” co–senior author Elvira Pirondini, PhD, assistant professor of physical medicine and rehabilitation at the University of Pittsburgh, said in the release.
“Even mild deficits resulting from a stroke can isolate people from social and professional lives and become very debilitating, with motor impairments in the arm and hand being especially taxing and impeding simple daily activities, such as writing, eating, and getting dressed,” she added.
This research was funded by the National Institutes of Health BRAIN Initiative, with additional research support provided by the Department of Neurological Surgery and the Department of Physical Medicine and Rehabilitation at Pitt, and the Department of Mechanical Engineering and the Neuroscience Institute at Carnegie Mellon University. Three investigators have financial interests in Reach Neuro, which has an interest in the technology being evaluated in this study.
A version of this article first appeared on Medscape.com.
The results provide “promising, albeit preliminary, evidence that spinal cord stimulation could be an assistive as well as a restorative approach for upper-limb recovery after stroke,” wrote first author Marc P. Powell, PhD, of Reach Neuro Inc., Pittsburgh, and colleagues.
The findings were published online in Nature Medicine.
Top cause of paralysis
“Stroke is the largest cause of paralysis in the world,” with nearly three-quarters of patients with stroke experiencing lasting deficits in motor control of their arm and hand, co–senior study author Marco Capogrosso, PhD, assistant professor of neurological surgery at the University of Pittsburgh, said during a press briefing.
Stroke can disrupt communication between the brain and the spinal cord, leading to motor deficits in the arm and hand. However, below the lesion, the spinal circuits that control movement remain intact and could be targeted to restore function, Dr. Capogrosso noted.
Spinal cord stimulation has shown promise in promoting long-lasting recovery of leg motor function in patients with spinal cord injury; but until now, it’s been largely unexplored for upper-limb recovery.
In this “first-in-human” study, the investigators percutaneously implanted two linear leads in the dorsolateral epidural space targeting neural circuits that control arm and hand muscles in two patients.
One of the patients was a woman (age, 31 years) who had experienced a right thalamic hemorrhagic stroke secondary to a cavernous malformation 9 years before enrolling in the pilot study.
The other patient was a woman (age, 47 years) who experienced a right ischemic middle cerebral artery (MCA) stroke secondary to a right carotid dissection, resulting in a large MCA territory infarct 3 years before entering the study.
In both patients, continuous stimulation of the targeted neural circuits led to significant and immediate improvement in arm and hand strength and dexterity. This enabled the patients to perform movements that they couldn’t perform without spinal cord stimulation.
The process also enabled fine motor skills, such as opening a lock and using utensils to eat independently – tasks that the younger woman had not been able to do for 9 years.
“Perhaps even more interesting, we found that after a few weeks of use, some of these improvements endure when the stimulation is switched off, indicating exciting avenues for the future of stroke therapies,” Dr. Capogrosso said in a news release.
No serious adverse events were reported.
‘Easily translated’
Dr. Capogrosso said that, thanks to years of preclinical research, the investigators have developed a practical, easy-to-use stimulation protocol adapting existing clinical technologies that “could be easily translated to the hospital and quickly moved from the lab to the clinic.”
The researchers noted, however, that further studies in larger cohorts will be required to validate the safety and efficacy of this approach.
They are currently working with more patients with stroke to fine-tune placement of the leads and stimulation protocol, as well as determine which patients are best suited for the approach.
“Creating effective neurorehabilitation solutions for people affected by movement impairment after stroke is becoming ever more urgent,” co–senior author Elvira Pirondini, PhD, assistant professor of physical medicine and rehabilitation at the University of Pittsburgh, said in the release.
“Even mild deficits resulting from a stroke can isolate people from social and professional lives and become very debilitating, with motor impairments in the arm and hand being especially taxing and impeding simple daily activities, such as writing, eating, and getting dressed,” she added.
