Sue Hughes

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

The risk of severe outcomes from COVID-19 infection in patients with multiple sclerosis (MS) seems to align with that seen in the general population, new U.S. data suggest. A separate study from the United Kingdom also found similar trends of rates of COVID-19 infection in patients with MS and the general population.

Both studies were presented Sept. 26 at a special session on multiple sclerosis and COVID-19 at a final “Encore” event as part of the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The U.S. data appear consistent with studies from several other countries, in that worse COVID-19 outcomes increase with age and higher disability levels, both of which would be expected from findings in the general population.

The U.S. data also show a clear effect of race in MS, with higher rates of adverse COVID-19 outcomes in Black patients, again in line with what is seen in the general population.

“I would say the results from our study and in general do not suggest that MS itself is associated with higher risks of severe COVID-19 outcomes, compared with the general population,” said Amber Salter, PhD.

Dr. Salter, who is assistant professor of biostatistics at Washington University, St. Louis, presented data from the COViMS North American registry, set up for health care providers to report persons with MS who are infected with COVID-19.

The COViMS registry so far has information on 858 patients with MS who have COVID-19 (80% verified by a positive test), as reported from 150 different health care providers in the United States and Canada. The average age was 48 years, with average disease duration of 13.6 years. MS clinical course was reported as relapsing remitting in 78%, secondary progressive in 15%, and primary progressive in 5%. Most patients (72%) were fully ambulatory, 16% could walk with assistance, and 12% were nonambulatory.

Severe COVID-19 outcomes were classified as mortality (which occurred in 5.7% of the cohort), mortality/ICU admission (13.6%) and mortality/ICU admission/hospitalization (30.2%).

Results were adjusted for many different covariates, including sex, age, smoking, MS clinical course (relapsing, progressive), disease duration, ambulation, individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease-modifying therapy use.

In multivariable logistic regression analyses, older age, having chronic renal disease, and being nonambulatory were consistently associated with increased odds of poorer outcomes. Chronic kidney disease had the strongest association with mortality (odds ratio, 28.6; P < .001). Other factors associated with mortality included cardiovascular disease (OR, 4.35; P = .009); age (OR per 10 years, 1.91; P = .012), and male sex (OR, 2.60; P = .041).

Patients who were nonambulatory had a higher risk of mortality/ICU admission/hospitalization (OR, 3.32; P = .003). This endpoint was also increased in patients on anti-CD20 drugs, compared with other disease-modifying treatment (OR, 2.31; P = .002), consistent with results from at least two other studies.

Disease-modifying therapy in general was not associated with an increased risk of worse outcomes. “There was some concern at the outset about the effect of disease-modifying therapies on COVID-19 outcomes, but most studies have not found an increased risk of worse outcomes in patients on such drug treatments, with the possible exception of anti-CD20 drugs,” Dr. Salter said.

“Some disease-modifying therapies may actually be protective (particularly interferon) and studies are investigating whether they may have a role in the treatment of COVID-19,” she added.

“The factors in MS patients that we and others have found to be associated with worse COVID-19 outcomes may not be specific to MS. Older age is known to be a primary risk factor for worse COVID-19 outcomes in the general population, and increasing disability presumably tracks with worse general heath,” Dr. Salter commented.

“I would say the overall data are fairly reassuring for MS patents,” she concluded.
 

Black patients have higher risk

One worrying finding in the North American data, however, was the effect of race. “We found an independent effect of race for worse COVID-19 outcomes in MS patients,” Dr. Slater said.

Of the 858 patients in the COViMS registry, 65.7% were White and 26.1% were Black. Black individuals were more likely to be younger, never smokers, have shorter MS duration, a relapsing MS course, and have comorbidities, compared with White patients. A higher proportion of Black patients had hypertension (40.2% vs 19.5%) and morbid obesity (17% vs. 9.5%).

Results showed that mortality rates were not statistically different between White and Black patients, but Black race was associated with increased risk of mortality and/or ICU admission, compared with White patients (16.9% vs. 12.8%), and multivariate logistic regression analysis showed Black race was independently associated with mortality/ICU admission after adjustments for covariates (OR, 3.7; P = .002).

Black race was also associated with increased risk of mortality/ICU admission/hospital admission (35.8% vs. 30.2%), and after adjustment for covariates this was found to be an independent predictor (OR, 1.7; P = .04).

“This higher COVID-19 risk in Black individuals is also seen in the general population, so these results are not that surprising and it doesn’t appear to be an effect specific to MS patients,” Dr. Salter commented.
 

U.K. data on risk of contracting COVID-19 

A U.K. study also suggested race to be an independent predictor in the risk of contracting COVID-19 in patients with MS.

The study of more than 5,000 patients with MS showed that those from a Black, Asian, and Minority Ethnic group were twice as likely to report having COVID-19 than those who were White.

The study, which was conducted during the U.K. lockdown, also found that the trend of COVID-19 infection in patients with MS is comparable with that of the U.K. general population.

Presenting the data, Afagh Garjani, MD, concluded: “During a period with strict physical distancing measures, patients with MS are not at an increased risk of contracting COVID-19.”

Dr. Garjani, a neurology clinical research fellow at the University of Nottingham, (England), explained that the COVID-19 pandemic has introduced uncertainties into the MS community, and the focus so far has been the severity of infection among people with MS who have COVID-19.

“This approach has left questions about the risk of contracting disease in people with MS unanswered, which has implications as society gradually returns to normal,” she said.

Dr. Garjani presented data from the United Kingdom MS Register (UKMSR), which has been collecting demographic and MS-related data since 2011 from patients with MS throughout the United Kingdom.

On March 17 – just before the lockdown in United Kingdom – existing participants of the UKMSR were asked to join the COVID-19 study. The study was also advertised through social media. In this ongoing study, people with MS answered a COVID-19–related survey at participation and a different follow-up survey every 2 weeks depending on whether they contracted COVID-19.

The COVID-19 study included 5,309 patients with MS. The mean age of the study population was 52.4 years, 76.1% were female, and 95.7% were White. Of the 5,309 patients, 535 (10%) reported a self-diagnosis of COVID-19. Because of limited availability of tests in the United Kingdom at the time, only 75 patents had a positive polymerase chain reaction result.

“To our knowledge, this is the largest community-based study of COVID-19 in patients with MS worldwide,” Dr. Garjani said. She presented results from the period March 23 to June 24, when the United Kingdom was in a period of lockdown with vulnerable groups encouraged to self-isolate completely.

In this MS cohort, 47% reported self-isolating at some point. Those at older age and higher Expanded Disability Status Scale (EDSS) score were more likely to have self-isolated.

The researchers did not find that patients with progressive MS or those on disease-modifying therapies in general isolated more, but patients on monoclonal antibody drugs and fingolimod were more likely to self-isolate versus those on other therapies. “This may be because there are concerns about infection with these drugs and patients on these therapies may be more concerned about contracting COVID-19,” Dr. Garjani suggested.

In terms of contracting COVID, the researchers found a reduced risk of COVID-19 (self-diagnosed) in patients with older age and higher EDSS. “This is not really surprising that these patients were more likely to self-isolate,” Dr. Garjani commented.

No association was seen between type of MS, disease duration, disease-modifying therapy in general, and risk of COVID-19. No individual drug treatment increased risk versus no therapy or versus self-injectables. But there was an increased risk of contracting the virus in patients whose race was Black, Asian, or Minority Ethnic (OR, 2.2), which is in line with findings from the general population.

“This study is unique – the denominator is all people with MS. We are looking primarily at the risk of contracting COVID-19. Other studies are focusing more on people with MS who have COVID and assessing risk of a severe COVID outcome. Our results are not contradicting the findings from those studies,” Dr. Garjani said.

The results were similar only when patients with a confirmed COVID-19 test were considered.

In terms of outcomes in those who reported COVID-19 infection, preliminary results have not shown any MS factors – such as EDSS, age, type of MS, drug therapy in general – to be associated with outcome.

