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Undertreatment of Women With MS Unjustified
COPENHAGEN — , even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.
“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.
This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.
Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.
The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.
They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).
In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).
The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).
Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.
In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).
The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.
The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.
“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.
“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.
Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.
In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.
“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.
First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.
Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.
“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.
He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”
However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.
Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”
Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”
Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.
Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.”
Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.
The study authors and commentators reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN — , even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.
“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.
This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.
Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.
The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.
They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).
In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).
The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).
Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.
In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).
The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.
The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.
“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.
“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.
Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.
In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.
“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.
First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.
Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.
“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.
He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”
However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.
Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”
Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”
Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.
Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.”
Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.
The study authors and commentators reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN — , even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.
“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.
This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.
Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.
The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.
They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).
In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).
The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).
Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.
In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).
The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.
The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.
“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.
“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.
Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.
In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.
“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.
First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.
Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.
“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.
He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”
However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.
Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”
Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”
Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.
Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.”
Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.
The study authors and commentators reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2024
Novel Agent First to Slow Disability in Nonrelapsing Secondary MS
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
COPENHAGEN — A new investigational drug has become the first agent to slow disability in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).
In addition, tolebrutinib almost doubled the number of patients who experienced confirmed disability improvement from 5% to 10%.
However, these benefits come with the potential safety issue of liver toxicity, with raised liver enzymes reported in 4% of patients and very severe liver enzyme rises occurring in 0.5% of patients, one of whom died after undergoing a liver transplant.
The results were presented by Robert Fox, MD, vice chair of research at the Cleveland Clinic’s Neurological Institute in Ohio, at the 2024 ECTRIMS annual meeting.
“We have finally found a therapy that can alter the compartmentalized inflammation that is driving progressive MS,” he said.
Dr. Fox pointed out that the population enrolled in the HERCULES trial had stopped having clinical relapses. “These are the patients for whom current immunomodulator therapies really don’t work at all — they don’t slow disability. This trial suggests that tolebrutinib can fill that void and now we have something to offer this patient group,” he said.
He estimated that up to 30% of patients with MS at his clinic may fall into this category.
A typical patient with nrSPMS who was included in this trial may have experienced a gradual decline in the distance they can walk or the ease with which they could climb stairs, he explained.
“I would project that this therapy will slow down that gradual decline, and, in some patients, it may actually stop the decline,” he added.
Dr. Fox said that BTK inhibitors are believed to have two main mechanisms of action relevant to MS — down-regulating B cells, probably mostly in the periphery, and, as these agents can cross the blood-brain barrier, they also appear to reduce the inflammatory activity of microglia and macrophages in the brain.
He noted that the disability progression in nrSPMS patients is thought to be caused by compartmentalized inflammation in the brain, which is what tolebrutinib may be targeting.
He noted that siponimod has also shown benefit in secondary progressive MS in the EXPAND trial, but the benefit was almost entirely restricted to patients who had experienced recent relapses.
Ocrelizumab has been shown to be beneficial in a trial in primary progressive MS, but again, a large proportion of patients in that study had active focal inflammation at baselineEngl J Med. 2017;376:209-220).
Trial Results
The HERCULES trial included 1131 patients with nrSPMS, defined as having an Expanded Disability Status Scale score (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
They were randomly assigned (2:1) to receive 60 mg tolebrutinib as an oral daily dose or placebo for up to approximately 48 months. This was an event-driven trial, with 288 6-month confirmed disability progression events required.
About 23% of patients in each group discontinued treatment and 12%-17% who had confirmed disability progression elected to crossover to open-label tolebrutinib.
The study population had an average age of 49 years, had a median EDSS score of 6, and a mean time since last clinical relapse of over 7 years.
“So, this was a really very quiescent patient population in terms of focal inflammation,” Dr. Fox noted.
Results showed that the primary endpoint showed a 31% reduction in the risk of 6-month confirmed disability progression (26.9% tolebrutinib vs. 37.2% placebo; hazard ratio [HR], 0.69; 95% CI, 0.55-0.88).
Rates of 3-month confirmed disability progression were 32.6% in the tolebrutinib group versus 41.5% with placebo — a 24% risk reduction.
In addition, 6-month confirmed disability improvement was achieved by 10% of tolebrutinib patients versus 5% in the placebo group (HR, 1.88; 95% CI, 1.10-3.21).
A ‘Head-scratcher’ Finding
Surprisingly, he noted, tolebrutinib did not appear to slow brain atrophy.
“Despite seeing a benefit on disability progression, we saw no significant slowing of brain atrophy or brain volume loss over the course of the study,” Dr. Fox reported.