This research was funded by the National Institutes of Health BRAIN Initiative, with additional research support provided by the Department of Neurological Surgery and the Department of Physical Medicine and Rehabilitation at Pitt, and the Department of Mechanical Engineering and the Neuroscience Institute at Carnegie Mellon University. Three investigators have financial interests in Reach Neuro, which has an interest in the technology being evaluated in this study.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
No advantage for full-term aspirin in preventing preterm preeclampsia
Stopping aspirin at 24-28 weeks of gestation has no disadvantage, compared with continuing aspirin full term, for preventing preterm preeclampsia in women at high risk of preeclampsia who have a normal fms-like tyrosine kinase 1 to placental growth factor (sFlt-1:PlGF) ratio, a randomized controlled trial has found.
The findings were published online in JAMA.
Editorialists advise careful consideration
However, in an accompanying editorial, Ukachi N. Emeruwa, MD, MPH, with the division of maternal fetal medicine, department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, and colleagues noted that the questions surrounding continuing or discontinuing aspirin in this high-risk population need further consideration.
They added that the results from this study – conducted in nine maternity hospitals across Spain – are hard to translate for the U.S. population.
In this study, Manel Mendoza, PhD, with the maternal fetal medicine unit, department of obstetrics, at the Universitat Autònoma de Barcelona, and colleagues compared the two approaches because of the potential to mitigate peripartum bleeding by discontinuing aspirin before full term (37 weeks’ gestation) and by an accurate selection of women in the first trimester at higher risk of preeclampsia.
Aspirin cuts preterm preeclampsia by 62% in women at high risk
While aspirin might be associated with an increased risk of peripartum bleeding, aspirin has been proven to reduce the incidence of preterm preeclampsia by 62% in pregnant women at high risk of preeclampsia.
In the multicenter, open-label, randomized, phase 3, noninferiority trial, pregnant women who had a high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24-28 weeks’ gestation were recruited between Aug. 20, 2019, and Sept. 15, 2021. Of those, 936 were analyzed (473 in the intervention group [stopping aspirin] and 473 in the control group [continuing]).
Screening for risk of preterm preeclampsia included analyzing maternal factors, uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein A, and placental growth factor. Follow-up was until delivery for all participants.
Incidence of preterm preeclampsia was 1.48% in the intervention group (discontinuing aspirin) and 1.73% in the control group (continuing aspirin until 36 weeks of gestation; absolute difference, –0.25%; 95% confidence interval, –1.86% to 1.36%), which indicates noninferiority for stopping aspirin. The bar for noninferiority was less than a 1.9% difference in preterm preeclampsia incidences between groups.
Researchers did find a higher incidence of minor antepartum bleeding in the group that continued aspirin (7.61% in the low-dose aspirin discontinuation group vs. 12.31% in the low-dose aspirin continuation group; absolute difference, –4.70; 95% CI, –8.53 to –0.87).
Differences in U.S. guidelines
Dr. Emeruwa and colleagues noted the study challenges a growing body of evidence favoring increasingly widespread use of low-dose aspirin in pregnancy.
They called the study “well designed and provocative,” but wrote that the findings are hard to interpret for a U.S. population. Some key differences in the U.S. preeclampsia prevention guidelines, compared with the practices of the study’s authors, included the reliance on clinical maternal factors in the United States for screening for low-dose aspirin prophylaxis as opposed to molecular biomarkers; a different aspirin dose prescribed in the United States (81 mg daily), compared with international societies (150 mg daily); and a lack of a recommendation in the United States to stop prophylactic low-dose aspirin at 36 weeks.
Dr. Emeruwa and colleagues also questioned the scope of the outcome measure used.
They wrote that limiting outcomes to preterm preeclampsia dims the effects of all types of preeclampsia on perinatal and maternal outcomes and that early-onset preeclampsia at less than 34 weeks “occurs in just 0.38% of pregnancies, while 3%-5% are affected by late-onset preeclampsia.”
‘Late-onset preeclampsia has a higher overall impact’
Dr. Emeruwa and colleagues wrote: “Though the odds of adverse perinatal and maternal outcomes are higher with preterm preeclampsia, due to its overall higher incidence, late-onset preeclampsia has a higher overall impact on perinatal and maternal morbidity and mortality.”
The study can inform future U.S. approaches, the editorialists wrote, and build on work already being done in the United States.