“Since the COVID-19 outbreak started there has been concern among MS patients, especially among those on disease-modifying therapies, about whether they are at increased risk of infection and severe disease,” Dr. Garjani said.

“We found similar trends of rates of infection in MS patients and the general population, and no signal of increased risks in those with higher EDSS or progressive MS. The caveat is that this study was conducted in a period of lockdown, but we adjusted for self-isolating behavior in the multivariable regression analysis,” she noted.

Dr. Salter is a statistical editor for the American Heart Association journal Circulation: Cardiovascular Imaging. Dr. Garjani has disclosed no relevant financial relationships.

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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

There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.

These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.

But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.

To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.

Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.

Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.

In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.

In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.

There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.

He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.

“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.

“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.

“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
 

Risk stratification

Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.

“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.

With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.

“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.

On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”

The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
 

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

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

The investigational drug masitinib (AB Science), which has a completely new mechanism of action for multiple sclerosis (MS), has shown a positive result in slowing disability in patients with primary progressive and secondary progressive forms of the disease and no signs of active inflammation in a phase 2b/3 study.

“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”

Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.

This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.

However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.   

In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.

Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said.  “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”

Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained. 

Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.

“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added. 

“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”  

The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.

The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years.  “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.

Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.

The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).

Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).

Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.

In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.  

He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.

No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.

Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”

“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”

A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added. 

Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”

“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”

“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.

The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
 

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

The investigational drug masitinib (AB Science), which has a completely new mechanism of action for multiple sclerosis (MS), has shown a positive result in slowing disability in patients with primary progressive and secondary progressive forms of the disease and no signs of active inflammation in a phase 2b/3 study.

“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”

Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.

This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.

However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.   

In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.

Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said.  “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”

Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained. 

Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.

“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added. 

“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”  

The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.

The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years.  “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.

Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.

The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).

Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).

Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.

In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.  

He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.

No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.

Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”

“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”

A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added. 

Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”

“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”

“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.

The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
 

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

The investigational drug masitinib (AB Science), which has a completely new mechanism of action for multiple sclerosis (MS), has shown a positive result in slowing disability in patients with primary progressive and secondary progressive forms of the disease and no signs of active inflammation in a phase 2b/3 study.

“This is the first time that we have seen significant activity in slowing disability in a population of nonactive primary progressive and secondary progressive MS,” lead investigator, Patrick Vermersch, MD, commented. “There are no drugs available for these patients, which make up the vast majority of progressive MS patients, so these results are impressive. They are definitely a big deal.”

Dr. Vermersch, who is professor of neurology at the University of Lille, France, presented the study at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“Masitinib – a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity – may provide a new treatment option for primary progressive and nonactive secondary progressive MS,” he concluded.

This study, known as AB07002, demonstrated a sustained and significant benefit for masitinib at a dose of 4.5 mg/kg per day in Expanded Disability Status Scale (EDSS) score change over 2 years versus placebo, with a 37% reduction in 3-month confirmed disability progression. This change “is relevant from a medical standpoint,” Dr. Vermersch reported.

However, a second dosing schedule, in which the drug was titrated up to 6 mg/kg per day, did not show significant benefit. Dr. Vermersch said this was because of an unexpected improvement in EDSS score in the placebo group.   

In the 4.5-mg/kg group, the benefit was demonstrated across a broad population, with no difference with regard to age, duration of disease, or baseline disability. The benefits were similar in both primary and secondary MS phenotypes and were present irrespective of baseline active inflammation status.

Masitinib showed a safety profile “suitable for long-term administration in this population,” Dr. Vermersch said.  “Masitinib addresses the huge unmet need in progressive MS,” he said. “The drugs currently used in MS target B cells and T cells. They are immunomodulating drugs and are used for relapsing/remitting MS. But in progressive forms of the disease, there is a strong involvement of innate immunity, so to be effective we need drugs that target this part of the immune system.”

Innate immunity is a major part of the immune system in primates; it is related to the immune cells inside tissues and the CNS and is separate from adaptive peripheral immunity, he explained. 

Masitinib is a novel drug for MS in that it inhibits tyrosine kinase and blocks the activity of immune cells involved in the innate immune system – mainly microglia and mast cells. “Both of these types of cells are very involved in progressive MS. Masitinib has no action against T or B cells. It is a small molecule and penetrates the CNS,” Dr. Vermersch noted.

“This has opened up a whole new area of opportunity to develop treatments for progressive MS,” he added. 

“We showed a positive significant result in slowing disability in patients with nonactive progressive MS,” he said. “The term ‘nonactive’ is important. Some other drugs [ocrelizumab and siponimod] have shown some modest activity in slowing progressive forms of MS, but this is driven by patients with some degree of inflammatory activity at baseline. Our study excluded such patients.”  

The trial tested two different dosing schedules independently, each with its own placebo group. There were two subsets, each with 300 patients. The first subset was randomly assigned in a 2:1 ratio to daily masitinib at 4.5 mg/kg orally or placebo. The second subset was randomly assigned in a 2:1 ratio to daily masitinib titrated to 6 mg/kg or placebo.

The inclusion criteria were patients with primary progressive or secondary progressive MS without relapse (as measured by EDSS progression) within the previous 2 years.  “No patients were enrolled who had superimposed relapses during the previous 2 years,” Dr. Vermersch stressed.

Baseline EDSS score was 5.0, and patients had an average disease duration of 15 years. Mean age was 50 years.

The primary endpoint was change from baseline in absolute EDSS value, which was measured every 12 weeks throughout the study, averaged over the 2-year study period (mean change in EDSS score).

Results in the 4.5-mg/kg group showed a mean increase in EDSS score in the masitinib recipients of 0.001 versus 0.098 in the placebo group, giving a mean difference of –0.097 for masitinib (P = 0.025). The results were similar in patients with primary or secondary progressive MS. Sensitivity analysis based on ordinal EDSS change showed a significant 39% increased probability of having more improvements in EDSS or fewer worsening EDSS scores with masitinib (odds ratio, 0.61; P = 0.044). Other results showed that masitinib reduced the risk for first disability progression by 42% (hazard ratio, 0.58; P = 0.034) and the risk for confirmed (3-month) disability progression by 37% (hazard ratio, 0.63; P = 0.15).

Masitinib also showed a 98% reduction in the risk of reaching an EDSS score of 7, corresponding to disability severe enough that the patient is restricted to a wheelchair (hazard ratio, 0.02; P = 0.009). No patients in the masitinib group reached the endpoint of confirmed (3-month) EDSS score of 7, compared with four patients in the placebo group.

In terms of safety in the 4.5-mg/kg group, the most common adverse events were rash (1,5%) gastrointestinal (GI) disturbances (1%), neutropenia (1%), and edema (1%). “We had a couple of patients with skin reactions and neutropenia, but all adverse events were mild to moderate and very manageable,” Dr. Vermersch commented.  

He showed just one slide on the subset who were titrated up 6 mg/kg. “Numerically the change in EDSS was comparable in the 6-mg/kg–titrated group as it was in the 4.5-mg/kg group; however, the placebo arm of the 6-mg/kg subset unusually showed an improvement relative to baseline after 96 weeks. The placebo group of the 4.5-mg/kg cohort was consistent with the literature and expected worsening in EDSS score over 96 weeks,” Dr. Vermersch reported.

No new safety signal was observed in the 6-mg/kg cohort. Only the 4.5-mg/kg cohort will be pursued in further trials in MS.

Dr. Vermersch noted that masitinib is also being investigated in other indications and “there are thousands of patient-years of experience which show reassuring safety data.”

“There is some GI disturbances and skin reactions, but a very small percentage of patients discontinue treatment. If the drug is titrated slowly there are fewer adverse effects,” he said. “We will do that in the next study.”

A second confirmatory study is now being planned. The trial will enroll around 700 patients and is expected to recruit quickly because there is such a big unmet need, Dr. Vermersch added. 

