Stroke

Janus kinase inhibitors (JAKis) do not appear to increase the risk for major adverse cardiovascular events (MACE) among people with atopic dermatitis (AD) treated in a real-world setting, suggested the results of a large, US-based, retrospective cohort study.

This holds true even in individuals aged 50 years or older, whose age puts them at increased cardiovascular (CV) risk, said Amina El Ayadi, PhD, of the University of Texas Medical Branch at Galveston. He presented the findings at the recent European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Specifically, the analysis looked at treatment with the oral JAK1 inhibitors upadacitinib (Rinvoq) and abrocitinib (Cibinqo), both approved for treating AD in the United States, and found that the relative risk for MACE, such as acute myocardial infarction, cardiac arrest, stroke, or acute deep vein thrombosis, was ≤ 1.0 compared with those not treated with a JAKi.

Similarly, the relative risk for other CV safety endpoints, such as having an abnormal ECG or pericardial effusion, was also around 1.0. There was a slight increase in the relative risk for arrhythmias, peripheral edema, angina pectoris, or heart failure, but no value went > 1.6 and CIs spanned 1.0, indicating the results lack statistical significance.
 

Reassurance for Dermatologists?

“This suggests that oral administration of these drugs to the patient with atopic dermatitis does not increase the risk of major adverse cardiac events, and dermatologists, based on our data, can safely consider JAK inhibitors for treating moderate to severe dermatitis, even in patients with high risk for these diseases,” El Ayadi said during a late-breaking news session at the meeting.

Yolanda Gilaberte Calzada, MD, PhD, head of the Dermatology Department at Miguel Servet University Hospital in Zaragoza, Spain, who was one of the chairs for the session, said that this was “very good news for us.”

Gilaberte Calzada, president of the Spanish Academy of Dermatology and Venereology, asked if there were any data on the duration of treatment with the two JAKis included in the analysis. El Ayadi said that this was something that would be looked at in future data analyses.

Gilaberte Calzada also observed that because the CIs were wide, with more time, “we will have more defined data.”
 

Analyses Overview

For the two analyses — one in the overall population of patients with AD and the other in those aged 50 years or older — electronic medical record (EMR) data from the TriNetX Research Network were used. This is a global, federated health research network that contains EMRs for more than 275 million patients from over 120 healthcare organizations, El Ayadi explained.

To perform the analyses, the research team queried the TriNetX database to find all patients diagnosed with AD via the International Classification of Diseases, Tenth Revision code L20. They then determined if patients had been treated with JAKi or not, and specifically, with upadacitinib or abrocitinib. Those who had not received any JAKi treatment were the control population.

For the first analysis, no age-specific filter was applied. The investigators identified 1674 people with AD who had been treated with the JAKis and around 1.2 million who had not. Propensity score matching, based on age at diagnosis, biologic sex, and CV comorbidities, was performed to give a total of 1674 patients who had and 1674 who had not been treated with these medications.

In the second analysis, only those aged 50 years or older were considered; 875 patients who had received JAKi treatment were identified and around 250,000 who had not. Propensity score matching based on the same variables gave two groups of 875 people who had or had not taken a JAKi.

Queried over the age cutoff used, El Ayadi noted, “We did an analysis looking at patients 65 and older. However, we came up with lower patient numbers. … We do have this data, and we did not see any significant risk.”

The study was independently supported. El Ayadi and Gilaberte Calzada reported no conflicts of interest in relation to the presented findings.

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

Janus kinase inhibitors (JAKis) do not appear to increase the risk for major adverse cardiovascular events (MACE) among people with atopic dermatitis (AD) treated in a real-world setting, suggested the results of a large, US-based, retrospective cohort study.

This holds true even in individuals aged 50 years or older, whose age puts them at increased cardiovascular (CV) risk, said Amina El Ayadi, PhD, of the University of Texas Medical Branch at Galveston. He presented the findings at the recent European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Specifically, the analysis looked at treatment with the oral JAK1 inhibitors upadacitinib (Rinvoq) and abrocitinib (Cibinqo), both approved for treating AD in the United States, and found that the relative risk for MACE, such as acute myocardial infarction, cardiac arrest, stroke, or acute deep vein thrombosis, was ≤ 1.0 compared with those not treated with a JAKi.

Similarly, the relative risk for other CV safety endpoints, such as having an abnormal ECG or pericardial effusion, was also around 1.0. There was a slight increase in the relative risk for arrhythmias, peripheral edema, angina pectoris, or heart failure, but no value went > 1.6 and CIs spanned 1.0, indicating the results lack statistical significance.
 

Reassurance for Dermatologists?

“This suggests that oral administration of these drugs to the patient with atopic dermatitis does not increase the risk of major adverse cardiac events, and dermatologists, based on our data, can safely consider JAK inhibitors for treating moderate to severe dermatitis, even in patients with high risk for these diseases,” El Ayadi said during a late-breaking news session at the meeting.

Yolanda Gilaberte Calzada, MD, PhD, head of the Dermatology Department at Miguel Servet University Hospital in Zaragoza, Spain, who was one of the chairs for the session, said that this was “very good news for us.”

Gilaberte Calzada, president of the Spanish Academy of Dermatology and Venereology, asked if there were any data on the duration of treatment with the two JAKis included in the analysis. El Ayadi said that this was something that would be looked at in future data analyses.

Gilaberte Calzada also observed that because the CIs were wide, with more time, “we will have more defined data.”
 

Analyses Overview

For the two analyses — one in the overall population of patients with AD and the other in those aged 50 years or older — electronic medical record (EMR) data from the TriNetX Research Network were used. This is a global, federated health research network that contains EMRs for more than 275 million patients from over 120 healthcare organizations, El Ayadi explained.

To perform the analyses, the research team queried the TriNetX database to find all patients diagnosed with AD via the International Classification of Diseases, Tenth Revision code L20. They then determined if patients had been treated with JAKi or not, and specifically, with upadacitinib or abrocitinib. Those who had not received any JAKi treatment were the control population.

For the first analysis, no age-specific filter was applied. The investigators identified 1674 people with AD who had been treated with the JAKis and around 1.2 million who had not. Propensity score matching, based on age at diagnosis, biologic sex, and CV comorbidities, was performed to give a total of 1674 patients who had and 1674 who had not been treated with these medications.

In the second analysis, only those aged 50 years or older were considered; 875 patients who had received JAKi treatment were identified and around 250,000 who had not. Propensity score matching based on the same variables gave two groups of 875 people who had or had not taken a JAKi.

Queried over the age cutoff used, El Ayadi noted, “We did an analysis looking at patients 65 and older. However, we came up with lower patient numbers. … We do have this data, and we did not see any significant risk.”

The study was independently supported. El Ayadi and Gilaberte Calzada reported no conflicts of interest in relation to the presented findings.

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

Janus kinase inhibitors (JAKis) do not appear to increase the risk for major adverse cardiovascular events (MACE) among people with atopic dermatitis (AD) treated in a real-world setting, suggested the results of a large, US-based, retrospective cohort study.

This holds true even in individuals aged 50 years or older, whose age puts them at increased cardiovascular (CV) risk, said Amina El Ayadi, PhD, of the University of Texas Medical Branch at Galveston. He presented the findings at the recent European Academy of Dermatology and Venereology (EADV) 2024 Congress.

Specifically, the analysis looked at treatment with the oral JAK1 inhibitors upadacitinib (Rinvoq) and abrocitinib (Cibinqo), both approved for treating AD in the United States, and found that the relative risk for MACE, such as acute myocardial infarction, cardiac arrest, stroke, or acute deep vein thrombosis, was ≤ 1.0 compared with those not treated with a JAKi.

Similarly, the relative risk for other CV safety endpoints, such as having an abnormal ECG or pericardial effusion, was also around 1.0. There was a slight increase in the relative risk for arrhythmias, peripheral edema, angina pectoris, or heart failure, but no value went > 1.6 and CIs spanned 1.0, indicating the results lack statistical significance.
 

Reassurance for Dermatologists?

“This suggests that oral administration of these drugs to the patient with atopic dermatitis does not increase the risk of major adverse cardiac events, and dermatologists, based on our data, can safely consider JAK inhibitors for treating moderate to severe dermatitis, even in patients with high risk for these diseases,” El Ayadi said during a late-breaking news session at the meeting.

Yolanda Gilaberte Calzada, MD, PhD, head of the Dermatology Department at Miguel Servet University Hospital in Zaragoza, Spain, who was one of the chairs for the session, said that this was “very good news for us.”

Gilaberte Calzada, president of the Spanish Academy of Dermatology and Venereology, asked if there were any data on the duration of treatment with the two JAKis included in the analysis. El Ayadi said that this was something that would be looked at in future data analyses.

Gilaberte Calzada also observed that because the CIs were wide, with more time, “we will have more defined data.”
 

Analyses Overview

For the two analyses — one in the overall population of patients with AD and the other in those aged 50 years or older — electronic medical record (EMR) data from the TriNetX Research Network were used. This is a global, federated health research network that contains EMRs for more than 275 million patients from over 120 healthcare organizations, El Ayadi explained.

To perform the analyses, the research team queried the TriNetX database to find all patients diagnosed with AD via the International Classification of Diseases, Tenth Revision code L20. They then determined if patients had been treated with JAKi or not, and specifically, with upadacitinib or abrocitinib. Those who had not received any JAKi treatment were the control population.

For the first analysis, no age-specific filter was applied. The investigators identified 1674 people with AD who had been treated with the JAKis and around 1.2 million who had not. Propensity score matching, based on age at diagnosis, biologic sex, and CV comorbidities, was performed to give a total of 1674 patients who had and 1674 who had not been treated with these medications.

In the second analysis, only those aged 50 years or older were considered; 875 patients who had received JAKi treatment were identified and around 250,000 who had not. Propensity score matching based on the same variables gave two groups of 875 people who had or had not taken a JAKi.