He described this discordance between disability rates and brain volume loss rates as “a bit of a head-scratcher.”
In terms of safety, the main concern is liver enzyme elevations, which occurred at greater than three times the upper limit of normal (ULN) in 4.1% of the tolebrutinib group vs 1.6% in the placebo group.
A small (0.5%) proportion of patients treated with tolebrutinib experienced very severe elevations (> 20 x ULN) in liver enzymes, and one of these patients had to have a liver transplant and died because of postoperative complications, “a reminder that this can be a very serious complication of this drug,” said Dr. Fox.
However, he noted that all the very severe liver enzyme rises occurred in the first 3 months and it is now recommended that patients undergo weekly liver enzyme monitoring for the first 12 weeks of treatment.
Other adverse effects that were increased slightly in tolebrutinib group were upper respiratory infections and possibly hypertension.
Weekly Liver Enzyme Testing
Dr. Fox cautioned that patients starting tolebrutinib would need to undergo weekly liver enzyme testing in the first few months of treatment. “They would need to be very attentive to this monitoring, but if they are willing to do that, then I think many of these patients will be very eager to take this drug that may slow down their disability progression.”
The drug’s manufacturer, Sanofi, said the trial results will form the basis for applications to global regulatory authorities with submissions starting later in 2024.
Commenting on the trial, Ludwig Kappos, MD, professor of neurology at University Hospital and University of Basel, Switzerland, said the trial was important as it had shown “a robust effect on confirmed disability progression in a population of secondary progressive MS with no or very low signs of focal inflammation.”
“The effect is similar and probably more pronounced than that seen in the siponimod trial also in advanced secondary progressive MS,” he added.
Dr. Kappos believes more work will be needed to make sure the liver toxicity can be prevented, “but if that can be resolved then patients could have a significant delay in accumulating disability.”
GEMINI Trials Also Show Slowed Disability
Two other phase 3 trials of tolebrutinib were presented during the same ECTRIMS session — GEMINI 1 and 2 — which compared the new drug with teriflunomide, a standard of care treatment, in participants with relapsing MS. Neither study met the primary endpoint of an improvement in annualized relapse rates, compared with teriflunomide.
However, with respect to the key secondary endpoint, in a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening by 29%, a finding in line with the main results of the HERCULES trial.
“The significant impact of tolebrutinib on disability accumulation versus teriflunomide, in the absence of a statistically superior impact on relapses, also suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses” Dr. Fox said.
The HERCULES trial was sponsored by Sanofi. Dr. Fox is a paid adviser to Sanofi. Dr. Kappos led the EXPAND trial of siponimod in SPMS.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2024
Fecal Transplant: A New Approach for Parkinson’s Disease?
, results of a new, randomized placebo-controlled trial show.
However, investigators discovered some interesting insights from the study, which they believe may help in designing future “improved, and hopefully successful, trials” with the intervention.
“Further studies — for example, through modified fecal microbiota transplantation approaches or bowel cleansing — are warranted,” they concluded.
The study was published online in JAMA Neurology.
Gut Dysfunction: An Early Symptom
Investigators led by Filip Scheperjans, MD, Helsinki University Hospital, Finland, explained that gut dysfunction is a prevalent, early symptom in Parkinson’s disease and is associated with more rapid disease progression.
Interventions targeting gut microbiota, such as FMT, have shown promising symptomatic, and potentially neuroprotective, effects in animal models of Parkinson’s disease.
Although several randomized clinical trials suggest efficacy of probiotics for Parkinson’s disease-related constipation, only limited clinical information on FMT is available.
In the current trial, 48 patients with Parkinson’s disease aged 35-75 years with mild to moderate symptoms and dysbiosis of fecal microbiota were randomized in a 2:1 ratio to receive FMT or placebo infused into the cecum via colonoscopy.
All patients had whole-bowel lavage starting the day before the colonoscopy. Fecal microbiota transplantation was administered as a single-dose and without antibiotic pretreatment.
Active treatment was a freeze-stored preparation of 30 g of feces from one of two donors who were healthy individuals without dysbiosis. The preparation was mixed with 150 mL of sterile physiologic saline and 20 mL of 85% glycerol for cryoprotection to improve viability of microbes. Placebo was the carrier solution alone, consisting of 180 mL of sterile physiologic saline and 20 mL of 85% glycerol.
The primary endpoint, a change in Parkinson’s disease symptoms as assessed on the Unified Parkinson’s Disease Rating Scale (UPDRS) at 6 months, did not differ between the two study groups.