The study investigators used biophysical and molecular markers to more accurately assess risk for starting low-dose aspirin prophylaxis in the first trimester and applied a growing body of data showing the high negative predictive value of second-trimester biomarkers.
The editorialists noted that the U.S. Preventive Services Task Force recommendations would have captured “less than 50% of the at-risk population” that Dr. Mendoza’s team found eligible for low-dose aspirin.
Those factors, the editorialists wrote, point to the potential to improve guidelines for personalized preeclampsia management in pregnancy.
They concluded: “U.S. practitioners and professional societies should reconsider current risk assessment strategies, which are largely based on maternal factors, and evaluate whether incorporation of molecular biomarkers would improve maternal and fetal/neonatal outcomes.”
The study authors acknowledged that 92% of participants in the study were White, thus limiting generalizability.
The authors and editorialists reported no relevant financial relationships.
Stopping aspirin at 24-28 weeks of gestation has no disadvantage, compared with continuing aspirin full term, for preventing preterm preeclampsia in women at high risk of preeclampsia who have a normal fms-like tyrosine kinase 1 to placental growth factor (sFlt-1:PlGF) ratio, a randomized controlled trial has found.
The findings were published online in JAMA.
Editorialists advise careful consideration
However, in an accompanying editorial, Ukachi N. Emeruwa, MD, MPH, with the division of maternal fetal medicine, department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, and colleagues noted that the questions surrounding continuing or discontinuing aspirin in this high-risk population need further consideration.
They added that the results from this study – conducted in nine maternity hospitals across Spain – are hard to translate for the U.S. population.
In this study, Manel Mendoza, PhD, with the maternal fetal medicine unit, department of obstetrics, at the Universitat Autònoma de Barcelona, and colleagues compared the two approaches because of the potential to mitigate peripartum bleeding by discontinuing aspirin before full term (37 weeks’ gestation) and by an accurate selection of women in the first trimester at higher risk of preeclampsia.
Aspirin cuts preterm preeclampsia by 62% in women at high risk
While aspirin might be associated with an increased risk of peripartum bleeding, aspirin has been proven to reduce the incidence of preterm preeclampsia by 62% in pregnant women at high risk of preeclampsia.
In the multicenter, open-label, randomized, phase 3, noninferiority trial, pregnant women who had a high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24-28 weeks’ gestation were recruited between Aug. 20, 2019, and Sept. 15, 2021. Of those, 936 were analyzed (473 in the intervention group [stopping aspirin] and 473 in the control group [continuing]).
Screening for risk of preterm preeclampsia included analyzing maternal factors, uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein A, and placental growth factor. Follow-up was until delivery for all participants.
Incidence of preterm preeclampsia was 1.48% in the intervention group (discontinuing aspirin) and 1.73% in the control group (continuing aspirin until 36 weeks of gestation; absolute difference, –0.25%; 95% confidence interval, –1.86% to 1.36%), which indicates noninferiority for stopping aspirin. The bar for noninferiority was less than a 1.9% difference in preterm preeclampsia incidences between groups.
Researchers did find a higher incidence of minor antepartum bleeding in the group that continued aspirin (7.61% in the low-dose aspirin discontinuation group vs. 12.31% in the low-dose aspirin continuation group; absolute difference, –4.70; 95% CI, –8.53 to –0.87).
Differences in U.S. guidelines
Dr. Emeruwa and colleagues noted the study challenges a growing body of evidence favoring increasingly widespread use of low-dose aspirin in pregnancy.
They called the study “well designed and provocative,” but wrote that the findings are hard to interpret for a U.S. population. Some key differences in the U.S. preeclampsia prevention guidelines, compared with the practices of the study’s authors, included the reliance on clinical maternal factors in the United States for screening for low-dose aspirin prophylaxis as opposed to molecular biomarkers; a different aspirin dose prescribed in the United States (81 mg daily), compared with international societies (150 mg daily); and a lack of a recommendation in the United States to stop prophylactic low-dose aspirin at 36 weeks.
Dr. Emeruwa and colleagues also questioned the scope of the outcome measure used.
