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Dual orexin receptor antagonists (DORAs), a class of drugs approved to treat insomnia, may also be effective for rapid eye movement sleep behavior disorder (RBD), a study suggests.

About 3 million people in the United States have RBD, which is often a precursor to Parkinson’s disease. People with the disorder act out their dreams by talking, flailing their arms and legs, punching, kicking, and exhibiting other behaviors while asleep.

Researchers used an animal model for the study, which they say is the first to identify a new form of treatment for RBD.

“REM behavior disorder is difficult to treat, and the treatments are mostly limited to clonazepam and melatonin,” which may have side effects, senior investigator Andrew Varga, MD, PhD, associate professor of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai, New York, told this news organization. “We’re using something completely different, which raises the possibility this might be something useful for REM behavior disorders.”

The findings, with Mount Sinai assistant professor Korey Kam, PhD, as lead author, were published online in the Journal of Neuroscience.
 

A new model for RBD?

RBD can signal risk for synucleinopathies, a group of neurological conditions such as Parkinson’s disease that involve the formation of clumps of alpha-synuclein protein in the brain.

Prior research on RBD was done in synucleinopathy mouse models. For this study, however, researchers used a tauopathy mouse model to investigate how the abnormal accumulation of tau protein might affect RBD.

Researchers collected data on biophysical properties when the mice were awake and in REM and non-REM sleep. They examined length of sleep, transitions from waking to sleep, and how some factors are related to age.

Nearly a third of the older animals showed behaviors similar to REM sleep behavior disorder in humans, including chewing and limb extension.

But after researchers administered a DORA medication twice during a 24-hour period, they noted that the medication not only helped the animals fall asleep faster and for longer, it also reduced levels of dream enactment that are a hallmark of RBD.
 

The ‘bigger highlight’

Finding RBD behaviors in a tauopathy animal model was surprising, Dr. Varga said, because RBD has been previously linked to synucleinopathies. There was no known correlation between RBD and abnormal accumulation of tau.

Another unexpected finding was the detection of RBD in some of the younger animals, who had not yet shown evidence of tau accumulation.

“It appears to be a biomarker or a signature of something that’s going on that predicts the impending tauopathy at a time where there is very little, or no, tau pathology going on in the brain,” Dr. Varga said.

If RBD is an early predictor of future tau accumulation, the model could guide future prevention and treatment. However, the more important finding is the potential new treatment for the condition.

“The bigger highlight here is less about what’s causing the RBD [than about] what you can do to make it better,” he said.

The next step in the work is to study whether the effect of DORAs on RBD seen in this tauopathy mouse model is evidenced in other animals and whether it is effective in humans with RBD, Dr. Varga said.

The study was funded by the Alzheimer’s Association and Merck Investigator Studies Program. Dr. Kam, Dr. Varga, and coauthors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dual orexin receptor antagonists (DORAs), a class of drugs approved to treat insomnia, may also be effective for rapid eye movement sleep behavior disorder (RBD), a study suggests.

About 3 million people in the United States have RBD, which is often a precursor to Parkinson’s disease. People with the disorder act out their dreams by talking, flailing their arms and legs, punching, kicking, and exhibiting other behaviors while asleep.

Researchers used an animal model for the study, which they say is the first to identify a new form of treatment for RBD.

“REM behavior disorder is difficult to treat, and the treatments are mostly limited to clonazepam and melatonin,” which may have side effects, senior investigator Andrew Varga, MD, PhD, associate professor of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai, New York, told this news organization. “We’re using something completely different, which raises the possibility this might be something useful for REM behavior disorders.”

The findings, with Mount Sinai assistant professor Korey Kam, PhD, as lead author, were published online in the Journal of Neuroscience.
 

A new model for RBD?

RBD can signal risk for synucleinopathies, a group of neurological conditions such as Parkinson’s disease that involve the formation of clumps of alpha-synuclein protein in the brain.

Prior research on RBD was done in synucleinopathy mouse models. For this study, however, researchers used a tauopathy mouse model to investigate how the abnormal accumulation of tau protein might affect RBD.

Researchers collected data on biophysical properties when the mice were awake and in REM and non-REM sleep. They examined length of sleep, transitions from waking to sleep, and how some factors are related to age.

Nearly a third of the older animals showed behaviors similar to REM sleep behavior disorder in humans, including chewing and limb extension.

But after researchers administered a DORA medication twice during a 24-hour period, they noted that the medication not only helped the animals fall asleep faster and for longer, it also reduced levels of dream enactment that are a hallmark of RBD.
 

The ‘bigger highlight’

Finding RBD behaviors in a tauopathy animal model was surprising, Dr. Varga said, because RBD has been previously linked to synucleinopathies. There was no known correlation between RBD and abnormal accumulation of tau.

Another unexpected finding was the detection of RBD in some of the younger animals, who had not yet shown evidence of tau accumulation.

“It appears to be a biomarker or a signature of something that’s going on that predicts the impending tauopathy at a time where there is very little, or no, tau pathology going on in the brain,” Dr. Varga said.

If RBD is an early predictor of future tau accumulation, the model could guide future prevention and treatment. However, the more important finding is the potential new treatment for the condition.

“The bigger highlight here is less about what’s causing the RBD [than about] what you can do to make it better,” he said.

The next step in the work is to study whether the effect of DORAs on RBD seen in this tauopathy mouse model is evidenced in other animals and whether it is effective in humans with RBD, Dr. Varga said.