Gastrointestinal adverse events were more frequent in the FMT group, occurring in 16 patients (53%) versus one patient (7%) in the placebo group. But no major safety concerns were observed.
Secondary outcomes and post hoc analyses showed a greater increase in dopaminergic medication, which may indicate faster disease progression, but also improvement in certain motor and nonmotor outcomes in the placebo group.
Microbiota changes were more pronounced after FMT, but dysbiosis status was reversed more frequently in the placebo group.
The researchers noted that the apparent futility in this trial is in contrast to several previous small clinical studies of fecal transplant that have suggested the potential for improvement of Parkinson’s disease symptoms.
In addition, encouraging results from the probiotics field suggest that an impact on motor and nonmotor Parkinson’s disease symptoms through gut microbiota manipulation is possible.
The researchers raised the possibility that the placebo procedure was not an inert comparator, given the relatively strong and sustained gut microbiota alteration and dysbiosis conversion observed in the placebo group, and suggested that the colonic cleansing procedure may also have had some beneficial effect.
“It seems possible that, after cleansing of a dysbiotic gut microbiota, recolonization leads to a more physiologic gut microbiota composition with symptom improvement in the placebo group. This warrants further exploration of modified fecal microbiota transplantation approaches and bowel cleansing in Parkinson’s disease,” they concluded.
Distinct Gut Microbiome
In an accompanying editorial, Timothy R. Sampson, PhD, assistant professor, Department of Cell Biology, Emory University School of Medicine, Atlanta, pointed out that dozens of independent studies have now demonstrated a distinct gut microbiome composition associated with Parkinson’s disease, and experimental data suggest that this has the capacity to incite inflammatory responses; degrade intestinal mucosa; and dysregulate a number of neuroactive and amyloidogenic molecules, which could contribute to the disease.
He noted that three other small placebo-controlled studies of fecal transplantation in Parkinson’s disease showed slightly more robust responses in the active treatment group, including improvements in UPDRS scores and gastrointestinal symptoms.
However, these studies tested different FMT procedures, including lyophilized oral capsules given at different dosing frequencies and either nasojejunal or colonic transfusion following a standard bowel preparation.
In addition, there is no consensus on pretransplant procedures, such as antibiotics or bowel clearance, and the choice of donor microbiome is probably essential, because there may be certain microbes required to shift the entire community, Dr. Sampson wrote.
Understanding how microbial contributions directly relate to Parkinson’s disease would identify individuals more likely to respond to peripheral interventions, and further exploration is needed to shed light on particular microbes that warrant targeting for either enrichment or depletion, he added.
“Despite a lack of primary end point efficacy in this latest study, in-depth comparison across these studies may reveal opportunities to refine fecal microbiota transplantation approaches. Together, these studies will continue to refine the hypothesis of a microbial contribution to Parkinson’s disease and reveal new therapeutic avenues,” Dr. Sampson concluded.
‘Planting Grass in a Yard Full of Weeds’
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, New York, said that whether FMT are helpful remains to be determined.
“The key question that needs to be solved is how to best perform these transplants. One issue is that you cannot plant grass when the yard is full of weeds. However, if you take too hard an approach killing the weeds — that is, with powerful antibiotics — you jeopardize the new grass, or in this case, the bacteria in the transplant. Solving that issue will be important as we consider whether this is effective or not.”
Dr. Beck added that there is still much to be learned from research into the gut microbiota. “I am hopeful with additional effort we will have answers soon.”
A version of this article appeared on Medscape.com.
, results of a new, randomized placebo-controlled trial show.
However, investigators discovered some interesting insights from the study, which they believe may help in designing future “improved, and hopefully successful, trials” with the intervention.
“Further studies — for example, through modified fecal microbiota transplantation approaches or bowel cleansing — are warranted,” they concluded.
The study was published online in JAMA Neurology.
Gut Dysfunction: An Early Symptom
Investigators led by Filip Scheperjans, MD, Helsinki University Hospital, Finland, explained that gut dysfunction is a prevalent, early symptom in Parkinson’s disease and is associated with more rapid disease progression.
Interventions targeting gut microbiota, such as FMT, have shown promising symptomatic, and potentially neuroprotective, effects in animal models of Parkinson’s disease.
Although several randomized clinical trials suggest efficacy of probiotics for Parkinson’s disease-related constipation, only limited clinical information on FMT is available.
In the current trial, 48 patients with Parkinson’s disease aged 35-75 years with mild to moderate symptoms and dysbiosis of fecal microbiota were randomized in a 2:1 ratio to receive FMT or placebo infused into the cecum via colonoscopy.