They wrote that limiting outcomes to preterm preeclampsia dims the effects of all types of preeclampsia on perinatal and maternal outcomes and that early-onset preeclampsia at less than 34 weeks “occurs in just 0.38% of pregnancies, while 3%-5% are affected by late-onset preeclampsia.”
‘Late-onset preeclampsia has a higher overall impact’
Dr. Emeruwa and colleagues wrote: “Though the odds of adverse perinatal and maternal outcomes are higher with preterm preeclampsia, due to its overall higher incidence, late-onset preeclampsia has a higher overall impact on perinatal and maternal morbidity and mortality.”
The study can inform future U.S. approaches, the editorialists wrote, and build on work already being done in the United States.
The study investigators used biophysical and molecular markers to more accurately assess risk for starting low-dose aspirin prophylaxis in the first trimester and applied a growing body of data showing the high negative predictive value of second-trimester biomarkers.
The editorialists noted that the U.S. Preventive Services Task Force recommendations would have captured “less than 50% of the at-risk population” that Dr. Mendoza’s team found eligible for low-dose aspirin.
Those factors, the editorialists wrote, point to the potential to improve guidelines for personalized preeclampsia management in pregnancy.
They concluded: “U.S. practitioners and professional societies should reconsider current risk assessment strategies, which are largely based on maternal factors, and evaluate whether incorporation of molecular biomarkers would improve maternal and fetal/neonatal outcomes.”
The study authors acknowledged that 92% of participants in the study were White, thus limiting generalizability.
The authors and editorialists reported no relevant financial relationships.
Stopping aspirin at 24-28 weeks of gestation has no disadvantage, compared with continuing aspirin full term, for preventing preterm preeclampsia in women at high risk of preeclampsia who have a normal fms-like tyrosine kinase 1 to placental growth factor (sFlt-1:PlGF) ratio, a randomized controlled trial has found.
The findings were published online in JAMA.
Editorialists advise careful consideration
However, in an accompanying editorial, Ukachi N. Emeruwa, MD, MPH, with the division of maternal fetal medicine, department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, and colleagues noted that the questions surrounding continuing or discontinuing aspirin in this high-risk population need further consideration.
They added that the results from this study – conducted in nine maternity hospitals across Spain – are hard to translate for the U.S. population.
In this study, Manel Mendoza, PhD, with the maternal fetal medicine unit, department of obstetrics, at the Universitat Autònoma de Barcelona, and colleagues compared the two approaches because of the potential to mitigate peripartum bleeding by discontinuing aspirin before full term (37 weeks’ gestation) and by an accurate selection of women in the first trimester at higher risk of preeclampsia.
Aspirin cuts preterm preeclampsia by 62% in women at high risk
While aspirin might be associated with an increased risk of peripartum bleeding, aspirin has been proven to reduce the incidence of preterm preeclampsia by 62% in pregnant women at high risk of preeclampsia.
In the multicenter, open-label, randomized, phase 3, noninferiority trial, pregnant women who had a high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24-28 weeks’ gestation were recruited between Aug. 20, 2019, and Sept. 15, 2021. Of those, 936 were analyzed (473 in the intervention group [stopping aspirin] and 473 in the control group [continuing]).
Screening for risk of preterm preeclampsia included analyzing maternal factors, uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein A, and placental growth factor. Follow-up was until delivery for all participants.
Incidence of preterm preeclampsia was 1.48% in the intervention group (discontinuing aspirin) and 1.73% in the control group (continuing aspirin until 36 weeks of gestation; absolute difference, –0.25%; 95% confidence interval, –1.86% to 1.36%), which indicates noninferiority for stopping aspirin. The bar for noninferiority was less than a 1.9% difference in preterm preeclampsia incidences between groups.
Researchers did find a higher incidence of minor antepartum bleeding in the group that continued aspirin (7.61% in the low-dose aspirin discontinuation group vs. 12.31% in the low-dose aspirin continuation group; absolute difference, –4.70; 95% CI, –8.53 to –0.87).
Differences in U.S. guidelines
Dr. Emeruwa and colleagues noted the study challenges a growing body of evidence favoring increasingly widespread use of low-dose aspirin in pregnancy.