Queried over the age cutoff used, El Ayadi noted, “We did an analysis looking at patients 65 and older. However, we came up with lower patient numbers. … We do have this data, and we did not see any significant risk.”

The study was independently supported. El Ayadi and Gilaberte Calzada reported no conflicts of interest in relation to the presented findings.

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

TOPLINE:

There is no significant association between the use of proton pump inhibitors (PPIs) and risk for cardiovascular events, a meta-analysis shows. However, patients with gastroesophageal reflux disease (GERD) do experience a slight increase in cardiovascular events with PPI use.

METHODOLOGY:

• PPIs are commonly used gastric acid suppressants; however, they have pleiotropic effects, some of which have been hypothesized to augment cardiovascular disorders.
• Researchers conducted a meta-analysis of randomized clinical trials with at least 100 patients and treatment durations > 30 days, which compared groups receiving PPIs to those on placebo or other active treatments.
• The primary outcome was a composite of nonfatal myocardial infarctions, nonfatal strokes, fatal cardiovascular adverse events, coronary revascularizations, and hospitalizations for unstable angina.

TAKEAWAY:

• Researchers included data from 52 placebo-controlled trials, with 14,988 patients and 8323 patients randomized to receive a PPI or placebo, respectively; the mean treatment duration was 0.45 person-years for those treated with PPIs and 0.32 person-years for those treated with placebo.
• Among placebo-controlled trials, 24 were conducted in patients with GERD.
• Researchers also included 61 active-controlled trials that compared PPIs with histamine-2 receptor antagonists (51 trials) or other active treatments.
• The incidence rate ratio for the primary outcome was 0.72 when comparing PPI to placebo, indicating no significant association between PPI and cardiovascular events.
• Among patients with GERD, cardiovascular events occurred only in those treated with PPIs, leading to approximately one excess cardiovascular event per 100 person-years of PPI treatment relative to placebo.
• Researchers found no association between PPI treatment and the risk for cardiovascular events in trials comparing PPIs with other active treatments.

IN PRACTICE:

“We found no association of cardiovascular events with PPI treatment,” the authors wrote. “Cardiovascular events appeared more frequent with PPI treatment in GERD trials, but results from this subgroup should be interpreted with the limitations of the analysis in mind.”

SOURCE:

The study, led by Andrew D. Mosholder, MD, MPH, Division of Epidemiology, US Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, Maryland, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

This study lacked individual patient data, which precluded a time-to-event analysis or an analysis accounting for patient characteristics such as age or sex. The mean duration of PPI treatment in these trials was a few months, limiting the assessment of cardiovascular risk with extended use. The risk estimates were influenced the most by data on omeprazole and esomeprazole.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflicts of interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

There is no significant association between the use of proton pump inhibitors (PPIs) and risk for cardiovascular events, a meta-analysis shows. However, patients with gastroesophageal reflux disease (GERD) do experience a slight increase in cardiovascular events with PPI use.

METHODOLOGY:

• PPIs are commonly used gastric acid suppressants; however, they have pleiotropic effects, some of which have been hypothesized to augment cardiovascular disorders.
• Researchers conducted a meta-analysis of randomized clinical trials with at least 100 patients and treatment durations > 30 days, which compared groups receiving PPIs to those on placebo or other active treatments.
• The primary outcome was a composite of nonfatal myocardial infarctions, nonfatal strokes, fatal cardiovascular adverse events, coronary revascularizations, and hospitalizations for unstable angina.

TAKEAWAY:

• Researchers included data from 52 placebo-controlled trials, with 14,988 patients and 8323 patients randomized to receive a PPI or placebo, respectively; the mean treatment duration was 0.45 person-years for those treated with PPIs and 0.32 person-years for those treated with placebo.
• Among placebo-controlled trials, 24 were conducted in patients with GERD.
• Researchers also included 61 active-controlled trials that compared PPIs with histamine-2 receptor antagonists (51 trials) or other active treatments.
• The incidence rate ratio for the primary outcome was 0.72 when comparing PPI to placebo, indicating no significant association between PPI and cardiovascular events.
• Among patients with GERD, cardiovascular events occurred only in those treated with PPIs, leading to approximately one excess cardiovascular event per 100 person-years of PPI treatment relative to placebo.
• Researchers found no association between PPI treatment and the risk for cardiovascular events in trials comparing PPIs with other active treatments.

IN PRACTICE:

“We found no association of cardiovascular events with PPI treatment,” the authors wrote. “Cardiovascular events appeared more frequent with PPI treatment in GERD trials, but results from this subgroup should be interpreted with the limitations of the analysis in mind.”

SOURCE:

The study, led by Andrew D. Mosholder, MD, MPH, Division of Epidemiology, US Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, Maryland, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

This study lacked individual patient data, which precluded a time-to-event analysis or an analysis accounting for patient characteristics such as age or sex. The mean duration of PPI treatment in these trials was a few months, limiting the assessment of cardiovascular risk with extended use. The risk estimates were influenced the most by data on omeprazole and esomeprazole.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflicts of interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

There is no significant association between the use of proton pump inhibitors (PPIs) and risk for cardiovascular events, a meta-analysis shows. However, patients with gastroesophageal reflux disease (GERD) do experience a slight increase in cardiovascular events with PPI use.

METHODOLOGY:

• PPIs are commonly used gastric acid suppressants; however, they have pleiotropic effects, some of which have been hypothesized to augment cardiovascular disorders.
• Researchers conducted a meta-analysis of randomized clinical trials with at least 100 patients and treatment durations > 30 days, which compared groups receiving PPIs to those on placebo or other active treatments.
• The primary outcome was a composite of nonfatal myocardial infarctions, nonfatal strokes, fatal cardiovascular adverse events, coronary revascularizations, and hospitalizations for unstable angina.

TAKEAWAY:

• Researchers included data from 52 placebo-controlled trials, with 14,988 patients and 8323 patients randomized to receive a PPI or placebo, respectively; the mean treatment duration was 0.45 person-years for those treated with PPIs and 0.32 person-years for those treated with placebo.
• Among placebo-controlled trials, 24 were conducted in patients with GERD.
• Researchers also included 61 active-controlled trials that compared PPIs with histamine-2 receptor antagonists (51 trials) or other active treatments.
• The incidence rate ratio for the primary outcome was 0.72 when comparing PPI to placebo, indicating no significant association between PPI and cardiovascular events.
• Among patients with GERD, cardiovascular events occurred only in those treated with PPIs, leading to approximately one excess cardiovascular event per 100 person-years of PPI treatment relative to placebo.
• Researchers found no association between PPI treatment and the risk for cardiovascular events in trials comparing PPIs with other active treatments.

IN PRACTICE:

“We found no association of cardiovascular events with PPI treatment,” the authors wrote. “Cardiovascular events appeared more frequent with PPI treatment in GERD trials, but results from this subgroup should be interpreted with the limitations of the analysis in mind.”

SOURCE:

The study, led by Andrew D. Mosholder, MD, MPH, Division of Epidemiology, US Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, Maryland, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

This study lacked individual patient data, which precluded a time-to-event analysis or an analysis accounting for patient characteristics such as age or sex. The mean duration of PPI treatment in these trials was a few months, limiting the assessment of cardiovascular risk with extended use. The risk estimates were influenced the most by data on omeprazole and esomeprazole.

DISCLOSURES:

This study did not receive any funding. The authors declared no conflicts of interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Aspirin. Once upon a time, everybody over age 50 years was supposed to take a baby aspirin. Now we make it a point to tell people to stop. What is going on?  

Our recommendations vis-à-vis aspirin have evolved at a dizzying pace. The young’uns watching us right now don’t know what things were like in the 1980s. The Reagan era was a wild, heady time where nuclear war was imminent and we didn’t prescribe aspirin to patients. 

That only started in 1988, which was a banner year in human history. Not because a number of doves were incinerated by the lighting of the Olympic torch at the Seoul Olympics — look it up if you don’t know what I’m talking about — but because 1988 saw the publication of the ISIS-2 trial, which first showed a mortality benefit to prescribing aspirin post–myocardial infarction (MI).

Giving patients aspirin during or after a heart attack is not controversial. It’s one of the few things in this business that isn’t, but that’s secondary prevention — treating somebody after they develop a disease. Primary prevention, treating them before they have their incident event, is a very different ballgame. Here, things are messy. 

For one thing, the doses used have been very inconsistent. We should point out that the reason for 81 mg of aspirin is very arbitrary and is rooted in the old apothecary system of weights and measurements. A standard dose of aspirin was 5 grains, where 20 grains made 1 scruple, 3 scruples made 1 dram, 8 drams made 1 oz, and 12 oz made 1 lb - because screw you, metric system. Therefore, 5 grains was 325 mg of aspirin, and 1 quarter of the standard dose became 81 mg if you rounded out the decimal. 

People have tried all kinds of dosing structures with aspirin prophylaxis. The Physicians’ Health Study used a full-dose aspirin, 325 mg every 2 days, while the Hypertension Optimal Treatment (HOT) trial tested 75 mg daily and the Women’s Health Study tested 100 mg, but every other day. 

Ironically, almost no one has studied 81 mg every day, which is weird if you think about it. The bigger problem here is not the variability of doses used, but the discrepancy when you look at older vs newer studies.

Older studies, like the Physicians’ Health Study, did show a benefit, at least in the subgroup of patients over age 50 years, which is probably where the “everybody over 50 should be taking an aspirin” idea comes from, at least as near as I can tell. 

More recent studies, like the Women’s Health Study, ASPREE, or ASPIRE, didn’t show a benefit. I know what you’re thinking: Newer stuff is always better. That’s why you should never trust anybody over age 40 years. The context of primary prevention studies has changed. In the ‘80s and ‘90s, people smoked more and we didn’t have the same medications that we have today. We talked about all this in the beta-blocker video to explain why beta-blockers don’t seem to have a benefit post MI.