All patients had whole-bowel lavage starting the day before the colonoscopy. Fecal microbiota transplantation was administered as a single-dose and without antibiotic pretreatment.
Active treatment was a freeze-stored preparation of 30 g of feces from one of two donors who were healthy individuals without dysbiosis. The preparation was mixed with 150 mL of sterile physiologic saline and 20 mL of 85% glycerol for cryoprotection to improve viability of microbes. Placebo was the carrier solution alone, consisting of 180 mL of sterile physiologic saline and 20 mL of 85% glycerol.
The primary endpoint, a change in Parkinson’s disease symptoms as assessed on the Unified Parkinson’s Disease Rating Scale (UPDRS) at 6 months, did not differ between the two study groups.
Gastrointestinal adverse events were more frequent in the FMT group, occurring in 16 patients (53%) versus one patient (7%) in the placebo group. But no major safety concerns were observed.
Secondary outcomes and post hoc analyses showed a greater increase in dopaminergic medication, which may indicate faster disease progression, but also improvement in certain motor and nonmotor outcomes in the placebo group.
Microbiota changes were more pronounced after FMT, but dysbiosis status was reversed more frequently in the placebo group.
The researchers noted that the apparent futility in this trial is in contrast to several previous small clinical studies of fecal transplant that have suggested the potential for improvement of Parkinson’s disease symptoms.
In addition, encouraging results from the probiotics field suggest that an impact on motor and nonmotor Parkinson’s disease symptoms through gut microbiota manipulation is possible.
The researchers raised the possibility that the placebo procedure was not an inert comparator, given the relatively strong and sustained gut microbiota alteration and dysbiosis conversion observed in the placebo group, and suggested that the colonic cleansing procedure may also have had some beneficial effect.
“It seems possible that, after cleansing of a dysbiotic gut microbiota, recolonization leads to a more physiologic gut microbiota composition with symptom improvement in the placebo group. This warrants further exploration of modified fecal microbiota transplantation approaches and bowel cleansing in Parkinson’s disease,” they concluded.
Distinct Gut Microbiome
In an accompanying editorial, Timothy R. Sampson, PhD, assistant professor, Department of Cell Biology, Emory University School of Medicine, Atlanta, pointed out that dozens of independent studies have now demonstrated a distinct gut microbiome composition associated with Parkinson’s disease, and experimental data suggest that this has the capacity to incite inflammatory responses; degrade intestinal mucosa; and dysregulate a number of neuroactive and amyloidogenic molecules, which could contribute to the disease.
He noted that three other small placebo-controlled studies of fecal transplantation in Parkinson’s disease showed slightly more robust responses in the active treatment group, including improvements in UPDRS scores and gastrointestinal symptoms.
However, these studies tested different FMT procedures, including lyophilized oral capsules given at different dosing frequencies and either nasojejunal or colonic transfusion following a standard bowel preparation.
In addition, there is no consensus on pretransplant procedures, such as antibiotics or bowel clearance, and the choice of donor microbiome is probably essential, because there may be certain microbes required to shift the entire community, Dr. Sampson wrote.
Understanding how microbial contributions directly relate to Parkinson’s disease would identify individuals more likely to respond to peripheral interventions, and further exploration is needed to shed light on particular microbes that warrant targeting for either enrichment or depletion, he added.
“Despite a lack of primary end point efficacy in this latest study, in-depth comparison across these studies may reveal opportunities to refine fecal microbiota transplantation approaches. Together, these studies will continue to refine the hypothesis of a microbial contribution to Parkinson’s disease and reveal new therapeutic avenues,” Dr. Sampson concluded.
‘Planting Grass in a Yard Full of Weeds’
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, New York, said that whether FMT are helpful remains to be determined.
“The key question that needs to be solved is how to best perform these transplants. One issue is that you cannot plant grass when the yard is full of weeds. However, if you take too hard an approach killing the weeds — that is, with powerful antibiotics — you jeopardize the new grass, or in this case, the bacteria in the transplant. Solving that issue will be important as we consider whether this is effective or not.”
Dr. Beck added that there is still much to be learned from research into the gut microbiota. “I am hopeful with additional effort we will have answers soon.”
A version of this article appeared on Medscape.com.
, results of a new, randomized placebo-controlled trial show.
However, investigators discovered some interesting insights from the study, which they believe may help in designing future “improved, and hopefully successful, trials” with the intervention.
“Further studies — for example, through modified fecal microbiota transplantation approaches or bowel cleansing — are warranted,” they concluded.
The study was published online in JAMA Neurology.