They called the study “well designed and provocative,” but wrote that the findings are hard to interpret for a U.S. population. Some key differences in the U.S. preeclampsia prevention guidelines, compared with the practices of the study’s authors, included the reliance on clinical maternal factors in the United States for screening for low-dose aspirin prophylaxis as opposed to molecular biomarkers; a different aspirin dose prescribed in the United States (81 mg daily), compared with international societies (150 mg daily); and a lack of a recommendation in the United States to stop prophylactic low-dose aspirin at 36 weeks.
Dr. Emeruwa and colleagues also questioned the scope of the outcome measure used.
They wrote that limiting outcomes to preterm preeclampsia dims the effects of all types of preeclampsia on perinatal and maternal outcomes and that early-onset preeclampsia at less than 34 weeks “occurs in just 0.38% of pregnancies, while 3%-5% are affected by late-onset preeclampsia.”
‘Late-onset preeclampsia has a higher overall impact’
Dr. Emeruwa and colleagues wrote: “Though the odds of adverse perinatal and maternal outcomes are higher with preterm preeclampsia, due to its overall higher incidence, late-onset preeclampsia has a higher overall impact on perinatal and maternal morbidity and mortality.”
The study can inform future U.S. approaches, the editorialists wrote, and build on work already being done in the United States.
The study investigators used biophysical and molecular markers to more accurately assess risk for starting low-dose aspirin prophylaxis in the first trimester and applied a growing body of data showing the high negative predictive value of second-trimester biomarkers.
The editorialists noted that the U.S. Preventive Services Task Force recommendations would have captured “less than 50% of the at-risk population” that Dr. Mendoza’s team found eligible for low-dose aspirin.
Those factors, the editorialists wrote, point to the potential to improve guidelines for personalized preeclampsia management in pregnancy.
They concluded: “U.S. practitioners and professional societies should reconsider current risk assessment strategies, which are largely based on maternal factors, and evaluate whether incorporation of molecular biomarkers would improve maternal and fetal/neonatal outcomes.”
The study authors acknowledged that 92% of participants in the study were White, thus limiting generalizability.
The authors and editorialists reported no relevant financial relationships.
FROM JAMA
Two cups of coffee increase heart dangers with hypertension
according to researchers at Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo.
What to know
People with severely high blood pressure who drink two or more cups of caffeinated coffee each day could double their risk of dying from a heart attack, stroke, or any type of cardiovascular disease.
Too much coffee may raise blood pressure and lead to anxiety, heart palpitations, and difficulty sleeping.
An 8-ounce cup of coffee has 80-100 mg of caffeine, while an 8-ounce cup of green or black tea has 30-50 mg.
Drinking one cup of coffee a day or any amount of green tea was not associated with risk of death across any blood pressure categories, and drinking green tea was not associated with increased risk of death related to cardiovascular disease at any blood pressure level.
Frequent consumers of coffee were more likely to be younger, current smokers, current drinkers, to eat fewer vegetables, and to have higher total cholesterol levels and lower systolic blood pressure regardless of their blood pressure category.
This is a summary of the article “Coffee and Green Tea Consumption and Cardiovascular Disease Mortality Among People With and Without Hypertension,” published in the Journal of the American Heart Association.
A version of this article first appeared on Medscape.com.
according to researchers at Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo.
What to know
People with severely high blood pressure who drink two or more cups of caffeinated coffee each day could double their risk of dying from a heart attack, stroke, or any type of cardiovascular disease.
Too much coffee may raise blood pressure and lead to anxiety, heart palpitations, and difficulty sleeping.
An 8-ounce cup of coffee has 80-100 mg of caffeine, while an 8-ounce cup of green or black tea has 30-50 mg.
Drinking one cup of coffee a day or any amount of green tea was not associated with risk of death across any blood pressure categories, and drinking green tea was not associated with increased risk of death related to cardiovascular disease at any blood pressure level.
Frequent consumers of coffee were more likely to be younger, current smokers, current drinkers, to eat fewer vegetables, and to have higher total cholesterol levels and lower systolic blood pressure regardless of their blood pressure category.