We have a similar issue here. The magnitude of the benefit with aspirin primary prevention has decreased because we’re all just healthier overall. So, yay! Progress! Here’s where the numbers matter. No one is saying that aspirin doesn’t help. It does. 

If we look at the 2019 meta-analysis published in JAMA, there is a cardiovascular benefit. The numbers bear that out. I know you’re all here for the math, so here we go. Aspirin reduced the composite cardiovascular endpoint from 65.2 to 60.2 events per 10,000 patient-years; or to put it more meaningfully in absolute risk reduction terms, because that’s my jam, an absolute risk reduction of 0.41%, which means a number needed to treat of 241, which is okay-ish. It’s not super-great, but it may be justifiable for something that costs next to nothing. 

The tradeoff is bleeding. Major bleeding increased from 16.4 to 23.1 bleeds per 10,000 patient-years, or an absolute risk increase of 0.47%, which is a number needed to harm of 210. That’s the problem. Aspirin does prevent heart disease. The benefit is small, for sure, but the real problem is that it’s outweighed by the risk of bleeding, so you’re not really coming out ahead. 

The real tragedy here is that the public is locked into this idea of everyone over age 50 years should be taking an aspirin. Even today, even though guidelines have recommended against aspirin for primary prevention for some time, data from the National Health Interview Survey sample found that nearly one in three older adults take aspirin for primary prevention when they shouldn’t be. That’s a large number of people. That’s millions of Americans — and Canadians, but nobody cares about us. It’s fine. 

That’s the point. We’re not debunking aspirin. It does work. The benefits are just really small in a primary prevention population and offset by the admittedly also really small risks of bleeding. It’s a tradeoff that doesn’t really work in your favor.

But that’s aspirin for cardiovascular disease. When it comes to cancer or DVT prophylaxis, that’s another really interesting story. We might have to save that for another time. Do I know how to tease a sequel or what?

Labos, a cardiologist at Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Aspirin. Once upon a time, everybody over age 50 years was supposed to take a baby aspirin. Now we make it a point to tell people to stop. What is going on?  

Our recommendations vis-à-vis aspirin have evolved at a dizzying pace. The young’uns watching us right now don’t know what things were like in the 1980s. The Reagan era was a wild, heady time where nuclear war was imminent and we didn’t prescribe aspirin to patients. 

That only started in 1988, which was a banner year in human history. Not because a number of doves were incinerated by the lighting of the Olympic torch at the Seoul Olympics — look it up if you don’t know what I’m talking about — but because 1988 saw the publication of the ISIS-2 trial, which first showed a mortality benefit to prescribing aspirin post–myocardial infarction (MI).

Giving patients aspirin during or after a heart attack is not controversial. It’s one of the few things in this business that isn’t, but that’s secondary prevention — treating somebody after they develop a disease. Primary prevention, treating them before they have their incident event, is a very different ballgame. Here, things are messy. 

For one thing, the doses used have been very inconsistent. We should point out that the reason for 81 mg of aspirin is very arbitrary and is rooted in the old apothecary system of weights and measurements. A standard dose of aspirin was 5 grains, where 20 grains made 1 scruple, 3 scruples made 1 dram, 8 drams made 1 oz, and 12 oz made 1 lb - because screw you, metric system. Therefore, 5 grains was 325 mg of aspirin, and 1 quarter of the standard dose became 81 mg if you rounded out the decimal. 

People have tried all kinds of dosing structures with aspirin prophylaxis. The Physicians’ Health Study used a full-dose aspirin, 325 mg every 2 days, while the Hypertension Optimal Treatment (HOT) trial tested 75 mg daily and the Women’s Health Study tested 100 mg, but every other day. 

Ironically, almost no one has studied 81 mg every day, which is weird if you think about it. The bigger problem here is not the variability of doses used, but the discrepancy when you look at older vs newer studies.

Older studies, like the Physicians’ Health Study, did show a benefit, at least in the subgroup of patients over age 50 years, which is probably where the “everybody over 50 should be taking an aspirin” idea comes from, at least as near as I can tell. 

More recent studies, like the Women’s Health Study, ASPREE, or ASPIRE, didn’t show a benefit. I know what you’re thinking: Newer stuff is always better. That’s why you should never trust anybody over age 40 years. The context of primary prevention studies has changed. In the ‘80s and ‘90s, people smoked more and we didn’t have the same medications that we have today. We talked about all this in the beta-blocker video to explain why beta-blockers don’t seem to have a benefit post MI.

We have a similar issue here. The magnitude of the benefit with aspirin primary prevention has decreased because we’re all just healthier overall. So, yay! Progress! Here’s where the numbers matter. No one is saying that aspirin doesn’t help. It does. 

If we look at the 2019 meta-analysis published in JAMA, there is a cardiovascular benefit. The numbers bear that out. I know you’re all here for the math, so here we go. Aspirin reduced the composite cardiovascular endpoint from 65.2 to 60.2 events per 10,000 patient-years; or to put it more meaningfully in absolute risk reduction terms, because that’s my jam, an absolute risk reduction of 0.41%, which means a number needed to treat of 241, which is okay-ish. It’s not super-great, but it may be justifiable for something that costs next to nothing. 

The tradeoff is bleeding. Major bleeding increased from 16.4 to 23.1 bleeds per 10,000 patient-years, or an absolute risk increase of 0.47%, which is a number needed to harm of 210. That’s the problem. Aspirin does prevent heart disease. The benefit is small, for sure, but the real problem is that it’s outweighed by the risk of bleeding, so you’re not really coming out ahead. 

The real tragedy here is that the public is locked into this idea of everyone over age 50 years should be taking an aspirin. Even today, even though guidelines have recommended against aspirin for primary prevention for some time, data from the National Health Interview Survey sample found that nearly one in three older adults take aspirin for primary prevention when they shouldn’t be. That’s a large number of people. That’s millions of Americans — and Canadians, but nobody cares about us. It’s fine. 

That’s the point. We’re not debunking aspirin. It does work. The benefits are just really small in a primary prevention population and offset by the admittedly also really small risks of bleeding. It’s a tradeoff that doesn’t really work in your favor.

But that’s aspirin for cardiovascular disease. When it comes to cancer or DVT prophylaxis, that’s another really interesting story. We might have to save that for another time. Do I know how to tease a sequel or what?

Labos, a cardiologist at Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Aspirin. Once upon a time, everybody over age 50 years was supposed to take a baby aspirin. Now we make it a point to tell people to stop. What is going on?  

Our recommendations vis-à-vis aspirin have evolved at a dizzying pace. The young’uns watching us right now don’t know what things were like in the 1980s. The Reagan era was a wild, heady time where nuclear war was imminent and we didn’t prescribe aspirin to patients. 

That only started in 1988, which was a banner year in human history. Not because a number of doves were incinerated by the lighting of the Olympic torch at the Seoul Olympics — look it up if you don’t know what I’m talking about — but because 1988 saw the publication of the ISIS-2 trial, which first showed a mortality benefit to prescribing aspirin post–myocardial infarction (MI).

Giving patients aspirin during or after a heart attack is not controversial. It’s one of the few things in this business that isn’t, but that’s secondary prevention — treating somebody after they develop a disease. Primary prevention, treating them before they have their incident event, is a very different ballgame. Here, things are messy. 

For one thing, the doses used have been very inconsistent. We should point out that the reason for 81 mg of aspirin is very arbitrary and is rooted in the old apothecary system of weights and measurements. A standard dose of aspirin was 5 grains, where 20 grains made 1 scruple, 3 scruples made 1 dram, 8 drams made 1 oz, and 12 oz made 1 lb - because screw you, metric system. Therefore, 5 grains was 325 mg of aspirin, and 1 quarter of the standard dose became 81 mg if you rounded out the decimal. 

People have tried all kinds of dosing structures with aspirin prophylaxis. The Physicians’ Health Study used a full-dose aspirin, 325 mg every 2 days, while the Hypertension Optimal Treatment (HOT) trial tested 75 mg daily and the Women’s Health Study tested 100 mg, but every other day. 

Ironically, almost no one has studied 81 mg every day, which is weird if you think about it. The bigger problem here is not the variability of doses used, but the discrepancy when you look at older vs newer studies.

Older studies, like the Physicians’ Health Study, did show a benefit, at least in the subgroup of patients over age 50 years, which is probably where the “everybody over 50 should be taking an aspirin” idea comes from, at least as near as I can tell. 

More recent studies, like the Women’s Health Study, ASPREE, or ASPIRE, didn’t show a benefit. I know what you’re thinking: Newer stuff is always better. That’s why you should never trust anybody over age 40 years. The context of primary prevention studies has changed. In the ‘80s and ‘90s, people smoked more and we didn’t have the same medications that we have today. We talked about all this in the beta-blocker video to explain why beta-blockers don’t seem to have a benefit post MI.

We have a similar issue here. The magnitude of the benefit with aspirin primary prevention has decreased because we’re all just healthier overall. So, yay! Progress! Here’s where the numbers matter. No one is saying that aspirin doesn’t help. It does. 

If we look at the 2019 meta-analysis published in JAMA, there is a cardiovascular benefit. The numbers bear that out. I know you’re all here for the math, so here we go. Aspirin reduced the composite cardiovascular endpoint from 65.2 to 60.2 events per 10,000 patient-years; or to put it more meaningfully in absolute risk reduction terms, because that’s my jam, an absolute risk reduction of 0.41%, which means a number needed to treat of 241, which is okay-ish. It’s not super-great, but it may be justifiable for something that costs next to nothing. 