The study was funded by the Alzheimer’s Association and Merck Investigator Studies Program. Dr. Kam, Dr. Varga, and coauthors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dual orexin receptor antagonists (DORAs), a class of drugs approved to treat insomnia, may also be effective for rapid eye movement sleep behavior disorder (RBD), a study suggests.

About 3 million people in the United States have RBD, which is often a precursor to Parkinson’s disease. People with the disorder act out their dreams by talking, flailing their arms and legs, punching, kicking, and exhibiting other behaviors while asleep.

Researchers used an animal model for the study, which they say is the first to identify a new form of treatment for RBD.

“REM behavior disorder is difficult to treat, and the treatments are mostly limited to clonazepam and melatonin,” which may have side effects, senior investigator Andrew Varga, MD, PhD, associate professor of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai, New York, told this news organization. “We’re using something completely different, which raises the possibility this might be something useful for REM behavior disorders.”

The findings, with Mount Sinai assistant professor Korey Kam, PhD, as lead author, were published online in the Journal of Neuroscience.
 

A new model for RBD?

RBD can signal risk for synucleinopathies, a group of neurological conditions such as Parkinson’s disease that involve the formation of clumps of alpha-synuclein protein in the brain.

Prior research on RBD was done in synucleinopathy mouse models. For this study, however, researchers used a tauopathy mouse model to investigate how the abnormal accumulation of tau protein might affect RBD.

Researchers collected data on biophysical properties when the mice were awake and in REM and non-REM sleep. They examined length of sleep, transitions from waking to sleep, and how some factors are related to age.

Nearly a third of the older animals showed behaviors similar to REM sleep behavior disorder in humans, including chewing and limb extension.

But after researchers administered a DORA medication twice during a 24-hour period, they noted that the medication not only helped the animals fall asleep faster and for longer, it also reduced levels of dream enactment that are a hallmark of RBD.
 

The ‘bigger highlight’

Finding RBD behaviors in a tauopathy animal model was surprising, Dr. Varga said, because RBD has been previously linked to synucleinopathies. There was no known correlation between RBD and abnormal accumulation of tau.

Another unexpected finding was the detection of RBD in some of the younger animals, who had not yet shown evidence of tau accumulation.

“It appears to be a biomarker or a signature of something that’s going on that predicts the impending tauopathy at a time where there is very little, or no, tau pathology going on in the brain,” Dr. Varga said.

If RBD is an early predictor of future tau accumulation, the model could guide future prevention and treatment. However, the more important finding is the potential new treatment for the condition.

“The bigger highlight here is less about what’s causing the RBD [than about] what you can do to make it better,” he said.

The next step in the work is to study whether the effect of DORAs on RBD seen in this tauopathy mouse model is evidenced in other animals and whether it is effective in humans with RBD, Dr. Varga said.

The study was funded by the Alzheimer’s Association and Merck Investigator Studies Program. Dr. Kam, Dr. Varga, and coauthors report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The American Psychiatric Association has released an online screening and assessment tool for eating disorders.

“People with eating disorders have a high rate of mortality and [the disorder is] growing in prevalence among young adults and adolescents,” APA CEO and medical director Saul Levin, MD, MPA, said in a news release.

“It is vital that we equip our clinicians, especially primary care clinicians, with the latest evidence from the APA to empower their decision-making and improve care for their patients,” Dr. Levin added.

The clinical decision support tool was developed by the APA’s guideline writing group in collaboration with AvoMD, a software company that translates clinical evidence into the workflow.

The tool guides clinicians through the screening, assessing, diagnosing, and treatment planning of patients with anorexia nervosa, bulimia nervosa, binge-eating disorder, and other eating disorders.

It’s available free in the electronic health record, on the APA website, and on the AvoMD mobile app.

The tool is based on the APA’s updated practice guidelines for the management of eating disorders, which were released in March.

The tool incorporates guidance on screening tools, levels of care, nutrition, exercise, psychotherapy, and more. Additionally, the tool provides a summary of responses that can be leveraged for easy documentation.

It is intended for use by pediatricians, family physicians, and other primary care and mental health clinicians, including psychiatrists and therapists.

Data published earlier this year show that more than 1 in 5 children worldwide are at risk of developing an eating disorder. Girls are significantly more likely than boys to have disordered eating.

Early diagnosis and treatment are associated with a higher rate of recovery, and extended illness is associated with potentially devastating consequences, the APA notes.

“As an internal medicine physician myself, I see a wide variety of patients and clinical issues,” Joongheum Park, MD, head of product and engineering at AvoMD, said in the release.

“Easy access to the expertise in me and my peers’ workflow is essential to ensuring high-quality care, and partnering with the leading authority on eating disorders to provide this tool will improve clinician efficiency and most importantly, patient outcomes,” Dr. Park added.

A version of this article first appeared on Medscape.com.

The American Psychiatric Association has released an online screening and assessment tool for eating disorders.

“People with eating disorders have a high rate of mortality and [the disorder is] growing in prevalence among young adults and adolescents,” APA CEO and medical director Saul Levin, MD, MPA, said in a news release.

“It is vital that we equip our clinicians, especially primary care clinicians, with the latest evidence from the APA to empower their decision-making and improve care for their patients,” Dr. Levin added.