This is a summary of the article “Coffee and Green Tea Consumption and Cardiovascular Disease Mortality Among People With and Without Hypertension,” published in the Journal of the American Heart Association.
A version of this article first appeared on Medscape.com.
according to researchers at Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo.
What to know
People with severely high blood pressure who drink two or more cups of caffeinated coffee each day could double their risk of dying from a heart attack, stroke, or any type of cardiovascular disease.
Too much coffee may raise blood pressure and lead to anxiety, heart palpitations, and difficulty sleeping.
An 8-ounce cup of coffee has 80-100 mg of caffeine, while an 8-ounce cup of green or black tea has 30-50 mg.
Drinking one cup of coffee a day or any amount of green tea was not associated with risk of death across any blood pressure categories, and drinking green tea was not associated with increased risk of death related to cardiovascular disease at any blood pressure level.
Frequent consumers of coffee were more likely to be younger, current smokers, current drinkers, to eat fewer vegetables, and to have higher total cholesterol levels and lower systolic blood pressure regardless of their blood pressure category.
This is a summary of the article “Coffee and Green Tea Consumption and Cardiovascular Disease Mortality Among People With and Without Hypertension,” published in the Journal of the American Heart Association.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF AMERICAN HEART ASSOCIATION
Endovascular therapy benefits large infarction: ANGEL-ASPECT
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Similar effect of early, late BP reduction in stroke: CATIS-2
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Thrombolysis not necessary in mild nondisabling stroke: ARAMIS
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Diabetes drug tied to lower dementia risk
new research suggests.
Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.
However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.
“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.
However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.
This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.
The results were published online in Neurology.
Dose-response relationship
Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.
This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.
Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.
Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.
Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.
There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).
A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
Several limitations
The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).
The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.
The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).
“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.
However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.
The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.
There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
More data needed
In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”
However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.
They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.
They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.
“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.
For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.
The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests.
Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.
However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.
“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.
However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.
This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.
The results were published online in Neurology.
Dose-response relationship
Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.
This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.
Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.
Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.
Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.
There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).
A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
Several limitations
The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).
The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.
The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).
“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.
However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.
The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.
There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
More data needed
In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”
However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.
They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.
They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.
“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.
For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.
The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests.
Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.
However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.
“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.
However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.
This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.
The results were published online in Neurology.
Dose-response relationship
Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.
This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.
Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.
Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.
Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.
There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).
A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
Several limitations
The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).
The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.
The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).
“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.
However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.
The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.
There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
More data needed
In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”
However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.
They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.
They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.
“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.
For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.
The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM NEUROLOGY
Novel celery seed–derived drug may improve stroke outcomes
a new report suggests.
Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.
Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.
“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”
The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Studying stroke outcomes
The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.
In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.
The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.
Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.
The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).
Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.
Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.
Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).
In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.
Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
Ongoing questions
Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.
“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.
Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.
“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.
Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.
“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”
The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new report suggests.
Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.
Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.
“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”
The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Studying stroke outcomes
The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.
In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.
The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.
Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.
The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).
Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.
Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.
Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).
In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.
Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
Ongoing questions
Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.
“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.
Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.
“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.
Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.
“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”
The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new report suggests.
Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.
Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.
“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”
The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Studying stroke outcomes
The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.
In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.
The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.
Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.
The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).
Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.
Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.
Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).
In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.
Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
Ongoing questions
Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.
“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.
Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.
“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.
Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.
“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”
The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Drug combo promising in vascular cognitive impairment: LACI-2 trial results
and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.
The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.
“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.
“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.
The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).
They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.
“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”
Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”
“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
‘Very intriguing results’
Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”
He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”
“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”
Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”
“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.
“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”
Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.
“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.
LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:
- 40-60 mg/day of oral isosorbide mononitrate alone.
- 200 mg/day of oral cilostazol alone.
- Both medications.
- Neither medication.
Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.
Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.
The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).
The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.
Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).
During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”
Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.
“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.
Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”
The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.
The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.
“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.
“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.
The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).
They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.
“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”
Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”
“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
‘Very intriguing results’
Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”
He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”
“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”
Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”
“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.
“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”
Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.