The tradeoff is bleeding. Major bleeding increased from 16.4 to 23.1 bleeds per 10,000 patient-years, or an absolute risk increase of 0.47%, which is a number needed to harm of 210. That’s the problem. Aspirin does prevent heart disease. The benefit is small, for sure, but the real problem is that it’s outweighed by the risk of bleeding, so you’re not really coming out ahead. 

The real tragedy here is that the public is locked into this idea of everyone over age 50 years should be taking an aspirin. Even today, even though guidelines have recommended against aspirin for primary prevention for some time, data from the National Health Interview Survey sample found that nearly one in three older adults take aspirin for primary prevention when they shouldn’t be. That’s a large number of people. That’s millions of Americans — and Canadians, but nobody cares about us. It’s fine. 

That’s the point. We’re not debunking aspirin. It does work. The benefits are just really small in a primary prevention population and offset by the admittedly also really small risks of bleeding. It’s a tradeoff that doesn’t really work in your favor.

But that’s aspirin for cardiovascular disease. When it comes to cancer or DVT prophylaxis, that’s another really interesting story. We might have to save that for another time. Do I know how to tease a sequel or what?

Labos, a cardiologist at Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

A growing body of research explores the link between stroke risk and regular consumption of coffee, tea, soda, and alcohol. This research roundup reviews the latest findings, highlighting both promising insights and remaining uncertainties to help guide discussions with your patients.

Coffee and Tea: Good or Bad? 

In the INTERSTROKE study, high coffee consumption (> 4 cups daily) was associated with an significantly increased risk for all strokes (odds ratio [OR], 1.37) or ischemic stroke (OR, 1.31), while low to moderate coffee had no link to increased stroke risk. In contrast, tea consumption was associated with lower odds of all stroke (OR, 0.81 for highest intake) or ischemic stroke (OR, 0.81). 

In a recent UK Biobank study, consumption of coffee or tea was associated with reduced risk for stroke and dementia, with the biggest benefit associated with consuming both beverages. 

Specifically, the investigators found that individuals who drank two to three cups of coffee and two to three cups of tea per day had a 30% decrease in incidence of stroke and a 28% lower risk for dementia versus those who did not.

A recent systematic review and dose-response meta-analysis showed that each daily cup increase in tea was associated with an average 4% reduced risk for stroke and a 2% reduced risk for cardiovascular disease (CVD) events. 

The protective effect of coffee and tea on stroke risk may be driven, in part, by flavonoids, which have antioxidant and anti-inflammatory properties, as well as positive effects on vascular function.

“The advice to patients should be that coffee and tea may protect against stroke, but that sweetening either beverage with sugar probably should be minimized,” said Cheryl Bushnell, MD, MHS, of Wake Forest University School of Medicine in Winston-Salem, North Carolina, and chair of the American Stroke Association (ASA) 2024 Guideline for the Primary Prevention of Stroke. 

Taylor Wallace, PhD, a certified food scientist, said, “most people should consume a cup or two of unsweetened tea per day in moderation for cardiometabolic health. It is an easy step in the right direction for good health but not a cure-all.”

When it comes to coffee, adults who like it should drink it “in moderation — just lay off the cream and sugar,” said Wallace, adjunct associate professor at George Washington University, Washington, DC, and Tufts University, Boston, Massachusetts.

“A cup or two of black coffee with low-fat or nonfat milk with breakfast is a healthy way to start the day, especially when you’re like me and have an 8-year-old that is full of energy!” Wallace said. 
 

The Skinny on Soda

When it comes to sugar-sweetened and diet beverages, data from the Nurses’ Health Study and Health Professionals Follow-Up Study, showed a 16% increased risk for stroke with one or more daily servings of sugar-sweetened or low-calorie soda per day (vs none), independent of established dietary and nondietary cardiovascular risk factors. 

In the Women’s Health Initiative Observational Study of postmenopausal women, a higher intake of artificially sweetened beverages was associated with increased risk for all stroke (adjusted hazard ratio [aHR], 1.23), ischemic stroke (aHR, 1.31), coronary heart disease (aHR, 1.29) and all-cause mortality (aHR, 1.16).

In the Framingham Heart Study Offspring cohort, consumption of one can of diet soda or more each day (vs none) was associated with a nearly threefold increased risk for stroke and dementia over a 10-year follow-up period. 

A separate French study showed that total artificial sweetener intake from all sources was associated with increased overall risk for cardiovascular and cerebrovascular disease.

However, given the limitations of these studies, it’s hard to draw any firm conclusions, Wallace cautioned. 

“We know that sugar-sweetened beverages are correlated with weight gain and cardiometabolic dysfunction promotion in children and adults,” he said. 

Yet, “there really isn’t any convincing evidence that diet soda has much impact on human health at all. Most observational studies are mixed and likely very confounded by other diet and lifestyle factors. That doesn’t mean go overboard; a daily diet soda is probably fine, but that doesn’t mean go drink 10 of them every day,” he added. 
 

Alcohol: Moderation or Abstinence?

Evidence on alcohol use and stroke risk have been mixed over the years. For decades, the evidence was suggestive that a moderate amount of alcohol daily (one to two drinks in men and one drink in women) may be beneficial at reducing major vascular outcomes.

Yet, over the past few years, some research has found no evidence of benefit with moderate alcohol intake. And the detrimental effects of excessive alcohol use are clear. 

A large meta-analysis showed that light to moderate alcohol consumption (up to one drink per day) was associated with a reduced risk for ischemic stroke. However, heavy drinking (more than two drinks per day) significantly increased the risk for both ischemic and hemorrhagic stroke.

A separate study showed young adults who are moderate to heavy drinkers are at increased risk for stroke — and the risk increases with more years of imbibing.

In the INTERSTROKE study, high to moderate alcohol consumption was associated with increased stroke risk, whereas low alcohol consumption conferred no increased risk. 

However, Bushnell pointed out that the study data was derived from based on self-report, and that other healthy behaviors may counteract the risk for alcohol consumption.

“For alcohol, regardless of stroke risk, the most important data shows that any alcohol consumption is associated with worse cognitive function, so generally, the lower the alcohol consumption the better,” Bushnell said. 

She noted that, currently, the American Heart Association (AHA)/ASA recommend a maximum of two drinks per day for men and one drink per day for women to reduce stroke risk.

“However, the data for the risk for cognitive impairment with any alcohol is convincing and should be kept in mind in addition to the maximum alcohol recommended by the AHA/ASA,” Bushnell advised. 

“We know excessive intake puts you at major risk for CVD, cancer, cognitive decline, and a whole host of other health ailments — no question there,” said Wallace.

The impact of moderate intake, on the other hand, is less clear. “Alcohol is a highly biased and political issue and the evidence (or lack thereof) on both sides is shoddy at best,” Wallace added.

A key challenge is that accurate self-reporting of alcohol intake is difficult, even for scientists, and most studies rely on self-reported data from observational cohorts. These often include limited dietary assessments, which provide only a partial picture of long-term consumption patterns, Wallace noted. 

“The short answer is we don’t know if moderation is beneficial, detrimental, or null with respect to health,” he said.

Bushnell reports no relevant disclosures. Wallace (www.drtaylorwallace.com) is CEO of Think Healthy Group; editor of The Journal of Dietary Supplements, deputy editor of The Journal of the American Nutrition Association (www.nutrition.org), nutrition section editor of Annals of Medicine, and an advisory board member with Forbes Health.

A version of this article appeared on Medscape.com.

A growing body of research explores the link between stroke risk and regular consumption of coffee, tea, soda, and alcohol. This research roundup reviews the latest findings, highlighting both promising insights and remaining uncertainties to help guide discussions with your patients.

Coffee and Tea: Good or Bad? 

In the INTERSTROKE study, high coffee consumption (> 4 cups daily) was associated with an significantly increased risk for all strokes (odds ratio [OR], 1.37) or ischemic stroke (OR, 1.31), while low to moderate coffee had no link to increased stroke risk. In contrast, tea consumption was associated with lower odds of all stroke (OR, 0.81 for highest intake) or ischemic stroke (OR, 0.81). 

In a recent UK Biobank study, consumption of coffee or tea was associated with reduced risk for stroke and dementia, with the biggest benefit associated with consuming both beverages. 

Specifically, the investigators found that individuals who drank two to three cups of coffee and two to three cups of tea per day had a 30% decrease in incidence of stroke and a 28% lower risk for dementia versus those who did not.

A recent systematic review and dose-response meta-analysis showed that each daily cup increase in tea was associated with an average 4% reduced risk for stroke and a 2% reduced risk for cardiovascular disease (CVD) events. 

The protective effect of coffee and tea on stroke risk may be driven, in part, by flavonoids, which have antioxidant and anti-inflammatory properties, as well as positive effects on vascular function.

“The advice to patients should be that coffee and tea may protect against stroke, but that sweetening either beverage with sugar probably should be minimized,” said Cheryl Bushnell, MD, MHS, of Wake Forest University School of Medicine in Winston-Salem, North Carolina, and chair of the American Stroke Association (ASA) 2024 Guideline for the Primary Prevention of Stroke. 

Taylor Wallace, PhD, a certified food scientist, said, “most people should consume a cup or two of unsweetened tea per day in moderation for cardiometabolic health. It is an easy step in the right direction for good health but not a cure-all.”

When it comes to coffee, adults who like it should drink it “in moderation — just lay off the cream and sugar,” said Wallace, adjunct associate professor at George Washington University, Washington, DC, and Tufts University, Boston, Massachusetts.

“A cup or two of black coffee with low-fat or nonfat milk with breakfast is a healthy way to start the day, especially when you’re like me and have an 8-year-old that is full of energy!” Wallace said. 
 