Gut Dysfunction: An Early Symptom
Investigators led by Filip Scheperjans, MD, Helsinki University Hospital, Finland, explained that gut dysfunction is a prevalent, early symptom in Parkinson’s disease and is associated with more rapid disease progression.
Interventions targeting gut microbiota, such as FMT, have shown promising symptomatic, and potentially neuroprotective, effects in animal models of Parkinson’s disease.
Although several randomized clinical trials suggest efficacy of probiotics for Parkinson’s disease-related constipation, only limited clinical information on FMT is available.
In the current trial, 48 patients with Parkinson’s disease aged 35-75 years with mild to moderate symptoms and dysbiosis of fecal microbiota were randomized in a 2:1 ratio to receive FMT or placebo infused into the cecum via colonoscopy.
All patients had whole-bowel lavage starting the day before the colonoscopy. Fecal microbiota transplantation was administered as a single-dose and without antibiotic pretreatment.
Active treatment was a freeze-stored preparation of 30 g of feces from one of two donors who were healthy individuals without dysbiosis. The preparation was mixed with 150 mL of sterile physiologic saline and 20 mL of 85% glycerol for cryoprotection to improve viability of microbes. Placebo was the carrier solution alone, consisting of 180 mL of sterile physiologic saline and 20 mL of 85% glycerol.
The primary endpoint, a change in Parkinson’s disease symptoms as assessed on the Unified Parkinson’s Disease Rating Scale (UPDRS) at 6 months, did not differ between the two study groups.
Gastrointestinal adverse events were more frequent in the FMT group, occurring in 16 patients (53%) versus one patient (7%) in the placebo group. But no major safety concerns were observed.
Secondary outcomes and post hoc analyses showed a greater increase in dopaminergic medication, which may indicate faster disease progression, but also improvement in certain motor and nonmotor outcomes in the placebo group.
Microbiota changes were more pronounced after FMT, but dysbiosis status was reversed more frequently in the placebo group.
The researchers noted that the apparent futility in this trial is in contrast to several previous small clinical studies of fecal transplant that have suggested the potential for improvement of Parkinson’s disease symptoms.
In addition, encouraging results from the probiotics field suggest that an impact on motor and nonmotor Parkinson’s disease symptoms through gut microbiota manipulation is possible.
The researchers raised the possibility that the placebo procedure was not an inert comparator, given the relatively strong and sustained gut microbiota alteration and dysbiosis conversion observed in the placebo group, and suggested that the colonic cleansing procedure may also have had some beneficial effect.
“It seems possible that, after cleansing of a dysbiotic gut microbiota, recolonization leads to a more physiologic gut microbiota composition with symptom improvement in the placebo group. This warrants further exploration of modified fecal microbiota transplantation approaches and bowel cleansing in Parkinson’s disease,” they concluded.
Distinct Gut Microbiome
In an accompanying editorial, Timothy R. Sampson, PhD, assistant professor, Department of Cell Biology, Emory University School of Medicine, Atlanta, pointed out that dozens of independent studies have now demonstrated a distinct gut microbiome composition associated with Parkinson’s disease, and experimental data suggest that this has the capacity to incite inflammatory responses; degrade intestinal mucosa; and dysregulate a number of neuroactive and amyloidogenic molecules, which could contribute to the disease.
He noted that three other small placebo-controlled studies of fecal transplantation in Parkinson’s disease showed slightly more robust responses in the active treatment group, including improvements in UPDRS scores and gastrointestinal symptoms.
However, these studies tested different FMT procedures, including lyophilized oral capsules given at different dosing frequencies and either nasojejunal or colonic transfusion following a standard bowel preparation.
In addition, there is no consensus on pretransplant procedures, such as antibiotics or bowel clearance, and the choice of donor microbiome is probably essential, because there may be certain microbes required to shift the entire community, Dr. Sampson wrote.
Understanding how microbial contributions directly relate to Parkinson’s disease would identify individuals more likely to respond to peripheral interventions, and further exploration is needed to shed light on particular microbes that warrant targeting for either enrichment or depletion, he added.
“Despite a lack of primary end point efficacy in this latest study, in-depth comparison across these studies may reveal opportunities to refine fecal microbiota transplantation approaches. Together, these studies will continue to refine the hypothesis of a microbial contribution to Parkinson’s disease and reveal new therapeutic avenues,” Dr. Sampson concluded.
‘Planting Grass in a Yard Full of Weeds’
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, New York, said that whether FMT are helpful remains to be determined.