“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.
LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:
- 40-60 mg/day of oral isosorbide mononitrate alone.
- 200 mg/day of oral cilostazol alone.
- Both medications.
- Neither medication.
Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.
Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.
The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).
The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.
Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).
During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”
Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.
“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.
Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”
The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
and is seen as a new therapeutic approach for patients with cerebral small-vessel disease. The drugs – isosorbide mononitrate and cilostazol – stabilize endothelial function, which is a new therapeutic target for patients with small-vessel disease stroke.
The phase 2 LACI-2 study, evaluating these drugs individually and in combination in patients with lacunar stroke, showed promising trends toward reductions in recurrent stroke, cognitive impairment, and dependency, some of which became significant when the drugs were given together. There was also some suggestion of positive impacts on mood and quality of life.
“Isosorbide mononitrate was associated with a reduction in recurrent stroke, a tendency toward a reduction in dependency and a reduction in cognitive impairment, and cilostazol also seemed to reduce dependency,” study investigator Joanna M. Wardlaw, MD, professor of applied neuroimaging at Edinburgh University, reported.
“When used together, they seemed to have more benefits than either drug on its own. So this is good preliminary evidence that the drugs are working together in a positive way,” she said. But she cautioned that these potential benefits will need to be confirmed in a larger phase 3 trial.
The LACI-2 study was presented at the International Stroke Conference by Dr. Wardlaw and coinvestigator Philip Bath, DSc, professor of medicine at the University of Nottingham (England).
They both highlighted the effect seen on cognitive impairment at the conference presented by the American Stroke Association, a division of the American Heart Association.
“We saw a significant reduction in the number of patients with cognitive impairment with the two drugs together in this phase 2 study,” Dr. Wardlaw said. “This is very encouraging since no study has previously found any medications that positively affect cognitive impairment in small-vessel disease strokes. We cautiously hope that these medications may have wider implications for other types of small-vessel disease as well.”
Dr. Bath added: “The results on cognitive impairment are particularly important. Many patients rate cognitive impairment as one of the most dreaded outcomes of a stroke even if they also have quite significant physical disability. People simply don’t want to lose their memory and thinking ability.”
“The results of LACI-2 also raise interesting questions about whether these drugs would be beneficial for other types of small-vessel disease which do not present as stroke, but maybe may manifest as headaches or memory impairment,” he noted.
‘Very intriguing results’
Outside experts were enthusiastic about these preliminary results. In an ISC highlights presentation, program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “It is refreshing to finally see some positive signals in studies in small-vessel stroke. This is an area where we haven’t had answers for a long time.”
He described the reduction in cognitive impairment seen in the study as “very intriguing and very important.”
“I think we have underestimated the burden that cognitive impairment has in stroke, and the burden in general in society of vascular cognitive impairment. This is a very promising approach that definitely deserves to be investigated more thoroughly in a larger trial.”
Commenting on the study findings, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York, said this study “provides evidence that points us in at least two important directions.”
“First, it suggests that endothelial dysfunction, or problems with the lining of the blood vessels, may be an important contributor to small-vessel disease and the cognitive decline that often accompanies it. This is a new mechanism of action and different from blood clotting, blood pressure, and other conventional targets of treatment,” Dr. Elkind said.
“Second, and more generally, it suggests that stroke trials, particularly in the subtype of small-vessel disease, can and should explore not only the incidence of recurrent acute events but also the steady decline that occurs after stroke. Poststroke cognitive decline is a relatively new area of stroke research.”
Dr. Wardlaw noted that lacunar stroke is a common type of ischemic stroke, but it has been rather neglected in terms of research. It is assumed to be caused by atherosclerosis of the small vessel but there is now mounting evidence suggesting that it is a result of problems in the endothelium of the small vessels.
“We looked for potential available drugs that targeted endothelial dysfunction. Both the drugs we tested are already widely used – isosorbide mononitrate for the treatment of coronary artery disease and angina, and cilostazol, mainly in Asia, for stroke prevention,” she said.