The Skinny on Soda

When it comes to sugar-sweetened and diet beverages, data from the Nurses’ Health Study and Health Professionals Follow-Up Study, showed a 16% increased risk for stroke with one or more daily servings of sugar-sweetened or low-calorie soda per day (vs none), independent of established dietary and nondietary cardiovascular risk factors. 

In the Women’s Health Initiative Observational Study of postmenopausal women, a higher intake of artificially sweetened beverages was associated with increased risk for all stroke (adjusted hazard ratio [aHR], 1.23), ischemic stroke (aHR, 1.31), coronary heart disease (aHR, 1.29) and all-cause mortality (aHR, 1.16).

In the Framingham Heart Study Offspring cohort, consumption of one can of diet soda or more each day (vs none) was associated with a nearly threefold increased risk for stroke and dementia over a 10-year follow-up period. 

A separate French study showed that total artificial sweetener intake from all sources was associated with increased overall risk for cardiovascular and cerebrovascular disease.

However, given the limitations of these studies, it’s hard to draw any firm conclusions, Wallace cautioned. 

“We know that sugar-sweetened beverages are correlated with weight gain and cardiometabolic dysfunction promotion in children and adults,” he said. 

Yet, “there really isn’t any convincing evidence that diet soda has much impact on human health at all. Most observational studies are mixed and likely very confounded by other diet and lifestyle factors. That doesn’t mean go overboard; a daily diet soda is probably fine, but that doesn’t mean go drink 10 of them every day,” he added. 
 

Alcohol: Moderation or Abstinence?

Evidence on alcohol use and stroke risk have been mixed over the years. For decades, the evidence was suggestive that a moderate amount of alcohol daily (one to two drinks in men and one drink in women) may be beneficial at reducing major vascular outcomes.

Yet, over the past few years, some research has found no evidence of benefit with moderate alcohol intake. And the detrimental effects of excessive alcohol use are clear. 

A large meta-analysis showed that light to moderate alcohol consumption (up to one drink per day) was associated with a reduced risk for ischemic stroke. However, heavy drinking (more than two drinks per day) significantly increased the risk for both ischemic and hemorrhagic stroke.

A separate study showed young adults who are moderate to heavy drinkers are at increased risk for stroke — and the risk increases with more years of imbibing.

In the INTERSTROKE study, high to moderate alcohol consumption was associated with increased stroke risk, whereas low alcohol consumption conferred no increased risk. 

However, Bushnell pointed out that the study data was derived from based on self-report, and that other healthy behaviors may counteract the risk for alcohol consumption.

“For alcohol, regardless of stroke risk, the most important data shows that any alcohol consumption is associated with worse cognitive function, so generally, the lower the alcohol consumption the better,” Bushnell said. 

She noted that, currently, the American Heart Association (AHA)/ASA recommend a maximum of two drinks per day for men and one drink per day for women to reduce stroke risk.

“However, the data for the risk for cognitive impairment with any alcohol is convincing and should be kept in mind in addition to the maximum alcohol recommended by the AHA/ASA,” Bushnell advised. 

“We know excessive intake puts you at major risk for CVD, cancer, cognitive decline, and a whole host of other health ailments — no question there,” said Wallace.

The impact of moderate intake, on the other hand, is less clear. “Alcohol is a highly biased and political issue and the evidence (or lack thereof) on both sides is shoddy at best,” Wallace added.

A key challenge is that accurate self-reporting of alcohol intake is difficult, even for scientists, and most studies rely on self-reported data from observational cohorts. These often include limited dietary assessments, which provide only a partial picture of long-term consumption patterns, Wallace noted. 

“The short answer is we don’t know if moderation is beneficial, detrimental, or null with respect to health,” he said.

Bushnell reports no relevant disclosures. Wallace (www.drtaylorwallace.com) is CEO of Think Healthy Group; editor of The Journal of Dietary Supplements, deputy editor of The Journal of the American Nutrition Association (www.nutrition.org), nutrition section editor of Annals of Medicine, and an advisory board member with Forbes Health.

A version of this article appeared on Medscape.com.

A growing body of research explores the link between stroke risk and regular consumption of coffee, tea, soda, and alcohol. This research roundup reviews the latest findings, highlighting both promising insights and remaining uncertainties to help guide discussions with your patients.

Coffee and Tea: Good or Bad? 

In the INTERSTROKE study, high coffee consumption (> 4 cups daily) was associated with an significantly increased risk for all strokes (odds ratio [OR], 1.37) or ischemic stroke (OR, 1.31), while low to moderate coffee had no link to increased stroke risk. In contrast, tea consumption was associated with lower odds of all stroke (OR, 0.81 for highest intake) or ischemic stroke (OR, 0.81). 

In a recent UK Biobank study, consumption of coffee or tea was associated with reduced risk for stroke and dementia, with the biggest benefit associated with consuming both beverages. 

Specifically, the investigators found that individuals who drank two to three cups of coffee and two to three cups of tea per day had a 30% decrease in incidence of stroke and a 28% lower risk for dementia versus those who did not.

A recent systematic review and dose-response meta-analysis showed that each daily cup increase in tea was associated with an average 4% reduced risk for stroke and a 2% reduced risk for cardiovascular disease (CVD) events. 

The protective effect of coffee and tea on stroke risk may be driven, in part, by flavonoids, which have antioxidant and anti-inflammatory properties, as well as positive effects on vascular function.

“The advice to patients should be that coffee and tea may protect against stroke, but that sweetening either beverage with sugar probably should be minimized,” said Cheryl Bushnell, MD, MHS, of Wake Forest University School of Medicine in Winston-Salem, North Carolina, and chair of the American Stroke Association (ASA) 2024 Guideline for the Primary Prevention of Stroke. 

Taylor Wallace, PhD, a certified food scientist, said, “most people should consume a cup or two of unsweetened tea per day in moderation for cardiometabolic health. It is an easy step in the right direction for good health but not a cure-all.”

When it comes to coffee, adults who like it should drink it “in moderation — just lay off the cream and sugar,” said Wallace, adjunct associate professor at George Washington University, Washington, DC, and Tufts University, Boston, Massachusetts.

“A cup or two of black coffee with low-fat or nonfat milk with breakfast is a healthy way to start the day, especially when you’re like me and have an 8-year-old that is full of energy!” Wallace said. 
 

The Skinny on Soda

When it comes to sugar-sweetened and diet beverages, data from the Nurses’ Health Study and Health Professionals Follow-Up Study, showed a 16% increased risk for stroke with one or more daily servings of sugar-sweetened or low-calorie soda per day (vs none), independent of established dietary and nondietary cardiovascular risk factors. 

In the Women’s Health Initiative Observational Study of postmenopausal women, a higher intake of artificially sweetened beverages was associated with increased risk for all stroke (adjusted hazard ratio [aHR], 1.23), ischemic stroke (aHR, 1.31), coronary heart disease (aHR, 1.29) and all-cause mortality (aHR, 1.16).

In the Framingham Heart Study Offspring cohort, consumption of one can of diet soda or more each day (vs none) was associated with a nearly threefold increased risk for stroke and dementia over a 10-year follow-up period. 

A separate French study showed that total artificial sweetener intake from all sources was associated with increased overall risk for cardiovascular and cerebrovascular disease.

However, given the limitations of these studies, it’s hard to draw any firm conclusions, Wallace cautioned. 

“We know that sugar-sweetened beverages are correlated with weight gain and cardiometabolic dysfunction promotion in children and adults,” he said. 

Yet, “there really isn’t any convincing evidence that diet soda has much impact on human health at all. Most observational studies are mixed and likely very confounded by other diet and lifestyle factors. That doesn’t mean go overboard; a daily diet soda is probably fine, but that doesn’t mean go drink 10 of them every day,” he added. 
 

Alcohol: Moderation or Abstinence?

Evidence on alcohol use and stroke risk have been mixed over the years. For decades, the evidence was suggestive that a moderate amount of alcohol daily (one to two drinks in men and one drink in women) may be beneficial at reducing major vascular outcomes.

Yet, over the past few years, some research has found no evidence of benefit with moderate alcohol intake. And the detrimental effects of excessive alcohol use are clear. 

A large meta-analysis showed that light to moderate alcohol consumption (up to one drink per day) was associated with a reduced risk for ischemic stroke. However, heavy drinking (more than two drinks per day) significantly increased the risk for both ischemic and hemorrhagic stroke.

A separate study showed young adults who are moderate to heavy drinkers are at increased risk for stroke — and the risk increases with more years of imbibing.

In the INTERSTROKE study, high to moderate alcohol consumption was associated with increased stroke risk, whereas low alcohol consumption conferred no increased risk. 

However, Bushnell pointed out that the study data was derived from based on self-report, and that other healthy behaviors may counteract the risk for alcohol consumption.

“For alcohol, regardless of stroke risk, the most important data shows that any alcohol consumption is associated with worse cognitive function, so generally, the lower the alcohol consumption the better,” Bushnell said. 

She noted that, currently, the American Heart Association (AHA)/ASA recommend a maximum of two drinks per day for men and one drink per day for women to reduce stroke risk.

“However, the data for the risk for cognitive impairment with any alcohol is convincing and should be kept in mind in addition to the maximum alcohol recommended by the AHA/ASA,” Bushnell advised. 

“We know excessive intake puts you at major risk for CVD, cancer, cognitive decline, and a whole host of other health ailments — no question there,” said Wallace.

The impact of moderate intake, on the other hand, is less clear. “Alcohol is a highly biased and political issue and the evidence (or lack thereof) on both sides is shoddy at best,” Wallace added.

A key challenge is that accurate self-reporting of alcohol intake is difficult, even for scientists, and most studies rely on self-reported data from observational cohorts. These often include limited dietary assessments, which provide only a partial picture of long-term consumption patterns, Wallace noted. 

“The short answer is we don’t know if moderation is beneficial, detrimental, or null with respect to health,” he said.