Commenting on the findings, ACTRIMS president Jeffrey Cohen, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, said this is “an interesting study from several perspectives.”

“Masitinib is a new drug for MS with a completely novel mechanism of action targeting the innate immune system”, he said. “The study had several innovative features in that it combined primary and secondary progressive MS patients and measured disability in a different way to what we are used to.”

“It did show a slowing of disability, which is great news as we do not have any drugs for these patients at the moment, so this is a very hopeful result,” Dr. Cohen said.

The study was supported by AB Science. Dr. Vermersch reports sitting on advisory boards for Biogen, Sanofi-Genzyme, Teva, Roche, Novartis, Celgene, and Merck KGaA.
 

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

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

“It is time that the prodromal phase of multiple sclerosis [MS] is formally recognized.” That was the conclusion of Helen Tremlett, PhD, delivering the opening plenary session lecture at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

“There is now no doubt that there is an MS prodrome measurable by increased healthcare usage and lifestyle changes that are recognizable 5-10 years before the clinical recognition of MS. There is a myriad of prodromal features but none that are specific to MS,” Dr. Tremlett said.

“These findings show that in future there could be an earlier window of opportunity to identify and manage MS,” she suggested.

In an interview, Dr. Tremlett, who is professor and Canada Research Chair in Neuroepidemiology and Multiple Sclerosis at the University of British Columbia, Vancouver, explained that for MS a prodrome is a relatively new concept. “Right up until the year 2000, MS leaders were specifically saying that a prodrome did not exist,” she said. “But things have changed. Studies started emerging in the last decade suggestive of a prodrome, and I think we can now say there is definitely proof that a prodrome does exist. If you ask MS patients, the vast majority of them will say they had an increase in health issues in the years before diagnosis.”

In her plenary talk, Dr. Tremlett summarized the available evidence showing that, in the years before the first demyelinating event, patients are more likely to be have multiple health issues and an increase in hospitalizations and physician visits.

In a 2018 study, her group analyzed data from four Canadian provinces, including 14,000 patients with MS and 75,000 matched controls, and found a 75% increase in the rate of hospitalization, a 88% higher rate of physician service use, and a 49% increase in prescription numbers in the 5 years before the first demyelinating event in the patients with MS, compared with controls.

This included a 50% increase in mental health visits to physicians and increased rates of fibromyalgia, pain, headache, migraine, sleep disturbances, urology, and dermatology referrals, as well as irritable bowel syndrome. In addition, there were fewer pregnancies and increased prescriptions for contraception in the female patients later diagnosed with MS.

“There is a huge range of nonspecific symptoms in the 5 years before MS diagnosis, and some of these are really intriguing and unanticipated,” Dr. Tremlett said. “We are not surprised by the findings that fatigue, mental health issues, and bladder and bowel symptoms are increased, but the finding that there are more visits to a dermatologist and an increase in prescriptions for skin conditions was completely unexpected.”

The researchers found that dermatology referrals increased in patients who went on to develop relapsing remitting but not primary progressive forms of MS, which correlates with the established knowledge that the relapsing form has an inflammatory component not seen in progressive MS.

In a large U.K. population study of 10,000 patients with MS and 39,000 matched controls sourced from primary care doctors’ records, there was an increase in gastrointestinal and urinary issues, pain, anxiety and depression, insomnia, and fatigue in the 10 years before the first diagnosis of MS or clinically isolated syndrome (CIS) in patients later diagnosed with those conditions, compared with controls, Dr. Tremlett reported.

Other data have suggested that sex and age may affect the prodrome. In a study published this year, anemia was increased in the year before the first demyelinating event and pain was increased for 5 years beforehand. But anemia was more common in male patients later diagnosed with MS/CIS (odds ratio compared with controls, 2.4) than in female patients (OR compared with controls, 1.2).

The increase in pain seemed to be greater with age, with ORs of 1.8 for those younger than 30 years, 2.1 for those age 30-49 years, and 2.4 for those older than 50 years compared with controls.

A Norwegian military study in men that included 900 patients with MS and 19,000 matched controls found that cognitive performance was reduced in the 2 years before MS symptoms developed and up to 20 years before symptoms in those who developed primary progressive MS. “This suggests that primary progressive MS could start decades before the first apparent symptoms become obvious,” Dr. Tremlett commented.

A study in pediatric MS found that the mothers of the patients had higher use of health care (rate ratio, 1.16) and mental health (rate ratio, 1.33) services in the 5 years before their children had their first demyelinating event.

A study in Bavaria, Germany, including 10,000 patients with MS and 73,000 controls, concluded that “many physician visits before MS diagnosis were, in hindsight, likely a demyelinating event,” with the implication that this is evidence of missed opportunity for earlier diagnosis, Dr. Tremlett noted.

In a 2019 study, psychiatric symptoms were more common before MS diagnosis across various different immune-mediated disease (MS, rheumatoid arthritis, inflammatory bowel disease), with an incidence rate ratio of 1.6. The rate was even increased 10 years before diagnosis (incidence rate ratio, 1.5).

“This is evidence for shared prodromal features across immune diseases, but there isn’t a single feature specific to MS,” Dr. Tremlett said. She also referred to evidence that the blood biomarker of neuronal damage, neurofilament light chain (NfL), is raised several years before MS diagnosis. In a U.S. military study that examined serum repository samples, NfL was increased for 6 years before disease onset in 30 patients with MS, compared with 30 matched controls.
 

What are the implications?

Dr. Tremlett said the immediate impact of these observations about the prodrome is focused on research, particularly investigation of risk factors for MS. “If we want to know what causes MS, we have to be very careful that we are not detecting prodromal symptoms and mistaking that for a causal MS risk factor. We need to make sure we look further back than just the last few years when looking for risk factors.”

She gave the example of the observation that women in the years before MS diagnosis are less likely to have a pregnancy and more likely to fill a prescription for contraception. “This has led to the idea that avoiding pregnancy and using contraceptives increases the risk of MS, but I interpret it as these women know that something odd is going on and make the lifestyle decision not to become pregnant.”

She believes the longer-term impact of the prodrome is going to require much thought. “There is no such diagnosis of prodromal MS at the moment, but there could be in future. But the idea that we can use this information to detect MS earlier is going to require collaboration from many international stakeholders and MS organizations. We can’t automatically suspect MS in people who have these symptoms because they are so nonspecific. I think to request an MRI in patients experiencing headaches/fatigue/bowel issues is jumping the gun at the present moment as these symptoms are very common.”

On the idea of measuring NfL in patients with some of these symptoms, she believes that may be a possibility in the future but much more data are required.“We do have some evidence suggesting that the NfL blood biomarker is raised before MS diagnosis, and this was from a very well-designed study, but it was small so I think it is too early to start looking at this in clinical practice,” she said. “But it does justify doing this as part of a research study. We definitely need more data on this. We must be cautious as NfL is not specific for MS – many other conditions are also associated with raised levels, but it is certainly an interesting marker if used carefully.”
 

Following in the footsteps of Parkinson disease

She suggested that the way forward will be to package up these symptoms with information on biomarkers, such as NfL and imaging information, to enhance the ability to identify prodromal MS. “We could create a risk score and when a certain level of confidence is reached that this could be prodromal MS, then these patients could be enrolled in an intervention research study.”

Dr. Tremlett pointed out that, in the Parkinson disease field, a set of validated criteria for a prodrome have already been identified. “This is not used in clinical practice yet, but it is being used to identify patients for enrollment into clinical trials. I’m hoping that MS will follow in their footsteps.”

Commenting on the presentation, ACTRIMS president, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, said: “There is no doubt that the MS disease process begins prior to the first attack (in the case of relapsing MS) or the onset of overt disability progression (in the case of primary progressive MS).”