The clinical decision support tool was developed by the APA’s guideline writing group in collaboration with AvoMD, a software company that translates clinical evidence into the workflow.

The tool guides clinicians through the screening, assessing, diagnosing, and treatment planning of patients with anorexia nervosa, bulimia nervosa, binge-eating disorder, and other eating disorders.

It’s available free in the electronic health record, on the APA website, and on the AvoMD mobile app.

The tool is based on the APA’s updated practice guidelines for the management of eating disorders, which were released in March.

The tool incorporates guidance on screening tools, levels of care, nutrition, exercise, psychotherapy, and more. Additionally, the tool provides a summary of responses that can be leveraged for easy documentation.

It is intended for use by pediatricians, family physicians, and other primary care and mental health clinicians, including psychiatrists and therapists.

Data published earlier this year show that more than 1 in 5 children worldwide are at risk of developing an eating disorder. Girls are significantly more likely than boys to have disordered eating.

Early diagnosis and treatment are associated with a higher rate of recovery, and extended illness is associated with potentially devastating consequences, the APA notes.

“As an internal medicine physician myself, I see a wide variety of patients and clinical issues,” Joongheum Park, MD, head of product and engineering at AvoMD, said in the release.

“Easy access to the expertise in me and my peers’ workflow is essential to ensuring high-quality care, and partnering with the leading authority on eating disorders to provide this tool will improve clinician efficiency and most importantly, patient outcomes,” Dr. Park added.

A version of this article first appeared on Medscape.com.

The American Psychiatric Association has released an online screening and assessment tool for eating disorders.

“People with eating disorders have a high rate of mortality and [the disorder is] growing in prevalence among young adults and adolescents,” APA CEO and medical director Saul Levin, MD, MPA, said in a news release.

“It is vital that we equip our clinicians, especially primary care clinicians, with the latest evidence from the APA to empower their decision-making and improve care for their patients,” Dr. Levin added.

The clinical decision support tool was developed by the APA’s guideline writing group in collaboration with AvoMD, a software company that translates clinical evidence into the workflow.

The tool guides clinicians through the screening, assessing, diagnosing, and treatment planning of patients with anorexia nervosa, bulimia nervosa, binge-eating disorder, and other eating disorders.

It’s available free in the electronic health record, on the APA website, and on the AvoMD mobile app.

The tool is based on the APA’s updated practice guidelines for the management of eating disorders, which were released in March.

The tool incorporates guidance on screening tools, levels of care, nutrition, exercise, psychotherapy, and more. Additionally, the tool provides a summary of responses that can be leveraged for easy documentation.

It is intended for use by pediatricians, family physicians, and other primary care and mental health clinicians, including psychiatrists and therapists.

Data published earlier this year show that more than 1 in 5 children worldwide are at risk of developing an eating disorder. Girls are significantly more likely than boys to have disordered eating.

Early diagnosis and treatment are associated with a higher rate of recovery, and extended illness is associated with potentially devastating consequences, the APA notes.

“As an internal medicine physician myself, I see a wide variety of patients and clinical issues,” Joongheum Park, MD, head of product and engineering at AvoMD, said in the release.

“Easy access to the expertise in me and my peers’ workflow is essential to ensuring high-quality care, and partnering with the leading authority on eating disorders to provide this tool will improve clinician efficiency and most importantly, patient outcomes,” Dr. Park added.

A version of this article first appeared on Medscape.com.

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

A version of this article first appeared on Medscape.com.

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

A version of this article first appeared on Medscape.com.

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

A version of this article first appeared on Medscape.com.

United Healthcare (UHC) has announced it will not go forward with a plan to require prior authorization for colonoscopies and other endoscopic procedures.

Instead, the giant health insurer will adopt an “advance notification” program for nonscreening and nonemergent gastrointestinal procedures.

The company has not made any changes to their policy regarding screening colonoscopies for preventive care, and the advance notification policy does not impact screening colonoscopies.

UHC alerted physicians to changes to the program yesterday, including updated notices on UHCProvider.com with a new Frequently Asked Questions document.

The advance notification program “will not result in the denial of care for clinical reasons or for failure to notify and will help educate physicians who are not following clinical best practices. Provider groups who do not submit advance notification during this period will not be eligible for the United Healthcare Gold Card program,” a spokesperson for the company said.

The previously announced Gold Card program, which is scheduled to start in early 2024, would eliminate prior authorization requirements for providers that meet certain eligibility requirements.

The American Gastroenterological Association remains “extremely concerned” that UHC’s advance notification program is a “temporary patch” likely to have significant repercussions for patient access. The organization says the program only temporarily postpones prior authorization requirements set to impact the insurer’s 27.4 million commercial beneficiaries while increasing the administrative burden on clinicians.

The AGA called the program “nebulous” and “poorly defined.” It would ostensibly require physicians to input “copious” amounts of highly complex and granular patient data prior to performing colonoscopies and endoscopies, the AGA says.

AGA President Barbara H. Jung, MD, AGAF, said UHC’s “slap-dash approach to rolling out a policy that will ultimately control patient access to critical, often life-saving, medical procedures flies in the face of common sense and responsible medical practice.”

“It also indicates that UHC does not currently have data that show any significant overutilization of critical endoscopy and colonoscopy procedures that would ostensibly justify this program or prior authorization. UHC is not acting in good faith, and its actions will compromise patient access to potentially lifesaving procedures,” Dr. Jung added. 