Bushnell reports no relevant disclosures. Wallace (www.drtaylorwallace.com) is CEO of Think Healthy Group; editor of The Journal of Dietary Supplements, deputy editor of The Journal of the American Nutrition Association (www.nutrition.org), nutrition section editor of Annals of Medicine, and an advisory board member with Forbes Health.

A version of this article appeared on Medscape.com.

TOPLINE:

Stroke rates in Californians with sickle cell disease (SCD) have increased in both children and adults in the post-STOP era. The cumulative incidence of first ischemic stroke was 2.1% by age 20 and 13.5% by age 60.

METHODOLOGY:

• Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
• A total of 7636 patients with SCD were included in the study cohort.
• Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
• Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
• The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.

TAKEAWAY:

• The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
• Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
• Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
• The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.

IN PRACTICE:

“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.

SOURCE:

This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.

LIMITATIONS:

This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.

DISCLOSURES:

The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Stroke rates in Californians with sickle cell disease (SCD) have increased in both children and adults in the post-STOP era. The cumulative incidence of first ischemic stroke was 2.1% by age 20 and 13.5% by age 60.

METHODOLOGY:

• Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
• A total of 7636 patients with SCD were included in the study cohort.
• Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
• Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
• The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.

TAKEAWAY:

• The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
• Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
• Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
• The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.

IN PRACTICE:

“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.

SOURCE:

This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.

LIMITATIONS:

This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.

DISCLOSURES:

The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Stroke rates in Californians with sickle cell disease (SCD) have increased in both children and adults in the post-STOP era. The cumulative incidence of first ischemic stroke was 2.1% by age 20 and 13.5% by age 60.

METHODOLOGY:

• Researchers analyzed data from the California Department of Health Care Access and Innovation (HCAI), covering emergency department and hospitalization records from 1991 to 2019.
• A total of 7636 patients with SCD were included in the study cohort.
• Cumulative incidence and rates for primary and recurrent strokes and transient ischemic attacks (TIAs) were determined pre- and post STOP trial.
• Patients with SCD were identified using ICD-9 and ICD-10 codes, with specific criteria for inclusion based on hospitalization records.
• The study utilized Fine and Gray methodology to calculate cumulative incidence functions, accounting for the competing risk for death.

TAKEAWAY:

• The cumulative incidence of first ischemic stroke in patients with SCD was 2.1% by age 20 and 13.5% by age 60.
• Ischemic stroke rates increased significantly in children and adults in the 2010-2019 period, compared with the preceding decade.
• Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia.
• The study found a significant increase in rates of intracranial hemorrhage in adults aged 18-30 years and TIAs in children younger than 18 years from 2010 to 2019, compared with the prior decade.

IN PRACTICE:

“Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke,” the study’s authors wrote.

SOURCE:

This study was led by Olubusola B. Oluwole, MD, MS, University of Pittsburgh in Pennsylvania, and was published online in Blood.

LIMITATIONS:

This study’s reliance on administrative data may have introduced systematic errors, particularly with the transition from ICD-9 to ICD-10 codes. The lack of laboratory results and medication data in the HCAI database limited the ability to fully assess patient conditions and treatments. Additionally, the methodology changes in 2014 likely underreported death rates in people without PDD/EDU encounters in the calendar year preceding their death.

DISCLOSURES:

The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

ABU DHABI, UAE — The long-standing debate as to when to start anticoagulation in patients with an acute ischemic stroke and atrial fibrillation (AF) looks as though it’s settled.

Results of the OPTIMAS trial, the largest trial to address this question, showed that initiation of a direct oral anticoagulant (DOAC) within 4 days after ischemic stroke associated with AF was noninferior to delayed initiation (7-14 days) for the composite outcome of ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Importantly, early DOAC initiation was safe with a low rate of symptomatic hemorrhage, regardless of stroke severity.

In addition, a new meta-analysis, known as CATALYST, which included all four randomized trials now available on this issue, showed a clear benefit of earlier initiation (within 4 days) versus later (5 days and up) on its primary endpoint of new ischemic stroke, symptomatic intracerebral hemorrhage, and unclassified stroke at 30 days.

The results of the OPTIMAS trial and the meta-analysis were both presented at the 16th World Stroke Congress (WSC) 2024. The OPTIMAS trial was also simultaneously published online in The Lancet.

“Our findings do not support the guideline recommended practice of delaying DOAC initiation after ischemic stroke with AF regardless of clinical stroke severity, reperfusion or prior anticoagulation,” said OPTIMAS investigator David Werring, PhD, University College London in England.

Presenting the meta-analysis, Signild Åsberg, MD, Uppsala University, Uppsala, Sweden, said his group’s findings “support the early start of DOACs (within 4 days) in clinical practice.”

Werring pointed out that starting anticoagulation early also had important logistical advantages.

“This means we can start anticoagulation before patients are discharged from hospital, thus ensuring that this important secondary prevention medication is always prescribed, when appropriate. That’s going to be a key benefit in the real world.”
 

Clinical Dilemma

Werring noted that AF accounts for 20%-30% of ischemic strokes, which tend to be more severe than other stroke types. The pivotal trials of DOACs did not include patients within 30 days of an acute ischemic stroke, creating a clinical dilemma on when to start this treatment.

“On the one hand, we wish to start anticoagulation early to reduce early recurrence of ischemic stroke. But on the other hand, there are concerns that if we start anticoagulation early, it could cause intracranial bleeding, including hemorrhagic transformation of the acute infarct. Guidelines on this issue are inconsistent and have called for randomized control trials in this area,” he noted.

So far, three randomized trials on DOAC timing have been conducted, which Werring said suggested early DOAC treatment is safe. However, these trials have provided limited data on moderate to severe stroke, patients with hemorrhagic transformation, or those already taking oral anticoagulants — subgroups in which there are particular concerns about early oral anticoagulation.

The OPTIMAS trial included a broad population of patients with acute ischemic stroke associated with AF including these critical subgroups.

The trial, conducted at 100 hospitals in the United Kingdom, included 3648 patients with AF and acute ischemic stroke who were randomly assigned to early (≤ 4 days from stroke symptom onset) or delayed (7-14 days) anticoagulation initiation with any DOAC.

There was no restriction on stroke severity, and patients with hemorrhagic transformation were allowed, with the exception of parenchymal hematoma type 2, a rare and severe type of hemorrhagic transformation.

Approximately 35% of patients had been taking an oral anticoagulant, mainly DOACs, prior to their stroke, and about 30% had revascularization with thrombolysis, thrombectomy, or both. Nearly 900 participants (25%) had moderate to severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥ 11).

The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days. The initial analysis aimed to show noninferiority of early DOAC initiation, with a noninferiority margin of 2 percentage points, followed by testing for superiority.

Results showed that the primary outcome occurred in 3.3% of both groups (adjusted risk difference, 0.000; 95% CI, −0.011 to 0.012), with noninferiority criteria fulfilled. Superiority was not achieved.

Symptomatic intracranial hemorrhage occurred in 0.6% of patients in the early DOAC initiation group vs 0.7% of those in the delayed group — a nonsignificant difference.
 

Applicable to Real-World Practice

A time-to-event analysis of the primary outcome showed that there were fewer outcomes in the first 30 days in the early DOAC initiation group, but the curves subsequently came together.

Subgroup analysis showed consistent results across all whole trial population, with no modification of the effect of early DOAC initiation according to stroke severity, reperfusion treatment, or previous anticoagulation.

Werring said that strengths of the OPTIMAS trial included a large sample size, a broad population with generalizability to real-world practice, and the inclusion of patients at higher bleeding risk than included in previous studies.

During the discussion, it was noted that the trial included few (about 3%) patients — about 3% — with very severe stroke (NIHSS score > 21), with the question of whether the findings could be applied to this group.

Werring noted that there was no evidence of heterogeneity, and if anything, patients with more severe strokes may have had a slightly greater benefit with early DOAC initiation. “So my feeling is probably these results do generalize to the more severe patients,” he said.

In a commentary accompanying The Lancet publication of the OPTIMAS trial, Else Charlotte Sandset, MD, University of Oslo, in Norway, and Diana Aguiar de Sousa, MD, Central Lisbon University Hospital Centre, Lisbon, Portugal, noted that the “increasing body of evidence strongly supports the message that initiating anticoagulation early for patients with ischaemic stroke is safe. The consistent absence of heterogeneity in safety outcomes suggests that the risk of symptomatic intracranial haemorrhage is not a major concern, even in patients with large infarcts.”

Regardless of the size of the treatment effect, initiating early anticoagulation makes sense when it can be done safely, as it helps prevent recurrent ischemic strokes and other embolic events. Early intervention reduces embolization risk, particularly in high-risk patients, and allows secondary prevention measures to begin while patients are still hospitalized, they added.
 

CATALYST Findings

The CATALYST meta-analysis included four trials, namely, TIMING, ELAN, OPTIMAS, and START, of early versus later DOAC administration in a total of 5411 patients with acute ischemic stroke and AF. In this meta-analysis, early was defined as within 4 days of stroke and later as 5 days or more.

The primary outcome was a composite of ischemic stroke, symptomatic, intracerebral hemorrhage, or unclassified stroke at 30 days. This was significantly reduced in the early group (2.12%) versus 3.02% in the later group, giving an odds ratio of 0.70 (95% CI, 0.50-0.98; P =.04).

The results were consistent across all subgroups, all suggesting an advantage for early DOAC.

Further analysis showed a clear benefit of early DOAC initiation in ischemic stroke with the curves separating early.

The rate of symptomatic intracerebral hemorrhage was low in both groups (0.45% in the early group and 0.40% in the later group) as was extracranial hemorrhage (0.45% vs 0.55%).

At 90 days, there were still lower event rates in the early group than the later one, but the difference was no longer statistically significant.
 