He explained that this is demonstrated by the presence of old lesions on MRI in most patients at the time of presentation, the existence of so-called radiologically isolated syndrome (patients without symptoms of MS who undergo MRI for another reason and are found to have lesions suggesting of MS, many of whom go on to develop MS at a later date), and the occurrence of a variety of symptoms 5-10 years before presentation to a neurologist.

“Those symptoms are ones that are common in MS, though not specific for MS,” Dr. Cohen noted. “The main implication is that the timeline for MS needs to be moved earlier – for diagnosis, categorization of disease course, prognostic studies, and treatment. The issue is that the symptoms of the prodrome are rather nonspecific and most people with those symptoms do not have MS.”

New incoming president of ECTRIMS, Maria Pia Amato, MD, professor of neurology at the University of Florence (Italy), added: “The million-dollar question is when does progression really begin? This plenary talk tells us the disease is there years and years before it manifests itself with first demyelinating event. This opens up an immense opportunity for research and to open the window to the possibility of earlier diagnosis and treatment.”

Dr. Tremlett reports an investment in Precision NanoSystems.

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

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

The presence of cardiovascular risk factors in patients with multiple sclerosis (MS) is associated with a greater degree of brain atrophy even in young patients who are unlikely to have small vessel disease, a new study has shown.

The results were presented by Raffaello Bonacchi, MD, Vita-Salute San Raffaele University, Milan, Italy, at at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020. .

“Our results suggest that even low levels of exposure to cardiovascular risk factors are important in MS and might affect brain atrophy—and therefore long-term disability—even in young patients,” Dr. Bonacchi said. 

“It is not only smoking,” he added. “Other cardiovascular risk factors also appear to be implicated. We found a synergistic effect of the different risk factors.”

These are only preliminary data and need to be confirmed in other studies,” he said, “but it does suggest that MS neurologists need to pay attention to comprehensive care—not just MS disease activity.

“They also need to be discussing lifestyle with their patients, evaluating their cardiovascular risk factors, and giving advice on stopping smoking, lowering blood pressure, cholesterol, etc.”
 

Brain changes

Dr. Bonacchi explained that previous studies have suggested a relationship between cardiovascular risk factors and changes on magnetic resonance imaging (MRI) and clinical outcomes in patients with MS that may be mediated by small vessel disease and/or inflammation.  

“Small vessel disease is widespread in the population over 50 years of age, but in this study we wanted to look at the impact of cardiovascular risk factors in younger patients with MS who are not likely to have much small vessel disease to try and see whether there is still a relationship with brain atrophy or white/gray matter lesions,” he said.

Previous studies have not set an age limit for examining this relationship and they have also assessed the presence versus absence of cardiovascular risk factors, without attempting to grade the strength of exposure, he noted.

For the current study, the researchers examined several cardiovascular risk factors and in addition to just being present or absent. They also graded each risk factor as being stringent or not depending on a certain threshold.

For example, smoking was defined as a threshold of 5 pack-years (smoking 5 cigarettes a day for 20 years or 20 cigarettes a day for 5 years). And the more stringent definition was 10 pack-years.

For hypertension, the stringent definition was consistently high blood pressure levels and use of antihypertensive medication, with similar definitions used for cholesterol and diabetes.

This was a cross-sectional observational study in 124 patients with MS and 95 healthy controls. The researchers examined MRI scans and neurological exams and investigated whether the amount of cardiovascular risk factors a patient was exposed to was associated with degree of brain atrophy and white matter/gray matter volume. Results were adjusted for age, sex, disease duration, phenotype (relapsing-remitting versus progressive MS) and treatment.

Results showed no significant difference if patients were exposed to at least one classical risk factor versus no risk factors. But if a patient had at least two classical risk factors, significant differences were found in gray matter, white matter, and total brain volume.

Patients with MS and no risk factors had a mean brain volume of 1524 mL versus 1481 mL in those with at least two risk factors, a difference that was significant (P = 0.003). Mean gray matter volume was 856 mL in MS patients without cardiovascular risk factors and 836 mL in those with at least two risk factors (P = 0.01) Mean white matter volume was 668 mL in MS patients without cardiovascular risk factors and 845 mL in those with at least two risk factors (P = 0.03).

“This is one of the first studies to have graded degrees of risk factors and we found one stringent risk factor was associated with the same effects on brain atrophy as two less stringent risk factors,” Dr. Bonacchi reported.

Healthy controls showed no differences in any of the brain volume outcomes in those with or without cardiovascular risk factors.

“As our population was under aged 50 years, who are unlikely to have much small vessel disease, our results suggest that the influence of cardiovascular risk factors on brain atrophy in MS is not just mediated through small vessel disease and is probably also mediated by increased inflammation,” Dr. Bonacchi suggested. 
 

Impact of CV risk factors

Commenting on the study, Dalia Rotstein, MD, assistant professor, department of neurology, University of Toronto, Ontario, Canada, session cochair, said: “This is an interesting study that captures the impact of cardiovascular risk factors on various measures of brain atrophy in MS.”

The cohort was quite young, under age 50, and the effect on brain atrophy was increased with more severe cardiovascular risk factors, she noted.

“The investigators compared these effects to a population of healthy controls and did not observe as substantial an effect in controls. However, they were likely underpowered for the analysis in the healthy controls because of a relatively small number of subjects with cardiovascular risk factors in this group,” Dr. Rotstein noted.

“More research is needed to determine whether the observed relationship is unique to MS and whether treating cardiovascular risk factors may help protect against neurodegeneration in MS,” she added.

Dr. Bonacchi has reported no relevant financial relationships. Dr. Rotstein has reported acting as a consultant for Roche, Alexion, Novartis, EMD Serono, and Sanofi Aventis.

SOURCE: Bonacchi R. et al. MSVirtual2020. Session PS04.05.

This article originally appeared on Medscape.com .

The first randomized study to compare continuing versus stopping ACE inhibitors or angiotensin receptor blockers (ARBs) for patients with COVID-19 has shown no difference in key outcomes between the two approaches.

European Society of Cardiology

The BRACE CORONA trial – conducted in patients had been taking an ACE inhibitor or an ARB on a long-term basis and who were subsequently hospitalized with COVID-19 – showed no difference in the primary endpoint of number of days alive and out of hospital among those whose medication was suspended for 30 days and those who continued undergoing treatment with these agents.

“Because these data indicate that there is no clinical benefit from routinely interrupting these medications in hospitalized patients with mild to moderate COVID-19, they should generally be continued for those with an indication,” principal investigator Renato Lopes, MD, of Duke Clinical Research Institute, Durham, N.C., concluded.

The BRACE CORONA trial was presented at the European Society of Cardiology Congress 2020 on Sept. 1.

Dr. Lopes explained that there are two conflicting hypotheses about the role of ACE inhibitors and ARBs in COVID-19.

One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry. The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

The BRACE CORONA trial was an academic-led randomized study that tested two strategies: temporarily stopping the ACE inhibitor/ARB for 30 days or continuing these drugs for patients who had been taking these medications on a long-term basis and were hospitalized with a confirmed diagnosis of COVID-19.

The primary outcome was the number of days alive and out of hospital at 30 days. Patients who were using more than three antihypertensive drugs or sacubitril/valsartan or who were hemodynamically unstable at presentation were excluded from the study.

The trial enrolled 659 patients from 29 sites in Brazil. The mean age of patients was 56 years, 40% were women, and 52% were obese. ACE inhibitors were being taken by 15% of the trial participants; ARBs were being taken by 85%. The median duration of ACE inhibitor/ARB treatment was 5 years.

Patients were a median of 6 days from COVID-19 symptom onset. For 30% of the patients, oxygen saturation was below 94% at entry. In terms of COVID-19 symptoms, 57% were classified as mild, and 43% as moderate.

Those with severe COVID-19 symptoms who needed intubation or vasoactive drugs were excluded. Antihypertensive therapy would generally be discontinued in these patients anyway, Dr. Lopes said.