“The key question that needs to be solved is how to best perform these transplants. One issue is that you cannot plant grass when the yard is full of weeds. However, if you take too hard an approach killing the weeds — that is, with powerful antibiotics — you jeopardize the new grass, or in this case, the bacteria in the transplant. Solving that issue will be important as we consider whether this is effective or not.”
Dr. Beck added that there is still much to be learned from research into the gut microbiota. “I am hopeful with additional effort we will have answers soon.”
A version of this article appeared on Medscape.com.
FROM JAMA NEUROLOGY
Flu May Increase MI Risk Sixfold, More If No CVD History
“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.
“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.
The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.
The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.
The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).
The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).
A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.
In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.
They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.
“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
People Without Cardiovascular Disease at Highest Risk
The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.
“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.”
The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.
“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”
Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.
Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.
These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”
Clinical studies looking at such a strategy are currently underway.
‘Get Your Flu Shot’
The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.”
In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.
In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.
“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.
Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
Extend Flu Vaccination to Prevent ACS
This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.
“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.
“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.
The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”
A version of this article appeared on Medscape.com.
“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.
“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.
The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.
The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.
The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).
The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).
A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.
In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.
They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.
“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
People Without Cardiovascular Disease at Highest Risk
The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.
“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.”
The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.
“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”
Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.
Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.
These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”
Clinical studies looking at such a strategy are currently underway.
‘Get Your Flu Shot’
The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.”
In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.
In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.
“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.
Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
Extend Flu Vaccination to Prevent ACS
This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.
“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.
“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.
The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”
A version of this article appeared on Medscape.com.
“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.
“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.
The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.
The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.
The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).
The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).
A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.
In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.
They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.
“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
People Without Cardiovascular Disease at Highest Risk
The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.
“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.”
The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.
“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”
Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.
Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.
These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”
Clinical studies looking at such a strategy are currently underway.
‘Get Your Flu Shot’
The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.”
In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.
In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.
“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.
Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
Extend Flu Vaccination to Prevent ACS
This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.
“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.
“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.
The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”
A version of this article appeared on Medscape.com.
FROM NEJM EVIDENCE
Colchicine: A New Tool for Ischemic Stroke, CVD Event Recurrence?
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — However, the results did reveal a significant reduction in recurrent stroke and cardiovascular events in the per-protocol analysis and in the subgroup of patients with coronary artery disease.
“Although the primary endpoint was neutral, the CONVINCE results support the hypothesis that long-term anti-inflammatory therapy with colchicine may reduce recurrent stroke and cardiovascular events, specifically in stroke patients with atherosclerosis,” lead investigator Peter Kelly, MD, University College Dublin School of Medicine, Dublin, Ireland, concluded.
The results were presented at the European Stroke Organization Conference (ESOC) 2024.
Inflammation, Dr. Kelly said, plays an important role in the pathophysiology of atherosclerotic plaque, a major cause of cardiovascular events and ischemic strokes.
Colchicine, an established, widely available, low-cost drug that reduces inflammatory response, has been shown to reduce recurrent vascular events in patients with coronary artery disease.
The CONVINCE trial was conducted to see whether colchicine could show similar benefits in patients with non-severe, non-cardioembolic stroke or transient ischemic attack.
Conducted in 16 European countries and Canada, the CONVINCE trial included 3154 patients with a recent non-cardioembolic nondisabling ischemic stroke or high-risk transient ischemic attack. They were randomly assigned to receive colchicine (0.5 mg/d) or placebo.
Key exclusion criteria included evidence of atrial fibrillation or other source of cardioembolism, a defined cause of stroke other than atherosclerosis or small vessel disease, a glomerular filtration rate below 50 mL/min, and the use of drugs that interact with colchicine.
The primary endpoint was a composite of first recurrent ischemic stroke, myocardial infarction, cardiac arrest, or hospitalization for unstable angina. Study participants were followed-up over 36 months.
Results of the primary intention-to-treat analysis showed that the primary endpoint occurred in 153 patients randomized to low-dose colchicine (9.8%) versus 185 in the placebo group (11.8%). This translated into a hazard ratio (HR) of 0.84 (95% CI, 0.68-1.05; P = .12) — a nonsignificant result.
Reduced levels of C-reactive protein in the colchicine group showed the anti-inflammatory effect of treatment with colchicine, Dr. Kelly reported.
In a prespecified on-treatment analysis (excluding patients with major protocol violations), colchicine did show a significant benefit in the primary endpoint (HR, 0.80; 95% CI, 0.63-0.99).
A Novel Target for Stroke Treatment
In addition, significantly reduced rates of recurrent stroke or cardiovascular events were observed in the subgroup of patients with a history of coronary artery disease.
