Conference Coverage

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

mzoler@mdedge.com

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

The experimental monoclonal antibody bentracimab, which reverses the antiplatelet effects of ticagrelor, appears to be heading toward regulatory approval, on the basis of an interim analysis of the phase 3 REVERSE-IT trial.

“Rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases with no drug-related serious adverse events or allergic or infusion-related reactions,” reported Deepak L. Bhatt, MD, at the American Heart Association scientific sessions.

The interim analysis of this nonrandomized, single-arm study was requested by the Food and Drug Administration, which is considering a conditional accelerated approval of bentracimab (formerly PB2452) if efficacy and safety are established.

Upon administration, bentracimab binds to free ticagrelor so that ticagrelor cannot bind to the P2Y12 platelet receptor. This interrupts one of the key steps in the pathway of platelet aggregation.

REVERSE-IT is still enrolling patients. This interim analysis was conducted with the first 150 patients who met eligibility criteria and were treated. Of these, 142 patients were enrolled for an urgent surgical indication and 8 for a major bleeding indication. After some exclusions for lack of urgency and reclassifications following adjudication, there were 113 surgical cases and 9 major bleeding patients evaluable for hemostasis.
 

Platelet function assays test reversal

On the primary reversal endpoint, which was restoration of activity on the proprietary platelet function assays Verify Now and PRUTest, a rapid restoration of platelet function was achieved in both surgical and major-bleeding patients. Platelet reactivity climbed to near normal levels within 10 minutes of administration, and peak effects were sustained through the first 24 hours after administration.

On the basis of the platelet function assays, the pattern of response to bentracimab was “very similar in the surgical and bleeding patients,” reported Dr. Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Health, Boston.

The effect was also consistent across a broad array of prespecified subgroups, including stratifications by age, renal function, time from last dose of ticagrelor, race, and the presence of comorbidities, such as diabetes, renal dysfunction, hypertension, and history of MI.
 

Hemostasis documented in all but one patient

Adjudicated hemostasis was achieved in 100% of the 113 urgent surgical patients evaluated. In the nine major bleeding patients, six achieved excellent hemostasis and one achieved good hemostasis. One had poor hemostasis, and one was unevaluable.

Platelet rebound following bentracimab administration, measured by mean platelet volume, was not observed.

There were no serious adverse events, allergic reactions, or serious infusion-related reactions associated with the administration of bentracimab, Dr. Bhatt said.

While Dr. Bhatt acknowledged that the number of patients in the major-bleeding subgroup was small, he noted that the reduction in platelet reactivity relative to baseline was still significant. In addition, he characterized urgent surgery as “an excellent model of bleeding” and pointed out the consistency of results in the surgical and major-bleeding groups.

The interim results are also consistent with phase 1 data published 2 years ago, and with the subsequent phase 2 studies. All of these data are now under regulatory review both in the United States and in Europe, according to Dr. Bhatt.
 

No good current options for reversal

Evidence of efficacy and safety is encouraging, because current options for urgently reversing ticagrelor are “disappointing,” according to the invited discussant Gilles Montalescot, MD, PhD, professor of cardiology, Pitié-Salpêtrière Hôpital, Paris.

“Platelet transfusion has some value for clopidogrel and prasugrel, but it does not work for ticagrelor,” said Dr. Montalescot, referring to two other P2Y12 inhibitors. Substantiating the need for a reversal agent, he identified several other strategies that have proven ineffective, such as desmopressin and sorbent hemadsorption.

Overall, Dr. Montalescot acknowledged the need for a highly effective ticagrelor reversal agent, but he did have some criticisms of REVERSE-IT. For one, he was not convinced about the design.

“What was unethical in having a control group?” he asked, suggesting that it was feasible and would have addressed issues of relative efficacy and safety.

For example, the authors concluded that none of the thrombotic events were likely to be treatment related, but “four events occurred immediately after reversal without an alternate explanation,” Dr. Montalescot pointed out. “Was this a signal or background noise?”

Nevertheless, he agreed that the interim phase 3 data are consistent with the previously reported phase 2 studies, and he reiterated that a strategy to reverse ticagrelor’s effects is an important unmet need.

Dr. Bhatt has a financial relationship with a large number of pharmaceutical companies, including PhaseBio, which provided funding for the REVERSE-IT trial. Dr. Montalescot reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cell-Prothera, CSL-Behring, Europa, Idorsia, Servicer, Medtronic, Merck Sharpe & Dohme, Novartis, Pfizer, Quantum Genomics, and Sanofi-Aventis.
 

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

mzoler@mdedge.com

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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