Results showed that the average number of days alive and out of hospital was 21.9 days for patients who stopped taking ACE inhibitors/ARBs and 22.9 days for patients who continued taking these medications. The average difference between groups was –1.1 days.

The average ratio of days alive and out of hospital between the suspending and continuing groups was 0.95 (95% CI, 0.90-1.01; P = .09).

The proportion of patients alive and out of hospital by the end of 30 days in the suspending ACE inhibitor/ARB group was 91.8% versus 95% in the continuing group.

A similar 30-day mortality rate was seen for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). The median number of days that patients were alive and out of hospital was 25 in both groups.

Dr. Lopes said that there was no difference between the two groups with regard to many other secondary outcomes. These included COVID-19 disease progression (need for intubation, ventilation, need for vasoactive drugs, or imaging results) and cardiovascular endpoints (MI, stroke, thromboembolic events, worsening heart failure, myocarditis, or hypertensive crisis).

“Our results endorse with reliable and more definitive data what most medical and cardiovascular societies are recommending – that patients do not stop ACE inhibitor or ARB medication. This has been based on observational data so far, but BRACE CORONA now provides randomized data to support this recommendation,” Dr. Lopes concluded.

Dr. Lopes noted that several subgroups had been prespecified for analysis. Factors included age, obesity, difference between ACE inhibitors/ARBs, difference in oxygen saturation at presentation, time since COVID-19 symptom onset, degree of lung involvement on CT, and symptom severity on presentation.

“We saw very consistent effects of our main findings across all these subgroups, and we plan to report more details of these in the near future,” he said.
 

Protective for older patients?

The discussant of the study at the ESC Hotline session, Gianfranco Parati, MD, University of Milan-Bicocca and San Luca Hospital, Milan, congratulated Lopes and his team for conducting this important trial at such a difficult time.

He pointed out that patients in the BRACE CORONA trial were quite young (average age, 56 years) and that observational data so far suggest that ACE inhibitors and ARBs have a stronger protective effect in older COVID-19 patients.

He also noted that the percentage of patients alive and out of hospital at 30 days was higher for the patients who continued on treatment in this study (95% vs. 91.8%), which suggested an advantage in maintaining the medication.

Dr. Lopes replied that one-quarter of the population in the BRACE CORONA trial was older than 65 years, which he said was a “reasonable number.”

“Subgroup analysis by age did not show a significant interaction, but the effect of continuing treatment does seem to be more favorable in older patients and also in those who were sicker and had more comorbidities,” he added.

Dr. Parati also suggested that it would have been difficult to discern differences between ACE inhibitors and ARBs in the BRACE CORONA trial, because so few patents were taking ACE inhibitors; the follow-up period of 30 days was relatively short, inasmuch as these drugs may have long-term effects; and it would have been difficult to show differences in the main outcomes used in the study – mortality and time out of hospital – in these patients with mild to moderate disease.

Franz H. Messerli, MD, and Christoph Gräni, MD, University of Bern (Switzerland), said in a joint statement: “The BRACE CORONA trial provides answers to what we know from retrospective studies: if you have already COVID, don’t stop renin-angiotensin system blocker medication.”

But they added that the study does not answer the question about the risk/benefit of ACE inhibitors or ARBs with regard to possible enhanced viral entry through the ACE2 receptor. “What about all those on these drugs who are not infected with COVID? Do they need to stop them? We simply don’t know yet,” they said.

Dr. Messerli and Dr. Gräni added that they would like to see a study that compared patients before SARS-CoV-2 infection who were without hypertension, patients with hypertension who were taking ACE inhibitors or ARBs, and patients with hypertension taking other antihypertensive drugs.

The BRACE CORONA trial was sponsored by D’Or Institute for Research and Education and the Brazilian Clinical Research Institute. Dr. Lopes has disclosed no relevant financial relationships.

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

The first randomized study to compare continuing versus stopping ACE inhibitors or angiotensin receptor blockers (ARBs) for patients with COVID-19 has shown no difference in key outcomes between the two approaches.

European Society of Cardiology

The BRACE CORONA trial – conducted in patients had been taking an ACE inhibitor or an ARB on a long-term basis and who were subsequently hospitalized with COVID-19 – showed no difference in the primary endpoint of number of days alive and out of hospital among those whose medication was suspended for 30 days and those who continued undergoing treatment with these agents.

“Because these data indicate that there is no clinical benefit from routinely interrupting these medications in hospitalized patients with mild to moderate COVID-19, they should generally be continued for those with an indication,” principal investigator Renato Lopes, MD, of Duke Clinical Research Institute, Durham, N.C., concluded.

The BRACE CORONA trial was presented at the European Society of Cardiology Congress 2020 on Sept. 1.

Dr. Lopes explained that there are two conflicting hypotheses about the role of ACE inhibitors and ARBs in COVID-19.

One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry. The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

The BRACE CORONA trial was an academic-led randomized study that tested two strategies: temporarily stopping the ACE inhibitor/ARB for 30 days or continuing these drugs for patients who had been taking these medications on a long-term basis and were hospitalized with a confirmed diagnosis of COVID-19.

The primary outcome was the number of days alive and out of hospital at 30 days. Patients who were using more than three antihypertensive drugs or sacubitril/valsartan or who were hemodynamically unstable at presentation were excluded from the study.

The trial enrolled 659 patients from 29 sites in Brazil. The mean age of patients was 56 years, 40% were women, and 52% were obese. ACE inhibitors were being taken by 15% of the trial participants; ARBs were being taken by 85%. The median duration of ACE inhibitor/ARB treatment was 5 years.

Patients were a median of 6 days from COVID-19 symptom onset. For 30% of the patients, oxygen saturation was below 94% at entry. In terms of COVID-19 symptoms, 57% were classified as mild, and 43% as moderate.

Those with severe COVID-19 symptoms who needed intubation or vasoactive drugs were excluded. Antihypertensive therapy would generally be discontinued in these patients anyway, Dr. Lopes said.

Results showed that the average number of days alive and out of hospital was 21.9 days for patients who stopped taking ACE inhibitors/ARBs and 22.9 days for patients who continued taking these medications. The average difference between groups was –1.1 days.

The average ratio of days alive and out of hospital between the suspending and continuing groups was 0.95 (95% CI, 0.90-1.01; P = .09).

The proportion of patients alive and out of hospital by the end of 30 days in the suspending ACE inhibitor/ARB group was 91.8% versus 95% in the continuing group.

A similar 30-day mortality rate was seen for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). The median number of days that patients were alive and out of hospital was 25 in both groups.

Dr. Lopes said that there was no difference between the two groups with regard to many other secondary outcomes. These included COVID-19 disease progression (need for intubation, ventilation, need for vasoactive drugs, or imaging results) and cardiovascular endpoints (MI, stroke, thromboembolic events, worsening heart failure, myocarditis, or hypertensive crisis).

“Our results endorse with reliable and more definitive data what most medical and cardiovascular societies are recommending – that patients do not stop ACE inhibitor or ARB medication. This has been based on observational data so far, but BRACE CORONA now provides randomized data to support this recommendation,” Dr. Lopes concluded.

Dr. Lopes noted that several subgroups had been prespecified for analysis. Factors included age, obesity, difference between ACE inhibitors/ARBs, difference in oxygen saturation at presentation, time since COVID-19 symptom onset, degree of lung involvement on CT, and symptom severity on presentation.

“We saw very consistent effects of our main findings across all these subgroups, and we plan to report more details of these in the near future,” he said.
 

Protective for older patients?

The discussant of the study at the ESC Hotline session, Gianfranco Parati, MD, University of Milan-Bicocca and San Luca Hospital, Milan, congratulated Lopes and his team for conducting this important trial at such a difficult time.

He pointed out that patients in the BRACE CORONA trial were quite young (average age, 56 years) and that observational data so far suggest that ACE inhibitors and ARBs have a stronger protective effect in older COVID-19 patients.