Recent data show 62% of high-risk patients in the United States who had polyps removed had evidence of delayed or no use of surveillance colonoscopies after 10 years.

“If other prior authorization requirements imposed on patients for specialty care are any indication, we expect to see negative patient outcomes with an enormous cost to patient well-being and physician resources,” AGA Vice President Lawrence Kim, MD, wrote in a news release.

“Given the high percentage of eventual approvals by insurers mandating prior authorization, we anticipate there will be little to no benefit from this prior authorization requirement. When utilized this way, it becomes a nonsensical and harmful policy,” Dr. Kim added.

AGA says it will continue to work closely with its members to assess the full impact of the new requirements and urges UHC to make endoscopy procedures more accessible to patients.

A recent American Medical Association survey on prior authorization found that one-third (33%) of doctors said the insurance barrier has led to a serious adverse event such as hospitalization, permanent disability, or death for a patient in their care. Nearly half (46%) of physicians reported that prior authorization has led to immediate care and/or emergency department visits.

In a 2023 survey of AGA membership, conducted before UHC announced its proposed prior authorization policy, 95% of respondents said prior authorization restrictions have impacted patient access to clinically appropriate treatments and patient clinical outcomes. And 84% said the burdens associated with prior authorization policies have increased “significantly” (60%) or “somewhat” (24%) over the last 5 years.

A version of this article first appeared on Medscape.com.

United Healthcare (UHC) has announced it will not go forward with a plan to require prior authorization for colonoscopies and other endoscopic procedures.

Instead, the giant health insurer will adopt an “advance notification” program for nonscreening and nonemergent gastrointestinal procedures.

The company has not made any changes to their policy regarding screening colonoscopies for preventive care, and the advance notification policy does not impact screening colonoscopies.

UHC alerted physicians to changes to the program yesterday, including updated notices on UHCProvider.com with a new Frequently Asked Questions document.

The advance notification program “will not result in the denial of care for clinical reasons or for failure to notify and will help educate physicians who are not following clinical best practices. Provider groups who do not submit advance notification during this period will not be eligible for the United Healthcare Gold Card program,” a spokesperson for the company said.

The previously announced Gold Card program, which is scheduled to start in early 2024, would eliminate prior authorization requirements for providers that meet certain eligibility requirements.

The American Gastroenterological Association remains “extremely concerned” that UHC’s advance notification program is a “temporary patch” likely to have significant repercussions for patient access. The organization says the program only temporarily postpones prior authorization requirements set to impact the insurer’s 27.4 million commercial beneficiaries while increasing the administrative burden on clinicians.

The AGA called the program “nebulous” and “poorly defined.” It would ostensibly require physicians to input “copious” amounts of highly complex and granular patient data prior to performing colonoscopies and endoscopies, the AGA says.

AGA President Barbara H. Jung, MD, AGAF, said UHC’s “slap-dash approach to rolling out a policy that will ultimately control patient access to critical, often life-saving, medical procedures flies in the face of common sense and responsible medical practice.”

“It also indicates that UHC does not currently have data that show any significant overutilization of critical endoscopy and colonoscopy procedures that would ostensibly justify this program or prior authorization. UHC is not acting in good faith, and its actions will compromise patient access to potentially lifesaving procedures,” Dr. Jung added. 

Recent data show 62% of high-risk patients in the United States who had polyps removed had evidence of delayed or no use of surveillance colonoscopies after 10 years.

“If other prior authorization requirements imposed on patients for specialty care are any indication, we expect to see negative patient outcomes with an enormous cost to patient well-being and physician resources,” AGA Vice President Lawrence Kim, MD, wrote in a news release.

“Given the high percentage of eventual approvals by insurers mandating prior authorization, we anticipate there will be little to no benefit from this prior authorization requirement. When utilized this way, it becomes a nonsensical and harmful policy,” Dr. Kim added.

AGA says it will continue to work closely with its members to assess the full impact of the new requirements and urges UHC to make endoscopy procedures more accessible to patients.

A recent American Medical Association survey on prior authorization found that one-third (33%) of doctors said the insurance barrier has led to a serious adverse event such as hospitalization, permanent disability, or death for a patient in their care. Nearly half (46%) of physicians reported that prior authorization has led to immediate care and/or emergency department visits.

In a 2023 survey of AGA membership, conducted before UHC announced its proposed prior authorization policy, 95% of respondents said prior authorization restrictions have impacted patient access to clinically appropriate treatments and patient clinical outcomes. And 84% said the burdens associated with prior authorization policies have increased “significantly” (60%) or “somewhat” (24%) over the last 5 years.

A version of this article first appeared on Medscape.com.

United Healthcare (UHC) has announced it will not go forward with a plan to require prior authorization for colonoscopies and other endoscopic procedures.

Instead, the giant health insurer will adopt an “advance notification” program for nonscreening and nonemergent gastrointestinal procedures.

The company has not made any changes to their policy regarding screening colonoscopies for preventive care, and the advance notification policy does not impact screening colonoscopies.

UHC alerted physicians to changes to the program yesterday, including updated notices on UHCProvider.com with a new Frequently Asked Questions document.

The advance notification program “will not result in the denial of care for clinical reasons or for failure to notify and will help educate physicians who are not following clinical best practices. Provider groups who do not submit advance notification during this period will not be eligible for the United Healthcare Gold Card program,” a spokesperson for the company said.