‘Practice Changing’ Results

Commenting on both studies, chair of the WSC session where the results of both OPTIMAS trial and the meta-analysis were presented, Craig Anderson, MD, The George Institute for Global Health, Sydney, Australia, described these latest results as “practice changing.”

“When to start anticoagulation in acute ischemic stroke patients with AF has been uncertain for a long time. The dogma has always been that we should wait. Over the years, we’ve become a little bit more confident, but now we’ve got good data from randomized trials showing that early initiation is safe, with the meta-analysis showing benefit,” he said.

“These new data from OPTIMAS will reassure clinicians that there’s no excessive harm and, more importantly, no excessive harm across all patient groups. And the meta-analysis clearly showed an upfront benefit of starting anticoagulation early. That’s a very convincing result,” he added.

Anderson cautioned that there still may be concerns about starting DOACs early in some groups, including Asian populations that have a higher bleeding risk (these trials included predominantly White patients) and people who are older or frail, who may have extensive small vessel disease.

During the discussion, several questions centered on the lack of imaging data available on the patients in the studies. Anderson said imaging data would help reassure clinicians on the safety of early anticoagulation in patients with large infarcts.

“Stroke clinicians make decisions on the basis of the patient and on the basis of the brain, and we only have the patient information at the moment. We don’t have information on the brain — that comes from imaging.”

Regardless, he believes these new data will lead to a shift in practice. “But maybe, it won’t be as dramatic as we would hope because I think some clinicians may still hesitate to apply these results to patients at high risk of bleeding. With imaging data from the studies that might change.”

The OPTIMAS trial was funded by University College London and the British Heart Foundation. Werring reported consulting fees from Novo Nordisk, National Institute for Health and Care Excellence, and Alnylam; payments or speaker honoraria from Novo Nordisk, Bayer, and AstraZeneca/Alexion; participation on a data safety monitoring board for the OXHARP trial; and participation as steering committee chair for the MACE-ICH and PLINTH trials. Åsberg received institutional research grants and lecture fees to her institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Institut Produits Synthése. Sandset and de Sousa were both steering committee members of the ELAN trial. Anderson reported grant funding from Penumbra and Takeda China.
 

A version of this article appeared on Medscape.com.

ABU DHABI, UAE — The long-standing debate as to when to start anticoagulation in patients with an acute ischemic stroke and atrial fibrillation (AF) looks as though it’s settled.

Results of the OPTIMAS trial, the largest trial to address this question, showed that initiation of a direct oral anticoagulant (DOAC) within 4 days after ischemic stroke associated with AF was noninferior to delayed initiation (7-14 days) for the composite outcome of ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Importantly, early DOAC initiation was safe with a low rate of symptomatic hemorrhage, regardless of stroke severity.

In addition, a new meta-analysis, known as CATALYST, which included all four randomized trials now available on this issue, showed a clear benefit of earlier initiation (within 4 days) versus later (5 days and up) on its primary endpoint of new ischemic stroke, symptomatic intracerebral hemorrhage, and unclassified stroke at 30 days.

The results of the OPTIMAS trial and the meta-analysis were both presented at the 16th World Stroke Congress (WSC) 2024. The OPTIMAS trial was also simultaneously published online in The Lancet.

“Our findings do not support the guideline recommended practice of delaying DOAC initiation after ischemic stroke with AF regardless of clinical stroke severity, reperfusion or prior anticoagulation,” said OPTIMAS investigator David Werring, PhD, University College London in England.

Presenting the meta-analysis, Signild Åsberg, MD, Uppsala University, Uppsala, Sweden, said his group’s findings “support the early start of DOACs (within 4 days) in clinical practice.”

Werring pointed out that starting anticoagulation early also had important logistical advantages.

“This means we can start anticoagulation before patients are discharged from hospital, thus ensuring that this important secondary prevention medication is always prescribed, when appropriate. That’s going to be a key benefit in the real world.”
 

Clinical Dilemma

Werring noted that AF accounts for 20%-30% of ischemic strokes, which tend to be more severe than other stroke types. The pivotal trials of DOACs did not include patients within 30 days of an acute ischemic stroke, creating a clinical dilemma on when to start this treatment.

“On the one hand, we wish to start anticoagulation early to reduce early recurrence of ischemic stroke. But on the other hand, there are concerns that if we start anticoagulation early, it could cause intracranial bleeding, including hemorrhagic transformation of the acute infarct. Guidelines on this issue are inconsistent and have called for randomized control trials in this area,” he noted.

So far, three randomized trials on DOAC timing have been conducted, which Werring said suggested early DOAC treatment is safe. However, these trials have provided limited data on moderate to severe stroke, patients with hemorrhagic transformation, or those already taking oral anticoagulants — subgroups in which there are particular concerns about early oral anticoagulation.

The OPTIMAS trial included a broad population of patients with acute ischemic stroke associated with AF including these critical subgroups.

The trial, conducted at 100 hospitals in the United Kingdom, included 3648 patients with AF and acute ischemic stroke who were randomly assigned to early (≤ 4 days from stroke symptom onset) or delayed (7-14 days) anticoagulation initiation with any DOAC.

There was no restriction on stroke severity, and patients with hemorrhagic transformation were allowed, with the exception of parenchymal hematoma type 2, a rare and severe type of hemorrhagic transformation.

Approximately 35% of patients had been taking an oral anticoagulant, mainly DOACs, prior to their stroke, and about 30% had revascularization with thrombolysis, thrombectomy, or both. Nearly 900 participants (25%) had moderate to severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥ 11).

The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days. The initial analysis aimed to show noninferiority of early DOAC initiation, with a noninferiority margin of 2 percentage points, followed by testing for superiority.

Results showed that the primary outcome occurred in 3.3% of both groups (adjusted risk difference, 0.000; 95% CI, −0.011 to 0.012), with noninferiority criteria fulfilled. Superiority was not achieved.

Symptomatic intracranial hemorrhage occurred in 0.6% of patients in the early DOAC initiation group vs 0.7% of those in the delayed group — a nonsignificant difference.
 

Applicable to Real-World Practice

A time-to-event analysis of the primary outcome showed that there were fewer outcomes in the first 30 days in the early DOAC initiation group, but the curves subsequently came together.

Subgroup analysis showed consistent results across all whole trial population, with no modification of the effect of early DOAC initiation according to stroke severity, reperfusion treatment, or previous anticoagulation.

Werring said that strengths of the OPTIMAS trial included a large sample size, a broad population with generalizability to real-world practice, and the inclusion of patients at higher bleeding risk than included in previous studies.

During the discussion, it was noted that the trial included few (about 3%) patients — about 3% — with very severe stroke (NIHSS score > 21), with the question of whether the findings could be applied to this group.

Werring noted that there was no evidence of heterogeneity, and if anything, patients with more severe strokes may have had a slightly greater benefit with early DOAC initiation. “So my feeling is probably these results do generalize to the more severe patients,” he said.

In a commentary accompanying The Lancet publication of the OPTIMAS trial, Else Charlotte Sandset, MD, University of Oslo, in Norway, and Diana Aguiar de Sousa, MD, Central Lisbon University Hospital Centre, Lisbon, Portugal, noted that the “increasing body of evidence strongly supports the message that initiating anticoagulation early for patients with ischaemic stroke is safe. The consistent absence of heterogeneity in safety outcomes suggests that the risk of symptomatic intracranial haemorrhage is not a major concern, even in patients with large infarcts.”

Regardless of the size of the treatment effect, initiating early anticoagulation makes sense when it can be done safely, as it helps prevent recurrent ischemic strokes and other embolic events. Early intervention reduces embolization risk, particularly in high-risk patients, and allows secondary prevention measures to begin while patients are still hospitalized, they added.
 

CATALYST Findings

The CATALYST meta-analysis included four trials, namely, TIMING, ELAN, OPTIMAS, and START, of early versus later DOAC administration in a total of 5411 patients with acute ischemic stroke and AF. In this meta-analysis, early was defined as within 4 days of stroke and later as 5 days or more.

The primary outcome was a composite of ischemic stroke, symptomatic, intracerebral hemorrhage, or unclassified stroke at 30 days. This was significantly reduced in the early group (2.12%) versus 3.02% in the later group, giving an odds ratio of 0.70 (95% CI, 0.50-0.98; P =.04).

The results were consistent across all subgroups, all suggesting an advantage for early DOAC.

Further analysis showed a clear benefit of early DOAC initiation in ischemic stroke with the curves separating early.

The rate of symptomatic intracerebral hemorrhage was low in both groups (0.45% in the early group and 0.40% in the later group) as was extracranial hemorrhage (0.45% vs 0.55%).

At 90 days, there were still lower event rates in the early group than the later one, but the difference was no longer statistically significant.
 

‘Practice Changing’ Results

Commenting on both studies, chair of the WSC session where the results of both OPTIMAS trial and the meta-analysis were presented, Craig Anderson, MD, The George Institute for Global Health, Sydney, Australia, described these latest results as “practice changing.”

“When to start anticoagulation in acute ischemic stroke patients with AF has been uncertain for a long time. The dogma has always been that we should wait. Over the years, we’ve become a little bit more confident, but now we’ve got good data from randomized trials showing that early initiation is safe, with the meta-analysis showing benefit,” he said.

“These new data from OPTIMAS will reassure clinicians that there’s no excessive harm and, more importantly, no excessive harm across all patient groups. And the meta-analysis clearly showed an upfront benefit of starting anticoagulation early. That’s a very convincing result,” he added.

Anderson cautioned that there still may be concerns about starting DOACs early in some groups, including Asian populations that have a higher bleeding risk (these trials included predominantly White patients) and people who are older or frail, who may have extensive small vessel disease.

During the discussion, several questions centered on the lack of imaging data available on the patients in the studies. Anderson said imaging data would help reassure clinicians on the safety of early anticoagulation in patients with large infarcts.