He also noted that the percentage of patients alive and out of hospital at 30 days was higher for the patients who continued on treatment in this study (95% vs. 91.8%), which suggested an advantage in maintaining the medication.

Dr. Lopes replied that one-quarter of the population in the BRACE CORONA trial was older than 65 years, which he said was a “reasonable number.”

“Subgroup analysis by age did not show a significant interaction, but the effect of continuing treatment does seem to be more favorable in older patients and also in those who were sicker and had more comorbidities,” he added.

Dr. Parati also suggested that it would have been difficult to discern differences between ACE inhibitors and ARBs in the BRACE CORONA trial, because so few patents were taking ACE inhibitors; the follow-up period of 30 days was relatively short, inasmuch as these drugs may have long-term effects; and it would have been difficult to show differences in the main outcomes used in the study – mortality and time out of hospital – in these patients with mild to moderate disease.

Franz H. Messerli, MD, and Christoph Gräni, MD, University of Bern (Switzerland), said in a joint statement: “The BRACE CORONA trial provides answers to what we know from retrospective studies: if you have already COVID, don’t stop renin-angiotensin system blocker medication.”

But they added that the study does not answer the question about the risk/benefit of ACE inhibitors or ARBs with regard to possible enhanced viral entry through the ACE2 receptor. “What about all those on these drugs who are not infected with COVID? Do they need to stop them? We simply don’t know yet,” they said.

Dr. Messerli and Dr. Gräni added that they would like to see a study that compared patients before SARS-CoV-2 infection who were without hypertension, patients with hypertension who were taking ACE inhibitors or ARBs, and patients with hypertension taking other antihypertensive drugs.

The BRACE CORONA trial was sponsored by D’Or Institute for Research and Education and the Brazilian Clinical Research Institute. Dr. Lopes has disclosed no relevant financial relationships.

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

The first randomized study to compare continuing versus stopping ACE inhibitors or angiotensin receptor blockers (ARBs) for patients with COVID-19 has shown no difference in key outcomes between the two approaches.

European Society of Cardiology

The BRACE CORONA trial – conducted in patients had been taking an ACE inhibitor or an ARB on a long-term basis and who were subsequently hospitalized with COVID-19 – showed no difference in the primary endpoint of number of days alive and out of hospital among those whose medication was suspended for 30 days and those who continued undergoing treatment with these agents.

“Because these data indicate that there is no clinical benefit from routinely interrupting these medications in hospitalized patients with mild to moderate COVID-19, they should generally be continued for those with an indication,” principal investigator Renato Lopes, MD, of Duke Clinical Research Institute, Durham, N.C., concluded.

The BRACE CORONA trial was presented at the European Society of Cardiology Congress 2020 on Sept. 1.

Dr. Lopes explained that there are two conflicting hypotheses about the role of ACE inhibitors and ARBs in COVID-19.

One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry. The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

The BRACE CORONA trial was an academic-led randomized study that tested two strategies: temporarily stopping the ACE inhibitor/ARB for 30 days or continuing these drugs for patients who had been taking these medications on a long-term basis and were hospitalized with a confirmed diagnosis of COVID-19.

The primary outcome was the number of days alive and out of hospital at 30 days. Patients who were using more than three antihypertensive drugs or sacubitril/valsartan or who were hemodynamically unstable at presentation were excluded from the study.

The trial enrolled 659 patients from 29 sites in Brazil. The mean age of patients was 56 years, 40% were women, and 52% were obese. ACE inhibitors were being taken by 15% of the trial participants; ARBs were being taken by 85%. The median duration of ACE inhibitor/ARB treatment was 5 years.

Patients were a median of 6 days from COVID-19 symptom onset. For 30% of the patients, oxygen saturation was below 94% at entry. In terms of COVID-19 symptoms, 57% were classified as mild, and 43% as moderate.

Those with severe COVID-19 symptoms who needed intubation or vasoactive drugs were excluded. Antihypertensive therapy would generally be discontinued in these patients anyway, Dr. Lopes said.

Results showed that the average number of days alive and out of hospital was 21.9 days for patients who stopped taking ACE inhibitors/ARBs and 22.9 days for patients who continued taking these medications. The average difference between groups was –1.1 days.

The average ratio of days alive and out of hospital between the suspending and continuing groups was 0.95 (95% CI, 0.90-1.01; P = .09).

The proportion of patients alive and out of hospital by the end of 30 days in the suspending ACE inhibitor/ARB group was 91.8% versus 95% in the continuing group.

A similar 30-day mortality rate was seen for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). The median number of days that patients were alive and out of hospital was 25 in both groups.

Dr. Lopes said that there was no difference between the two groups with regard to many other secondary outcomes. These included COVID-19 disease progression (need for intubation, ventilation, need for vasoactive drugs, or imaging results) and cardiovascular endpoints (MI, stroke, thromboembolic events, worsening heart failure, myocarditis, or hypertensive crisis).

“Our results endorse with reliable and more definitive data what most medical and cardiovascular societies are recommending – that patients do not stop ACE inhibitor or ARB medication. This has been based on observational data so far, but BRACE CORONA now provides randomized data to support this recommendation,” Dr. Lopes concluded.

Dr. Lopes noted that several subgroups had been prespecified for analysis. Factors included age, obesity, difference between ACE inhibitors/ARBs, difference in oxygen saturation at presentation, time since COVID-19 symptom onset, degree of lung involvement on CT, and symptom severity on presentation.

“We saw very consistent effects of our main findings across all these subgroups, and we plan to report more details of these in the near future,” he said.
 

Protective for older patients?

The discussant of the study at the ESC Hotline session, Gianfranco Parati, MD, University of Milan-Bicocca and San Luca Hospital, Milan, congratulated Lopes and his team for conducting this important trial at such a difficult time.

He pointed out that patients in the BRACE CORONA trial were quite young (average age, 56 years) and that observational data so far suggest that ACE inhibitors and ARBs have a stronger protective effect in older COVID-19 patients.

He also noted that the percentage of patients alive and out of hospital at 30 days was higher for the patients who continued on treatment in this study (95% vs. 91.8%), which suggested an advantage in maintaining the medication.

Dr. Lopes replied that one-quarter of the population in the BRACE CORONA trial was older than 65 years, which he said was a “reasonable number.”

“Subgroup analysis by age did not show a significant interaction, but the effect of continuing treatment does seem to be more favorable in older patients and also in those who were sicker and had more comorbidities,” he added.

Dr. Parati also suggested that it would have been difficult to discern differences between ACE inhibitors and ARBs in the BRACE CORONA trial, because so few patents were taking ACE inhibitors; the follow-up period of 30 days was relatively short, inasmuch as these drugs may have long-term effects; and it would have been difficult to show differences in the main outcomes used in the study – mortality and time out of hospital – in these patients with mild to moderate disease.

Franz H. Messerli, MD, and Christoph Gräni, MD, University of Bern (Switzerland), said in a joint statement: “The BRACE CORONA trial provides answers to what we know from retrospective studies: if you have already COVID, don’t stop renin-angiotensin system blocker medication.”

But they added that the study does not answer the question about the risk/benefit of ACE inhibitors or ARBs with regard to possible enhanced viral entry through the ACE2 receptor. “What about all those on these drugs who are not infected with COVID? Do they need to stop them? We simply don’t know yet,” they said.

Dr. Messerli and Dr. Gräni added that they would like to see a study that compared patients before SARS-CoV-2 infection who were without hypertension, patients with hypertension who were taking ACE inhibitors or ARBs, and patients with hypertension taking other antihypertensive drugs.

The BRACE CORONA trial was sponsored by D’Or Institute for Research and Education and the Brazilian Clinical Research Institute. Dr. Lopes has disclosed no relevant financial relationships.

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

The PCSK9 monoclonal antibody evolocumab (Repatha) was well tolerated and effectively lowered LDL cholesterol by 38% compared with placebo in a randomized controlled trial in pediatric patients with heterozygous familial hypercholesterolemia (FH) already taking statins with or without ezetimibe.