The previously announced Gold Card program, which is scheduled to start in early 2024, would eliminate prior authorization requirements for providers that meet certain eligibility requirements.

The American Gastroenterological Association remains “extremely concerned” that UHC’s advance notification program is a “temporary patch” likely to have significant repercussions for patient access. The organization says the program only temporarily postpones prior authorization requirements set to impact the insurer’s 27.4 million commercial beneficiaries while increasing the administrative burden on clinicians.

The AGA called the program “nebulous” and “poorly defined.” It would ostensibly require physicians to input “copious” amounts of highly complex and granular patient data prior to performing colonoscopies and endoscopies, the AGA says.

AGA President Barbara H. Jung, MD, AGAF, said UHC’s “slap-dash approach to rolling out a policy that will ultimately control patient access to critical, often life-saving, medical procedures flies in the face of common sense and responsible medical practice.”

“It also indicates that UHC does not currently have data that show any significant overutilization of critical endoscopy and colonoscopy procedures that would ostensibly justify this program or prior authorization. UHC is not acting in good faith, and its actions will compromise patient access to potentially lifesaving procedures,” Dr. Jung added. 

Recent data show 62% of high-risk patients in the United States who had polyps removed had evidence of delayed or no use of surveillance colonoscopies after 10 years.

“If other prior authorization requirements imposed on patients for specialty care are any indication, we expect to see negative patient outcomes with an enormous cost to patient well-being and physician resources,” AGA Vice President Lawrence Kim, MD, wrote in a news release.

“Given the high percentage of eventual approvals by insurers mandating prior authorization, we anticipate there will be little to no benefit from this prior authorization requirement. When utilized this way, it becomes a nonsensical and harmful policy,” Dr. Kim added.

AGA says it will continue to work closely with its members to assess the full impact of the new requirements and urges UHC to make endoscopy procedures more accessible to patients.

A recent American Medical Association survey on prior authorization found that one-third (33%) of doctors said the insurance barrier has led to a serious adverse event such as hospitalization, permanent disability, or death for a patient in their care. Nearly half (46%) of physicians reported that prior authorization has led to immediate care and/or emergency department visits.

In a 2023 survey of AGA membership, conducted before UHC announced its proposed prior authorization policy, 95% of respondents said prior authorization restrictions have impacted patient access to clinically appropriate treatments and patient clinical outcomes. And 84% said the burdens associated with prior authorization policies have increased “significantly” (60%) or “somewhat” (24%) over the last 5 years.

A version of this article first appeared on Medscape.com.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

MILAN – Results of a phase 3 trial with the investigational drug telitacicept show that patients with systemic lupus erythematosus have a significantly greater rate of response to SLE response criteria, compared with placebo, while results from a phase 2 trial of the drug in patients with primary Sjögren’s syndrome (pSS) also show significant improvements versus placebo.

“With only a limited number of treatments available for patients with lupus, this additional option is certainly an advance and the trial shows a strong efficacy result,” said Ronald van Vollenhoven, MD, PhD, who was not an investigator for either trial but presented the results for both at the annual European Congress of Rheumatology. He is professor of clinical immunology and rheumatology at Amsterdam University Medical Center and VU University Medical Center, also in Amsterdam.

Becky McCall/MDedge News

Telitacicept is a recombinant fusion protein that targets B-lymphocyte stimulator and a proliferating-inducing ligand. It is currently undergoing testing in another phase 3 trial (REMESLE-1) at sites in the United States, Europe, and Asia. The current SLE results relate to the phase 3 study conducted in China, Dr. van Vollenhoven clarified.
 

SLE trial

The double-blind, placebo-controlled trial included 335 patients with SLE who had an average age of 35 years, a body mass index of 22-23 kg/m², and a mean SELENA-SLEDAI (Safety of Estrogens in Systemic Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) score of at least 11.5, indicating high disease activity. Most patients were on glucocorticoids and immunosuppressants.

Patients were randomized 1:1 to weekly subcutaneous injections of telitacicept (160 mg; n = 167) or placebo (n = 168) in combination with standard therapy for 52 weeks. The primary endpoint was the SLE Responder Index-4 (SRI4) response rate at week 52, while key secondary endpoints included SELENA-SLEDAI, physician global assessment, and levels of immunologic biomarkers including C3, C4, IgM, IgG, IgA, and CD19+ B cells. Safety was also assessed.

At week 52, Dr. van Vollenhoven reported that significantly more patients taking telitacicept achieved a SRI4 response, compared with placebo, at 67.1% versus 32.7%, respectively (P < .001). “The difference was seen at 4-8 weeks and stabilized at around 20 weeks,” he said.

Time to first SLE flare was also reduced in patients on the trial drug at a median of 198 days (95% confidence interval, 169-254 days), compared with placebo at 115 days (95% CI, 92-140 days).

“The secondary outcomes also supported efficacy in these patients,” Dr. van Vollenhoven added, noting that there was a rapid and sustained increase of C3 and C4, the latter being significantly greater than placebo, and reduction of IgM, IgG, IgA, and CD19+ B cells observed following telitacicept treatment.

A significantly higher proportion of patients in the telitacicept group showed improvement in SELENA-SLEDAI at week 52, defined as a 4-point or greater reduction, compared with placebo (70.1% vs. 40.5%).

Telitacicept did not increase the risk of infections. Treatment-emergent adverse events occurred in 84.5% with telitacicept versus 91.6% with placebo, with infections (mostly upper respiratory) seen in 65.3% and 60.1%, respectively.
 