In an updated meta-analysis of existing colchicine studies including CONVINCE, there was a significant reduction in the risk for ischemic stroke (risk ratio, 0.73; 95% CI, 0.58-0.90).
“The signals of benefit of colchicine in secondary analyses are in line with findings from previous trials and indicate the potential of colchicine in prevention after stroke,” Dr. Kelly said.
He pointed out that the COVID pandemic reduced the planned follow-up time in the CONVINCE trial, which led to the study being underpowered for the primary analysis.
“Further trials are needed in all stroke subtypes, but with particular focus on patients with objective evidence of atherosclerosis,” he said.
Commenting on the findings, Mira Katan, MD, University Hospital of Basel, Switzerland, noted that inflammation represents a novel target for stroke treatment.
“We have never before looked at treating inflammation in stroke. Although the primary endpoint was not reached in the CONVINCE study, the on-treatment analysis and meta-analysis showed a risk reduction, and we know colchicine works in cardiology. I think this is a fantastic trial, giving us a new target for stroke therapy,” Dr. Katan said.
“I think we have a new tool, but of course we need further trials to confirm that,” she added.
The CONVINCE trial was supported by Health Research Board Ireland, Deutsche Forschungsgesellschaft, Fonds Wetenschappelijk Onderzoek (FWO), and the Irish Heart Foundation. Dr. Kelly received funding from the Irish Heart Foundation. Dr. Katan reported no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
Guidelines on Rapid Blood Pressure Reduction in Acute Ischemic Stroke Challenged
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — New findings challenge the practice of rapidly lowering blood pressure (BP) in acute ischemic stroke to allow for speedy thrombolysis.
The observational cluster study showed that , even though this meant fewer patient received thrombolysis.
“We found insufficient evidence to recommend active blood pressure lowering in patients with ischemic stroke who have blood pressure levels exceeding the guidelines but are otherwise eligible for thrombolytic therapy,” said senior study author Nyika D. Kruyt, MD, PhD, Leiden University Medical Center, the Netherlands.
“Our results suggest that if the blood pressure is too high for thrombolysis, then it is best to wait and only treat with thrombolysis if the blood pressure drops spontaneously,” Dr. Kruyt said.
The findings were presented at the European Stroke Organisation Conference (ESOC) annual meeting and published online in The Lancet Neurology.
Guidelines Without Evidence?
Owing to concerns about high BP increasing the risk for intracerebral hemorrhage after thrombolysis, the original trials evaluating thrombolysis in stroke set an arbitrary threshold of 185/110 mm Hg, which has been incorporated into stroke guidelines. These trials cautioned against lowering BP rapidly, which is not included in guidelines.
Most stroke centers therefore tend to rapidly lower BP in patients who have values greater than 185/110 mm Hg and who are otherwise eligible for thrombolysis, investigators noted. Because thrombolysis is more effective the earlier it is administered, there is some urgency to reduce the BP quickly when patients first arrive at the hospital.
“But there has never been any evidence for the lowering of blood pressure with IV [intravenous] antihypertensives before thrombolysis, and some centers have never adopted this approach because of concerns that a rapid decline in blood pressure may reduce perfusion of the brain at a time when there is already ischemia present,” Dr. Kruyt noted.
However, if BP is lowered quickly, there is a greater chance that patients will not be able to receive thrombolysis because the 4.5-hour time limit could be exceeded.
For the prospective, observational TRUTH study, researchers compared outcomes in 853 patients treated at 27 stroke centers in the Netherlands with an active BP-lowering strategy vs 199 patients treated at 10 hospitals with no such strategy.
Baseline characteristics of participants in the two groups were similar.
Results showed a strong trend toward worse outcomes in participants whose BP was lowered, with an adjusted odds ratio (aOR) for a shift toward a worse 90-day functional outcome on the modified Rankin Scale of 1.27 (95% CI, 0.96-1.68).
This was despite the fact that many more patients whose BP was reduced received thrombolysis (94% vs 52% of those with no BP lowering) and had shorter times to treatment, with average door-to-needle times of 35 minutes (vs 47 minutes among those with no BP lowering).
Symptomatic intracranial hemorrhage occurred in 5% of the active BP-lowering group versus 3% of those who did not have their BP lowered (aOR, 1.28; 95% CI, 0.62-2.62).
Reconsider Guidelines?
These results are consistent with those from the INTERACT4 trial, which was also presented at the ESOC 2024 meeting. That trial showed a harmful effect of lowering BP in the ambulance in patients with acute ischemic stroke, but a beneficial effect in patients with hemorrhagic stroke.