“HAUSER-RCT is the largest study and the first placebo-controlled randomized trial of a PCSK9 inhibitor in pediatric FH,” senior author Daniel Gaudet, MD, PhD, Universite de Montreal, said in an interview.

“The study showed good safety and efficacy of the drug in this population, with an excellent 44% reduction in LDL cholesterol compared with 6% in the placebo group.”

The trial also found evolocumab to be well tolerated in this group, with adverse effects similar in the active and placebo groups. 

“Some people have wondered about using a drug with a monthly injection in a pediatric population, but this was not an issue in our study,” Dr. Gaudet said. “The idea of a monthly injection was well received, and no patient withdrew because of this.”

The HAUSER-RCT trial was presented on Aug. 29 at the virtual annual congress of the European Society of Cardiology (ESC Congress 2020) and simultaneously published online in the New England Journal of Medicine.

“With patients recruited from 23 countries in five continents, the study provides an accurate picture of the safety and efficacy of evolocumab in pediatric FH patients worldwide,” Dr. Gaudet said.  

The 24-week, randomized, double-blind, placebo-controlled trial involved 157 patients aged 10-17 years with heterozygous FH already taking statins with or without ezetimibe and who had an LDL cholesterol level of 130 mg/dL or more and a triglyceride level of 400 mg/dL or less.

They were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo.

Results showed that at week 24, the mean percentage change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, giving a difference of −38.3 percentage points (P < .001).

The absolute change in the LDL cholesterol level was −77.5 mg/dL in the evolocumab group and −9.0 mg/dL in the placebo group, giving a difference of −68.6 mg/dL (P < .001).

Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. Laboratory abnormalities did not differ between groups.

Dr. Gaudet noted that FH is the most common genetic disease worldwide, affecting 1 in 250 people. “It is very treatable, so it is important to identify these patients, but it is massively underdiagnosed, with only around 15%-20% of patients with the condition having been identified,” he said.

“The vast majority of pediatric FH patients can reach target LDL levels with statins and ezetimibe, but there are 5%-10% of patients who may need additional therapy. We have now shown that evolocumab is safe and effective for these patients and can be used to fill this gap,” Dr. Gaudet said. “We can now say that we can cover all situations in treating FH whatever the severity of the disease.”

However, the challenge remains to improve the diagnosis of FH.  “If there is one person with FH in a family, then it is essential that the whole extended family is tested. Our toolbox for treating this condition is now sufficiently effective, so there is no reason not to diagnose this disease,” Dr. Gaudet stressed.  

The HAUSER-RCT study was supported by Amgen. Gaudet reports grants and personal fees from Amgen during the conduct of the study.

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

The PCSK9 monoclonal antibody evolocumab (Repatha) was well tolerated and effectively lowered LDL cholesterol by 38% compared with placebo in a randomized controlled trial in pediatric patients with heterozygous familial hypercholesterolemia (FH) already taking statins with or without ezetimibe.

“HAUSER-RCT is the largest study and the first placebo-controlled randomized trial of a PCSK9 inhibitor in pediatric FH,” senior author Daniel Gaudet, MD, PhD, Universite de Montreal, said in an interview.

“The study showed good safety and efficacy of the drug in this population, with an excellent 44% reduction in LDL cholesterol compared with 6% in the placebo group.”

The trial also found evolocumab to be well tolerated in this group, with adverse effects similar in the active and placebo groups. 

“Some people have wondered about using a drug with a monthly injection in a pediatric population, but this was not an issue in our study,” Dr. Gaudet said. “The idea of a monthly injection was well received, and no patient withdrew because of this.”

The HAUSER-RCT trial was presented on Aug. 29 at the virtual annual congress of the European Society of Cardiology (ESC Congress 2020) and simultaneously published online in the New England Journal of Medicine.

“With patients recruited from 23 countries in five continents, the study provides an accurate picture of the safety and efficacy of evolocumab in pediatric FH patients worldwide,” Dr. Gaudet said.  

The 24-week, randomized, double-blind, placebo-controlled trial involved 157 patients aged 10-17 years with heterozygous FH already taking statins with or without ezetimibe and who had an LDL cholesterol level of 130 mg/dL or more and a triglyceride level of 400 mg/dL or less.

They were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo.

Results showed that at week 24, the mean percentage change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, giving a difference of −38.3 percentage points (P < .001).

The absolute change in the LDL cholesterol level was −77.5 mg/dL in the evolocumab group and −9.0 mg/dL in the placebo group, giving a difference of −68.6 mg/dL (P < .001).

Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. Laboratory abnormalities did not differ between groups.

Dr. Gaudet noted that FH is the most common genetic disease worldwide, affecting 1 in 250 people. “It is very treatable, so it is important to identify these patients, but it is massively underdiagnosed, with only around 15%-20% of patients with the condition having been identified,” he said.

“The vast majority of pediatric FH patients can reach target LDL levels with statins and ezetimibe, but there are 5%-10% of patients who may need additional therapy. We have now shown that evolocumab is safe and effective for these patients and can be used to fill this gap,” Dr. Gaudet said. “We can now say that we can cover all situations in treating FH whatever the severity of the disease.”

However, the challenge remains to improve the diagnosis of FH.  “If there is one person with FH in a family, then it is essential that the whole extended family is tested. Our toolbox for treating this condition is now sufficiently effective, so there is no reason not to diagnose this disease,” Dr. Gaudet stressed.  

The HAUSER-RCT study was supported by Amgen. Gaudet reports grants and personal fees from Amgen during the conduct of the study.

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

The PCSK9 monoclonal antibody evolocumab (Repatha) was well tolerated and effectively lowered LDL cholesterol by 38% compared with placebo in a randomized controlled trial in pediatric patients with heterozygous familial hypercholesterolemia (FH) already taking statins with or without ezetimibe.

“HAUSER-RCT is the largest study and the first placebo-controlled randomized trial of a PCSK9 inhibitor in pediatric FH,” senior author Daniel Gaudet, MD, PhD, Universite de Montreal, said in an interview.

“The study showed good safety and efficacy of the drug in this population, with an excellent 44% reduction in LDL cholesterol compared with 6% in the placebo group.”

The trial also found evolocumab to be well tolerated in this group, with adverse effects similar in the active and placebo groups. 

“Some people have wondered about using a drug with a monthly injection in a pediatric population, but this was not an issue in our study,” Dr. Gaudet said. “The idea of a monthly injection was well received, and no patient withdrew because of this.”

The HAUSER-RCT trial was presented on Aug. 29 at the virtual annual congress of the European Society of Cardiology (ESC Congress 2020) and simultaneously published online in the New England Journal of Medicine.

“With patients recruited from 23 countries in five continents, the study provides an accurate picture of the safety and efficacy of evolocumab in pediatric FH patients worldwide,” Dr. Gaudet said.  

The 24-week, randomized, double-blind, placebo-controlled trial involved 157 patients aged 10-17 years with heterozygous FH already taking statins with or without ezetimibe and who had an LDL cholesterol level of 130 mg/dL or more and a triglyceride level of 400 mg/dL or less.

They were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo.

Results showed that at week 24, the mean percentage change from baseline in LDL cholesterol level was −44.5% in the evolocumab group and −6.2% in the placebo group, giving a difference of −38.3 percentage points (P < .001).

The absolute change in the LDL cholesterol level was −77.5 mg/dL in the evolocumab group and −9.0 mg/dL in the placebo group, giving a difference of −68.6 mg/dL (P < .001).

Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. Laboratory abnormalities did not differ between groups.

Dr. Gaudet noted that FH is the most common genetic disease worldwide, affecting 1 in 250 people. “It is very treatable, so it is important to identify these patients, but it is massively underdiagnosed, with only around 15%-20% of patients with the condition having been identified,” he said.