Sjögren’s trial

The second trial was a phase 2, randomized, placebo-controlled, 24-week study in 42 patients with pSS. Patients (18-65 years) received telitacicept at 160 mg or 240 mg subcutaneously once a week, or placebo, for a total of 24 doses. Patients had a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 points or more, and were anti-SSA antibody positive.

“Compared with placebo, telitacicept treatment resulted in significant improvement in ESSDAI and MFI-20 [20-item Multidimensional Fatigue Inventory],” Dr. van Vollenhoven reported, adding that, “there was a trend for improvement in salivary gland function and lacrimal gland function relative to placebo, as well as a favorable safety profile.”

ESSDAI change from baseline was 0.5, –3.8, and –2.3 in placebo, 160-mg, and 240-mg telitacicept doses, respectively. MFI-20 change from baseline was 7.0, –4.0, and –5.1, respectively. Dr. Van Vollenhoven said the difference between the doses was not statistically significant.

“If these results are confirmed, it could be the first time a biologic is proven efficacious in this disease,” Dr. Van Vollenhoven said in an interview. “It’s encouraging to know that a new treatment is showing promise in this phase 2 trial. A phase 3 trial is warranted.”
 

Studies yield promising but confusing results

In an interview, Roy Fleischmann, MD, who was not involved with either study, wondered whether the results of the SLE study could be race specific given the magnitude of response to the drug and that the trial was conducted only in China, and whether the positive results of the small Sjögren’s study will pan out in a larger trial.

“The SLE study was very interesting, but the problem is that it’s a Chinese drug in Chinese patients with Chinese doctors, so they are very dramatic results,” he said, questioning whether “these results are race specific,” and that “we will find out when they do the multinational study, but we haven’t seen this type of separation before [in response]. It’s interesting.

“The Sjögren’s was a positive study, but it was confusing because the low dose seemed to be better than the higher dose, and there were very few patients,” said Dr. Fleischmann, clinical professor of medicine at the University of Texas Southwestern Medical Center and codirector of the Metroplex Clinical Research Center, both in Dallas. The left and right eyes gave different results, which was strange, and the salivary gland test was the same [mixed results], so what can we conclude? All in all, it was a small study with a suggestion of efficacy, but we have to do the phase 3 and see what it shows.”

Both trials were sponsored by RemeGen. Dr. van Vollenhoven reported serving as a paid adviser to AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Pfizer, RemeGen, and UCB. He has received research funding from Bristol-Myers Squibb and UCB and educational support from AstraZeneca, Galapagos, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Fleischmann said he had has no relevant financial relationships.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

A team of researchers has identified genomic variants that cause disabling pansclerotic morphea (DPM), a rare, severe inflammatory skin disorder, and report that the Janus kinase (JAK) inhibitor ruxolitinib may be a useful therapy, especially in patients who have not responded to other interventions.

DPM was first reported in 1923, and while a genetic cause has been suspected, it had not been identified until now. The disease is the most severe form of deep morphea, which affects individuals with juvenile localized scleroderma. Patients, generally children under age 14, experience rapid sclerosis of all layers of the skin, fascia, muscle, and bone. DPM is also deadly: Most patients do not live more than 10 years after diagnosis, as they contract squamous cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.

In the study, published in the New England Journal of Medicine, the researchers discovered that people with DPM have an overactive version of the protein STAT4, which regulates inflammation and wound healing. The scientists studied four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM.

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” Sarah Blackstone, a predoctoral fellow in the inflammatory disease section at the National Human Genome Research Institute and co–first author of the study, said in a statement from the National Institutes of Health describing the results. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea,” added Ms. Blackstone, also a medical student at the University of South Dakota, Sioux Falls.

The overactive STAT4 protein creates a positive feedback loop of inflammation and impaired wound-healing. By targeting JAK, the researchers were able to stop the feedback and patients’ wounds dramatically improved. After 18 months of treatment with oral ruxolitinib, one patient had discontinued all other medications, and had complete resolution of a chest rash, substantial clearing on the arms and legs, and global clinical improvement.

The authors said that oral systemic JAK inhibitor therapy is preferred over topical therapy. Their research also suggested that anti–interleukin-6 monoclonal antibodies – such as tocilizumab, approved for indications that include rheumatoid arthritis and systemic sclerosis–associated interstitial lung disease, “may be an alternative therapy or may be useful in combination with JAK inhibitors in patients with DPM,” the authors wrote.

Most current DPM therapies – including methotrexate, mycophenolate mofetil, and ultraviolet A light therapy – have been ineffective, and some have severe side effects.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” Dan Kastner, MD, PhD, an NIH distinguished investigator, head of the NHGRI’s inflammatory disease section, and a senior author of the paper, said in the NIH statement.

“We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader array of more common diseases,” Lori Broderick, MD, PhD, a senior author of the paper and an associate professor at University of California, San Diego, said in the statement.

The study was led by researchers at NHGRI in collaboration with researchers from UCSD and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases also participated.