“I think the guidelines need to be reconsidered after these studies and we should refrain from active blood pressure–lowering in patients with acute ischemic stroke,” Dr. Kruyt said.
But he acknowledged that not rapidly lowering BP will mean fewer patients will be able to receive thrombolysis within the 4.5-hour treatment window.
Dr. Kruyt estimated that the combination of being eligible for thrombolysis, with the only exclusion criterion being BP greater than 185/110 mm Hg, applies to about 10%-15% of patients.
“If we have a watch-and-wait policy, then about half of those patients will still get treated with thrombolysis within in the 4.5-hour limit but later than if blood pressure was reduced with IV antihypertensives,” he added.
Dr. Kruyt noted that there has never been a randomized trial on the practice of BP lowering in order to be able to administer thrombolysis.
“The 185/110 mm Hg blood pressure level is an arbitrary threshold that was chosen for the original thrombolysis stroke trials,” he said. “I believe we need trials to investigate whether we can give thrombolysis safely to patients with higher blood pressure levels than this, without needing to rapidly reduce the pressure.”
Caution Advised
Discussing the TRUTH study at the ESOC meeting, Guillaume Turc, MD, professor of neurology at Sainte-Anne Hospital, Paris, said he thought the findings were “very thought provoking.”
Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said the result was surprising, but she advised caution in acting on this finding.
“I don’t think this study can change practice or guidelines as it is not a randomized trial. Yes, it can generate a hypothesis, but we need more research before changing clinical practice,” she said.
In an accompanying editorial, Verónica Olavarría, MD, Clínica Alemana Universidad del Desarrollo, Santiago, Chile, also suggested the trial should be interpreted cautiously because there was “insufficient evidence for a definitive conclusion.”
But Dr. Kruyt noted that even though the TRUTH study was not a randomized trial, the results are in line with those of recent randomized trials such as INTERACT4.
He added that the ENCHANTED trial also showed no benefit of intensive BP management immediately after thrombolysis in mild to moderate stroke and even suggested harm in severe stroke. And other trials (OPTIMAL-BP and ENCHANTED2/MT) have shown worse outcomes with BP lowering in patients with acute ischemic stroke undergoing thrombectomy.
“All these studies are showing similar signals throughout the whole timeline in acute ischemic stroke. The results are very much in line with each other. I think this strengthens our findings,” Dr. Kruyt said.
“With this data, I think the guidelines should be revised, and until randomized data become available showing that reducing blood pressure in acute ischemic stroke patients in order for them to receive early thrombolysis is beneficial, then we should refrain from doing so,” he added.
INTERACT4 investigator Craig Anderson, MD, George Institute for Global Health, Sydney, New South Wales, Australia, agreed.
“The TRUTH study gives the same message as INTERACT4. They are completely in line with each other, both suggesting harm with blood pressure lowering in acute ischemic stroke. These two together are going to rattle the cage around blood pressure control in acute ischemic stroke patients,” Dr. Anderson said.
The TRUTH study was funded by a grant from Fonds NutsOhra. Dr. Kruyt reported no relevant financial disclosures. Dr. Olavarría reported receiving a grant from Boehringer Ingelheim for the RECCA registry and honoraria from Novo Nordisk.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
IV Thrombolysis Offers No Benefit for Mild Stroke
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — , a new trial has concluded.
Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.
The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.
“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.
“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”
The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
Very Little Data
Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.
Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.
However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.
Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.
The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.
The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.
Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).
The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.
The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).
Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.
More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).
There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).
The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.
Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.
Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.
Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
More Trials Needed
Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”
In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.
Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.
Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.
While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.
“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.
This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.
A version of this article appeared on Medscape.com.
FROM ESOC 2024
New Data to Change Practice on BP Control in Acute Stroke: INTERACT4
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.
BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients.
“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia.
“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.
The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine.
A Test of Early BP Control
The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke.
The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis.
For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).
The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg.
Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke.
At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group.
The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days.
Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar.
But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke.
‘Slam-Dunk’ Effect
Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.
“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”
The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.
The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said.
“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.”
Challenging Ischemic Stroke Guidelines
The INTERACT4 results in ischemic stroke patients are likely to be more controversial.
“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said.
Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly.
“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.”
He said the mechanisms behind the different stroke types would explain the results.
“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”
Accurate Diagnosis Necessary
Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance.
“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”
Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice.
“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated.
Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions.
In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke.
“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote.
The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.
A version of this article appeared on Medscape.com.