“Stroke clinicians make decisions on the basis of the patient and on the basis of the brain, and we only have the patient information at the moment. We don’t have information on the brain — that comes from imaging.”

Regardless, he believes these new data will lead to a shift in practice. “But maybe, it won’t be as dramatic as we would hope because I think some clinicians may still hesitate to apply these results to patients at high risk of bleeding. With imaging data from the studies that might change.”

The OPTIMAS trial was funded by University College London and the British Heart Foundation. Werring reported consulting fees from Novo Nordisk, National Institute for Health and Care Excellence, and Alnylam; payments or speaker honoraria from Novo Nordisk, Bayer, and AstraZeneca/Alexion; participation on a data safety monitoring board for the OXHARP trial; and participation as steering committee chair for the MACE-ICH and PLINTH trials. Åsberg received institutional research grants and lecture fees to her institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Institut Produits Synthése. Sandset and de Sousa were both steering committee members of the ELAN trial. Anderson reported grant funding from Penumbra and Takeda China.
 

A version of this article appeared on Medscape.com.

ABU DHABI, UAE — The long-standing debate as to when to start anticoagulation in patients with an acute ischemic stroke and atrial fibrillation (AF) looks as though it’s settled.

Results of the OPTIMAS trial, the largest trial to address this question, showed that initiation of a direct oral anticoagulant (DOAC) within 4 days after ischemic stroke associated with AF was noninferior to delayed initiation (7-14 days) for the composite outcome of ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Importantly, early DOAC initiation was safe with a low rate of symptomatic hemorrhage, regardless of stroke severity.

In addition, a new meta-analysis, known as CATALYST, which included all four randomized trials now available on this issue, showed a clear benefit of earlier initiation (within 4 days) versus later (5 days and up) on its primary endpoint of new ischemic stroke, symptomatic intracerebral hemorrhage, and unclassified stroke at 30 days.

The results of the OPTIMAS trial and the meta-analysis were both presented at the 16th World Stroke Congress (WSC) 2024. The OPTIMAS trial was also simultaneously published online in The Lancet.

“Our findings do not support the guideline recommended practice of delaying DOAC initiation after ischemic stroke with AF regardless of clinical stroke severity, reperfusion or prior anticoagulation,” said OPTIMAS investigator David Werring, PhD, University College London in England.

Presenting the meta-analysis, Signild Åsberg, MD, Uppsala University, Uppsala, Sweden, said his group’s findings “support the early start of DOACs (within 4 days) in clinical practice.”

Werring pointed out that starting anticoagulation early also had important logistical advantages.

“This means we can start anticoagulation before patients are discharged from hospital, thus ensuring that this important secondary prevention medication is always prescribed, when appropriate. That’s going to be a key benefit in the real world.”
 

Clinical Dilemma

Werring noted that AF accounts for 20%-30% of ischemic strokes, which tend to be more severe than other stroke types. The pivotal trials of DOACs did not include patients within 30 days of an acute ischemic stroke, creating a clinical dilemma on when to start this treatment.

“On the one hand, we wish to start anticoagulation early to reduce early recurrence of ischemic stroke. But on the other hand, there are concerns that if we start anticoagulation early, it could cause intracranial bleeding, including hemorrhagic transformation of the acute infarct. Guidelines on this issue are inconsistent and have called for randomized control trials in this area,” he noted.

So far, three randomized trials on DOAC timing have been conducted, which Werring said suggested early DOAC treatment is safe. However, these trials have provided limited data on moderate to severe stroke, patients with hemorrhagic transformation, or those already taking oral anticoagulants — subgroups in which there are particular concerns about early oral anticoagulation.

The OPTIMAS trial included a broad population of patients with acute ischemic stroke associated with AF including these critical subgroups.

The trial, conducted at 100 hospitals in the United Kingdom, included 3648 patients with AF and acute ischemic stroke who were randomly assigned to early (≤ 4 days from stroke symptom onset) or delayed (7-14 days) anticoagulation initiation with any DOAC.

There was no restriction on stroke severity, and patients with hemorrhagic transformation were allowed, with the exception of parenchymal hematoma type 2, a rare and severe type of hemorrhagic transformation.

Approximately 35% of patients had been taking an oral anticoagulant, mainly DOACs, prior to their stroke, and about 30% had revascularization with thrombolysis, thrombectomy, or both. Nearly 900 participants (25%) had moderate to severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥ 11).

The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days. The initial analysis aimed to show noninferiority of early DOAC initiation, with a noninferiority margin of 2 percentage points, followed by testing for superiority.

Results showed that the primary outcome occurred in 3.3% of both groups (adjusted risk difference, 0.000; 95% CI, −0.011 to 0.012), with noninferiority criteria fulfilled. Superiority was not achieved.

Symptomatic intracranial hemorrhage occurred in 0.6% of patients in the early DOAC initiation group vs 0.7% of those in the delayed group — a nonsignificant difference.
 

Applicable to Real-World Practice

A time-to-event analysis of the primary outcome showed that there were fewer outcomes in the first 30 days in the early DOAC initiation group, but the curves subsequently came together.

Subgroup analysis showed consistent results across all whole trial population, with no modification of the effect of early DOAC initiation according to stroke severity, reperfusion treatment, or previous anticoagulation.

Werring said that strengths of the OPTIMAS trial included a large sample size, a broad population with generalizability to real-world practice, and the inclusion of patients at higher bleeding risk than included in previous studies.

During the discussion, it was noted that the trial included few (about 3%) patients — about 3% — with very severe stroke (NIHSS score > 21), with the question of whether the findings could be applied to this group.

Werring noted that there was no evidence of heterogeneity, and if anything, patients with more severe strokes may have had a slightly greater benefit with early DOAC initiation. “So my feeling is probably these results do generalize to the more severe patients,” he said.

In a commentary accompanying The Lancet publication of the OPTIMAS trial, Else Charlotte Sandset, MD, University of Oslo, in Norway, and Diana Aguiar de Sousa, MD, Central Lisbon University Hospital Centre, Lisbon, Portugal, noted that the “increasing body of evidence strongly supports the message that initiating anticoagulation early for patients with ischaemic stroke is safe. The consistent absence of heterogeneity in safety outcomes suggests that the risk of symptomatic intracranial haemorrhage is not a major concern, even in patients with large infarcts.”

Regardless of the size of the treatment effect, initiating early anticoagulation makes sense when it can be done safely, as it helps prevent recurrent ischemic strokes and other embolic events. Early intervention reduces embolization risk, particularly in high-risk patients, and allows secondary prevention measures to begin while patients are still hospitalized, they added.
 

CATALYST Findings

The CATALYST meta-analysis included four trials, namely, TIMING, ELAN, OPTIMAS, and START, of early versus later DOAC administration in a total of 5411 patients with acute ischemic stroke and AF. In this meta-analysis, early was defined as within 4 days of stroke and later as 5 days or more.

The primary outcome was a composite of ischemic stroke, symptomatic, intracerebral hemorrhage, or unclassified stroke at 30 days. This was significantly reduced in the early group (2.12%) versus 3.02% in the later group, giving an odds ratio of 0.70 (95% CI, 0.50-0.98; P =.04).

The results were consistent across all subgroups, all suggesting an advantage for early DOAC.

Further analysis showed a clear benefit of early DOAC initiation in ischemic stroke with the curves separating early.

The rate of symptomatic intracerebral hemorrhage was low in both groups (0.45% in the early group and 0.40% in the later group) as was extracranial hemorrhage (0.45% vs 0.55%).

At 90 days, there were still lower event rates in the early group than the later one, but the difference was no longer statistically significant.
 

‘Practice Changing’ Results

Commenting on both studies, chair of the WSC session where the results of both OPTIMAS trial and the meta-analysis were presented, Craig Anderson, MD, The George Institute for Global Health, Sydney, Australia, described these latest results as “practice changing.”

“When to start anticoagulation in acute ischemic stroke patients with AF has been uncertain for a long time. The dogma has always been that we should wait. Over the years, we’ve become a little bit more confident, but now we’ve got good data from randomized trials showing that early initiation is safe, with the meta-analysis showing benefit,” he said.

“These new data from OPTIMAS will reassure clinicians that there’s no excessive harm and, more importantly, no excessive harm across all patient groups. And the meta-analysis clearly showed an upfront benefit of starting anticoagulation early. That’s a very convincing result,” he added.

Anderson cautioned that there still may be concerns about starting DOACs early in some groups, including Asian populations that have a higher bleeding risk (these trials included predominantly White patients) and people who are older or frail, who may have extensive small vessel disease.

During the discussion, several questions centered on the lack of imaging data available on the patients in the studies. Anderson said imaging data would help reassure clinicians on the safety of early anticoagulation in patients with large infarcts.

“Stroke clinicians make decisions on the basis of the patient and on the basis of the brain, and we only have the patient information at the moment. We don’t have information on the brain — that comes from imaging.”

Regardless, he believes these new data will lead to a shift in practice. “But maybe, it won’t be as dramatic as we would hope because I think some clinicians may still hesitate to apply these results to patients at high risk of bleeding. With imaging data from the studies that might change.”

The OPTIMAS trial was funded by University College London and the British Heart Foundation. Werring reported consulting fees from Novo Nordisk, National Institute for Health and Care Excellence, and Alnylam; payments or speaker honoraria from Novo Nordisk, Bayer, and AstraZeneca/Alexion; participation on a data safety monitoring board for the OXHARP trial; and participation as steering committee chair for the MACE-ICH and PLINTH trials. Åsberg received institutional research grants and lecture fees to her institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Institut Produits Synthése. Sandset and de Sousa were both steering committee members of the ELAN trial. Anderson reported grant funding from Penumbra and Takeda China.
 

A version of this article appeared on Medscape.com.