The study was supported by grants from the American Academy of Allergy, Asthma, and Immunology Foundation; the Ludwig Institute for Cancer Research; the University of California, San Diego, department of pediatrics; and the Novo Nordisk Foundation. Additional support and grants were given by the Deutsche Forschungsgemeinschaft, various institutes at the NIH, the California Institute for Regenerative Medicine, the Hydrocephalus Association, the Scleroderma Research Foundation, the Biowulf High-Performance Computing Cluster of the Center for Information Technology, the Undiagnosed Diseases Program of the Common Fund of the Office of the Director of the NIH, and the NIH Clinical Center.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

A version of this article first appeared on Medscape.com.

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

A version of this article first appeared on Medscape.com.

Endocrinologists report steady increases in pay in the Medscape Endocrinologist Compensation Report 2023, but more doctors dropped insurers that pay the least, compared with last year, and only about two-thirds of respondents say they would choose medicine again as a career if given the chance.

In the survey of more than 10,000 physicians in over 29 specialties, endocrinologists’ annual salaries were up by about 4% from last year’s average of $257,000, to $267,000.

Those earnings still place them in the lowest five specialties in terms of pay, above infectious diseases, family medicine, pediatrics, and public health and preventive medicine. The latter is at the bottom of the list, with average annual earnings of $249,000.

Conversely, the top three specialties were plastic surgery, at an average of $619,000 per annum, followed by orthopedics, at $573,000, and cardiology, at $507,000.

Specialties in which the most significant changes in annual compensation occurred were led by oncology, with a 13% increase from 2022, followed by gastroenterology, with an 11% increase. On the opposite end, ophthalmologists experienced a 7% decline in earnings, while emergency medicine had a 6% decrease from 2022.

Since Medscape’s 2015 report, annual salaries for endocrinologists have increased by 36%. Similar patterns in compensation increases since 2015 occurred across all specialties. In contrast to some other specialties, endocrinologists did not experience a significant decline in earnings during the pandemic.

Across all specialties, men still earned more than women in the 2023 report – with a gap of 19% ($386,000 vs. $300,000). However, there appears to be progress, as the difference represents the lowest gender pay gap in 5 years.

This gradual improvement should likely continue as awareness of pay discrepancies grows and new generations emerge, said Theresa Rohr-Kirchgraber, MD, president of the American Medical Women’s Association and professor of medicine at AU/USA Medical Partnership, Athens, Ga., in the report.

“Due to efforts by many, some institutions and health care organizations have reviewed their salary lines and recognized the discrepancies not only between the sexes but also between new hires” and more established workers, she explained in the report.

“[The new hires] can be offered significantly more than those more senior physicians who have been working there for years and hired under a different pay structure,” she noted.

Nearly half of endocrinologists (45%) reported taking on extra work outside of their profession, up from 39% in the 2022 report. Among them, 31% reported other medical-related work, 8% reported “medical moonlighting,” 7% reported non–medical-related work, and 2% added more hours to their primary job as a physician.

Endocrinologists were in the lowest third of specialties in terms of their impressions of fair compensation, with only 45% reporting that they felt adequately paid. On the lowest end was infectious disease, with only 35% feeling their compensation is fair. By contrast, the highest response, 68%, was among psychiatrists.

Nevertheless, 85% of endocrinologists report that they would choose the same specialty again if given the chance. Responses ranged from 61% in internal medicine to 97% in plastic surgery.

Of note, fewer – 71% of endocrinologists – responded that they would choose medicine again, down from the 76% of endocrinologists who answered yes to the same question in 2022. At the bottom of the list was emergency medicine, with only 61% saying they would choose medicine again. The highest rates were in dermatology, at 86%, and allergy and immunology, at 84%.

In terms of time spent seeing patients, endocrinologists are more likely to see patients less than 30 hours per week, at 24%, compared with physicians overall, at 19%; 61% of endocrinologists report seeing patients 30-40 hours per week, versus 53% of all physicians.

Only 12% report seeing patients 41-50 hours per week, compared with 16% of all physicians. And 4% reported seeing patients 51 hours or more weekly, versus 11% of physicians overall.

The proportion of endocrinologists who reported that they would drop insurers that pay the least was notably up in the current report, at 25%, versus just 15% in the 2022 report; 22% indicated they would not drop insurers because “I need all payers”; 16% said no because “it’s inappropriate”; and the remainder responded no for other reasons.

Overall, the leading response by physicians for the most rewarding aspects of their job were “being good at what I am doing/finding answers, diagnoses,” reported by 32%, followed by “gratitude from/relationships with patients” (24%) and “making the world a better place (for example, helping others),” at 22%.

Conversely, the most challenging aspect, described by 20%, is “having so many rules and regulations,” followed by “difficulties getting fair reimbursement from or dealing with Medicare and/or other insurers (17%).”

A version of this article first appeared on Medscape.com.

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

A version of this article first appeared on Medscape.com.

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

A version of this article first appeared on Medscape.com.

Giving very late thrombolysis to patients with large-vessel occlusion small core strokes did not show a significant benefit in the TIMELESS trial.

However, there were some encouraging trends, and there did not appear to be an increase in intracranial hemorrhage (ICH), leading to hope that the option of late thrombolysis in this group of patients may still have potential.

The TIMELESS study tested the approach of giving thrombolysis with tenecteplase (TNK) to patients with a large-vessel occlusion stroke up to 24 hours after symptom onset. Patients were selected by perfusion imaging, and those who had a stroke with a small core and large amount of salvageable brain tissue were included in the placebo-controlled study.