“The vast majority of pediatric FH patients can reach target LDL levels with statins and ezetimibe, but there are 5%-10% of patients who may need additional therapy. We have now shown that evolocumab is safe and effective for these patients and can be used to fill this gap,” Dr. Gaudet said. “We can now say that we can cover all situations in treating FH whatever the severity of the disease.”

However, the challenge remains to improve the diagnosis of FH.  “If there is one person with FH in a family, then it is essential that the whole extended family is tested. Our toolbox for treating this condition is now sufficiently effective, so there is no reason not to diagnose this disease,” Dr. Gaudet stressed.  

The HAUSER-RCT study was supported by Amgen. Gaudet reports grants and personal fees from Amgen during the conduct of the study.

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

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

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

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

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

Aspirin alone after transcatheter aortic valve implantation (TAVI) significantly reduced bleeding, compared with aspirin plus clopidogrel, without increasing thromboembolic events, in the latest results from the POPular TAVI study.

“Physicians can easily and safely reduce rate of bleeding by omitting clopidogrel after TAVI,” lead author, Jorn Brouwer, MD, St Antonius Hospital, Nieuwegein, the Netherlands, said.

“Aspirin alone should be used in patients undergoing TAVI who are not on oral anticoagulants and have not recently undergone coronary stenting,” he concluded.

Senior author, Jurriën ten Berg, MD, PhD, also from St Antonius Hospital, said in an interview: “I think we can say for TAVI patients, when it comes to antithrombotic therapy, less is definitely more.”

“This is a major change to clinical practice, with current guidelines recommending 3-6 months of dual antiplatelet therapy after a TAVI procedure,” he added. “We expected that these guidelines will change after our results.”

These latest results from POPular TAVI were presented at the virtual European Society of Cardiology Congress 2020 and simultaneously published online in The New England Journal of Medicine.

The trial was conducted in two cohorts of patients undergoing TAVI. The results from cohort B – in patients who were already taking an anticoagulant for another indication – were reported earlier this year and showed no benefit of adding clopidogrel and an increase in bleeding. Now the current results in cohort A – patients undergoing TAVI who do not have an established indication for long-term anticoagulation – show similar results, with aspirin alone preferred over aspirin plus clopidogrel.

Dr. ten Berg explained that the recommendation for dual antiplatelet therapy (DAPT) was adopted mainly because this has been shown to be beneficial in patients undergoing percutaneous coronary intervention (PCI) with stenting; it was thought the same benefits would be seen in TAVI, which also uses a stent-based delivery system.

“However, TAVI patients are a different population – they are generally much older than PCI patients, with an average age of 80 plus, and they have many more comorbidities, so they are much higher bleeding risk,” Dr. ten Berg explained. “In addition, the catheters used for TAVI are larger than those used for PCI, forcing the femoral route to be employed, and both of these factors increases bleeding risk.”

“We saw that, in the trial, patients on dual antiplatelet therapy had a much greater rate of major bleeding and the addition of clopidogrel did not reduce the risk of major thrombotic events,” such as stroke, myocardial infarction (MI), or cardiovascular (CV) death.

Given that the TAVI procedure is associated with an increase in stroke in the immediate few days after the procedure, it would seem logical that increased antiplatelet therapy would be beneficial in reducing this, Dr. ten Berg noted.

“But this is not what we are seeing,” he said. “The stroke incidence was similar in the two groups in POPular TAVI. This suggests that the strokes may not be platelet mediated. They might be caused by another mechanism, such as dislodgement of calcium from the valve or tissue from the aorta.”

For the current part of the study, 690 patients who were undergoing TAVI and did not have an indication for long-term anticoagulation were randomly assigned to receive aspirin alone or aspirin plus clopidogrel for 3 months.

The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non–procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as not procedure related.

Results showed that a bleeding event occurred in 15.1% of patients receiving aspirin alone and 26.6% of those receiving aspirin plus clopidogrel (risk ratio, 0.57; P = .001). Non–procedure-related bleeding occurred 15.1% of patients receiving aspirin alone vs 24.9% of those receiving aspirin plus clopidogrel (risk ratio, 0.61; P = .005). Major, life-threatening, or disabling bleeding occurred in 5.1% of the aspirin-alone group versus 10.8% of those in the aspirin plus clopidogrel group.

Two secondary outcomes included thromboembolic events. The secondary composite one endpoint of death from cardiovascular causes, non–procedure-related bleeding, stroke, or MI at 1 year occurred in 23.0% of those receiving aspirin alone and in 31.1% of those receiving aspirin plus clopidogrel (difference, −8.2 percentage points; P for noninferiority < .001; risk ratio, 0.74; P for superiority = .04).

The secondary composite two endpoint of death from cardiovascular causes, ischemic stroke, or MI at 1 year occurred in 9.7% of the aspirin-alone group versus 9.9% of the dual-antiplatelet group (difference, −0.2 percentage points; P for noninferiority = .004; risk ratio, 0.98; P for superiority = .93).

Dr. ten Berg pointed out that the trial was not strictly powered to look at thrombotic events, but he added: “There was no hint of an increase in the aspirin-alone group and there was quite a high event rate, so we should have seen something if it was there.”

The group has also performed a meta-analysis of these results, with some previous smaller studies also comparing aspirin and DAPT in TAVI which again showed no reduction in thrombotic events with dual-antiplatelet therapy.

Dr. ten Berg noted that the trial included all-comer TAVI patients. “The overall risk was quite a low [STS score, 2.5]. This is a reflection of the typical TAVI patient we are seeing but I would say our results apply to patients of all risk.”
 

Simplifies and clarifies

Discussant of the trial at the ESC Hotline session, Anna Sonia Petronio, MD, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, said, “This was an excellent and essential study that simplifies and clarifies aspects of TAVI treatment and needs to change the guidelines.”

“These results will have a large impact on clinical practice in this elderly population,” she said. But she added that more data are needed for younger patients and more complicated cases, such as valve-in-valve and bicuspid valves.

Commenting on the results, Robert Bonow, MD, Northwestern University, Chicago, said, “The optimal antithrombotic management of patients undergoing TAVI who do not otherwise have an indication for anticoagulation [such as atrial fibrillation] has been uncertain and debatable. Aspirin plus clopidogrel for 3-6 months has been the standard, based on the experience with coronary stents.”

“Thus, the current results of cohort A of the POPular TAVI trial showing significant reduction in bleeding events with aspirin alone compared to DAPT for 3 months, with no difference in ischemic events, are important observations,” he said. “It is noteworthy that most of the bleeding events occurred in the first 30 days.

“This is a relatively small randomized trial, so whether these results will be practice changing will depend on confirmation by additional studies, but it is reassuring to know that patients at higher risk for bleeding would appear to do well with low-dose aspirin alone after TAVI,” Dr. Bonow added.

“These results complete the circle in terms of antithrombotic therapy after TAVI,” commented Michael Reardon, MD, Houston Methodist DeBakey Heart & Vascular Institute, Texas.

“I would add two caveats: First is that most of the difference in the primary endpoint occurs in the first month and levels out between the groups after that,” Dr. Reardon said. “Second is that this does not address the issue of leaflet thickening and immobility.”

Ashish Pershad, MD, Banner – University Medicine Heart Institute, Phoenix, added: “This trial answers a very important question and shows dual-antiplatelet therapy is hazardous in TAVI patients. Clopidogrel is not needed.”

Dr. Pershad says he still wonders about patients who receive very small valves who may have a higher risk for valve-induced thrombosis. “While there were some of these patients in the trial, the numbers were small, so we need more data on this group,” he commented.

“But for bread-and-butter TAVI, aspirin alone is the best choice, and the previous results showed, for patients already taking oral anticoagulation, no additional antithrombotic therapy is required,” Dr. Pershad concluded. “This is a big deal and will change the way we treat patients.”

 The POPular trial was supported by the Netherlands Organization for Health Research and Development. Brouwer reports no disclosures.
 

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