LACI-2 was primarily a feasibility study looking at whether it was possible to recruit enough patients who had had a lacunar stroke and would take the drugs, individually or in combination, for up to a year. Outcomes were investigated on an exploratory basis. The study enrolled 363 patients who had experienced lacunar stroke from 26 stroke centers throughout the United Kingdom. They were randomly assigned to one of four treatment groups for 1 year:
- 40-60 mg/day of oral isosorbide mononitrate alone.
- 200 mg/day of oral cilostazol alone.
- Both medications.
- Neither medication.
Patients completed phone surveys at 6 and 12 months to assess health status, including recurrent stroke, myocardial infarction, cognitive tests, symptoms, quality of life surveys, and they also had brain imaging at 12 months.
Results showed 98% of patients were still taking their study medication at 1 year, and the drugs appeared to be safe on top of usual care with few deaths or hemorrhages in the study.
The composite outcome including recurrent stroke, MI, cognitive impairment, dependency (modified Rankin score > 2) and death was reduced by 20% in the isosorbide mononitrate–alone group (adjusted hazard ratio, 0.80; 95% confidence interval, 0.59-1.09).
The composite endpoint was reduced by 23% in the cilostazol group (aHR, 0.77; 95% CI, 0.57-1.05) and by 42% in the combination group (aHR, 0.58, 95% CI, 0.36-0.92) compared with those taking neither drug.
Isosorbide mononitrate alone showed trends toward a reduction in recurrent stroke, cognitive impairment, and dependency, whereas cilostazol alone reduced dependency with a trend toward a reduction in cognitive impairment. When used together, the drugs showed large reductions in cognitive impairment (aHR, 0.44; 95% CI, 0.19-0.99) and dependency (aHR ,0.14; 95% CI, 0.03-0.59).
During the highlights session, Dr. Jovin commented: “It is obvious that the investigators have put a lot of thought into the design of this trial. Presumably because of the composite score they were able to increase the power. We are used to trials which require thousands of patients, but here we are able to see significant results, although exploratory, with just a few hundred patients.”
Dr. Bath stressed that this was only a phase 2 study. “We now need to see if we can confirm these results in a larger phase 3 study.” That study, LACI-3, is planned to start later this year. He also suggested that it would be interesting to investigate whether these drugs would work in other types of ischemic stroke such as those caused by large-artery disease or cardioembolic strokes, as well as other forms of small-vessel disease such as patients with vascular cognitive impairment.
“There are many areas to investigate in future. It might be that in a few years’ time these drugs may be standard of care across many different forms of small-vessel disease,” he said.
Dr. Wardlaw noted that lacunar strokes are generally quite mild strokes, which could be one of the reasons why they have not been the target of much research to date. But Dr. Bath added: “While they may be labeled as a mild stroke on the NIHSS scale, patients can still be quite badly affected. About half of patients with a lacunar stroke develop cognitive impairment and eventually dementia – that is certainly not mild.”
The study was funded primarily by the British Heart Foundation, with support from the UK Alzheimer’s Society, the UK Dementia Research Institute, the Stroke Association, the Fondation Leducq, NHS Research Scotland, and the UK National Institutes of Health Research Clinical Research Networks. Dr. Bath is an adviser to CoMind, DiaMedica, Phagenesis, and Roche. Dr. Wardlaw reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Tenecteplase noninferior to alteplase for ischemic stroke: TRACE-2
, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.
The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”
The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Single bolus
Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.
Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.
The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.
The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.
Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.
Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
Showed noninferiority
The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).
The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.
There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.
The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.
Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).
The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.
Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.
The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
Strong evidence
Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.
He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.
However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.
Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.
“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”
But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.
“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”
The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.
The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”
The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Single bolus
Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.
Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.
The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.
The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.
Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.
Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
Showed noninferiority
The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).
The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.
There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.
The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.
Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).
The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.
Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.
The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
Strong evidence
Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.
He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.
However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.
Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.
“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”
But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.
“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”
The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.
The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”
The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Single bolus
Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.
Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.
The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.
The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.
Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.
Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
Showed noninferiority
The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).
The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.
There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.
The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.
Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).
The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.
Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.
The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
Strong evidence
Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.
He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.
However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.
Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.
“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”
But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.
“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”
The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023