“This is first trial to try giving a thrombolytic so late – up to 24 hours after last known well. While we did not meet the primary outcome, there were some promising findings,” lead author, Gregory Albers, MD, director of the Stanford (Calif.) Stroke Center and professor of neurology at Stanford University, said in an interview.

“The most encouraging observation was that we did not show any safety issues with giving TNK to this population at such a late time. Many people thought this would be too high risk but there was no increase in ICH, which was very low and the same in both groups,” Dr. Albers said.

“And we saw some evidence of drug effect. There appeared to be a benefit in patients with M1 occlusions, the most common type of large-vessel occlusion, who represented half the patients in the study,” he added.

The researchers also gained information on the logistics and timing of TNK administration in this late period which they hope can guide the design of a future trial.

Dr. Albers presented the TIMELESS trial at the annual European Stroke Organisation Conference.

He explained that there is increasing evidence that intravenous thrombolysis can improve outcome in selected patients even beyond the traditional 4.5-hour time window.

The phase 3, double-blind, randomized, placebo-controlled TIMELESS study sought to investigate whether tenecteplase administered to patients with ischemic stroke with large-vessel occlusion presenting between 4.5 and 24 hours after last known well would improve clinical outcome as measured by modified Rankin Scale (mRS) at day 90.

The trial included 458 patients with an internal carotid artery occlusion or middle cerebral artery segment 1 or 2 occlusion and presenting with salvageable tissue on imaging. They were randomly assigned 1:1 to either intravenous tenecteplase (0.25 mg/kg; maximum, 25 mg) or placebo.

The proportion of patients treated with mechanical thrombectomy were similar between the two treatment arms (around 77%). The study completion rate was higher than 96% in both treatment arms.

The primary endpoint analyses showed no significant difference in the odds of a lower mRS score at day 90, but there was a slight trend toward benefit in the TNK group in the shift analysis, with a common odds ratio of 1.13 (95% confidence interval, 0.81-1.56; P = .48).

The percentage of patients achieving a favorable outcome, defined as an mRS of 0-2, was not significantly different between the treatment groups: 46% in the TNK group versus 42% in the placebo group (nominal P = .41).


 

Promising safety data

There were no significant safety issues, and the risk for bleeding was not significantly increased in the tenecteplase group. Symptomatic ICH occurred in 3.2% of the TNK group versus 2.3% of the placebo group, a nonsignificant difference.

“The low rate of ICH with TNK at this late time point is very reassuring,” Dr. Albers said. “We believe the reason for the low ICH rate is probably because these patients were selected for small core strokes. We also found that there was a trend towards the most benefit from TNK in patients with the smallest cores, supporting the use of imaging to select patients.”

The secondary endpoint of complete recanalization at 24-hours post randomization was higher in the TNK group at 76.7%, compared with 63.9% in the placebo group (P = .006).
 

Benefit in M1 occlusions?

Subgroup analysis showed that there appeared to be a benefit of TNK in the 227 patients included who had an M1 occlusion. In this group, the common odds ratio for a more favorable outcome in the mRS shift analysis with TNK was 1.59 (95% CI, 1.00-2.52; adjusted nominal P = .051).

The percentage of patients with a favorable outcome (mRS, 0-2) at 90 days in the M1 occlusion subgroup was 45.9% for TNK versus 31.4% for placebo, giving an adjusted odds ratio of 2.03 (95% CI, 1.14-3.66; nominal P = .017).

But Dr. Albers cautioned that this was an exploratory analysis, and no formal conclusions should be drawn from these data.

“We saw very strong results in favor of giving thrombolysis in the patients with M1 occlusions. We had preliminary pilot data suggesting this approach may work in these patients,” he commented.

“But we included the smaller M2 occlusions as well, because we thought that as there should be less clot in an M2 occlusion it might be easier to dissolve with thrombolysis,” he added. “But surprisingly, the M2 occlusion patients seemed to do worse with TNK than placebo, and the M1 patients did better.”
 

Timing of TNK

Dr. Albers said that there was also information from in the study on the timing of TNK administration.

In patients who also received thrombectomy, who made up of the majority of those in the study, the average time of TNK administration was only 20 minutes before the thrombectomy procedure.

“We had hoped to have a longer time between thrombolysis and thrombectomy so the drug would have more time to work. The idea was that patients would be given TNK at the primary stroke center before being transferred for thrombectomy, but actually only a few patients received TNK at the primary stroke center,” Dr. Albers explained.

“But, again surprisingly, we found that patients given TNK right at the time of the thrombectomy procedure seemed to show a trend toward benefit over placebo,” he reported.

He suggested that this may be caused by the thrombolytic dissolving the small fragments that can sometimes break off and cause further occlusions when the clot is removed by thrombectomy.

“We have learned a lot from this study, and we are planning to go forward with the information gained to plan a second study, in which we will focus on patients with M1 occlusions and try to get the drug on board at primary stroke centers, so it has more time to work before thrombectomy,” he added.

Commenting on the TIMELESS study at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, said that he thought the trial had shown three important results: “Firstly, TNK appeared to be safe in this late window in these selected patients – that is a very important observation. Secondly, reperfusion rates at 24 hours were increased with TNK and we know that this translates into clinical benefit. And thirdly, there was a neutral effect on primary outcomes, but I think the sample size of 438 patients was not large enough to show efficacy.”

Dr. Tsivgoulis concluded that these points need to be addressed in future trials.

The TIMELESS trial was funded by Genentech.

A version of this article first appeared on Medscape.com.