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When Should Anticoagulation for Stroke be Initiated in Patients With Atrial Fibrillation?

  • Authors: News Author: Sue Hughes; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 6/30/2023
  • Valid for credit through: 6/30/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, neurologists, cardiologists, nurses/nurse practitioners, pharmacists, physician assistants, and other clinicians who treat and manage patients with stroke related to atrial fibrillation.

The goal of this activity is for members of the healthcare team to be better able to evaluate outcomes for early vs late initiation of direct oral anticoagulants among adults with stroke related to atrial fibrillation.

Upon completion of this activity, participants will:

  • Compare direct oral anticoagulants and warfarin in the treatment of postacute stroke among patients with atrial fibrillation
  • Evaluate outcomes for early vs late initiation of direct oral anticoagulants among adults with stroke related to atrial fibrillation
  • Outline implications for the healthcare team


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News Author

  • Sue Hughes

    Freelance writer, Medscape


    Sue Hughes has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: Boehringer Ingelheim Pharmaceuticals, Inc.; GlaxoSmithKline; Johnson & Johnson

Editor/Nurse Planner

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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When Should Anticoagulation for Stroke be Initiated in Patients With Atrial Fibrillation?

Authors: News Author: Sue Hughes; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 6/30/2023

Valid for credit through: 6/30/2024, 11:59 PM EST


Clinical Context

Direct oral anticoagulants (DOACs) have superior outcomes compared with warfarin in terms of the prevention of stroke and major bleeding events among adults with atrial fibrillation (AF), but many of the trials comparing DOACs with warfarin excluded patients in the immediate poststroke period. Dr Seiffge and colleagues addressed this issue with an analysis of 7 cohort studies focused on patients with AF treated with anticoagulants within 3 months of an ischemic stroke. Their study was published in the June 2019 issue of the Annals of Neurology.[1]

Data were available for 4912 patients, who had a mean age of 78 years. The mean time since stroke to receive both warfarin and DOACs was 5 days. Overall, DOACs were marginally superior in the combined outcome of recurrent ischemic stroke, intracerebral hemorrhage, or mortality (hazard ratio [HR], 0.62-1.00), with a respective HR for intracerebral hemorrhage of 0.42 (95% CI, 0.24-0.71). The rates of recurrent stroke and mortality were similar in comparing the 2 groups.

Nonetheless, the risks for both repeat ischemic stroke and intracerebral hemorrhage are highest in the early weeks after a stroke. That has led to variable practice, with a delay in anticoagulation for up to 2 weeks in cases of severe stroke. The current randomized trial compares strategies of early vs late anticoagulation with DOACs among patients with AF and acute stroke.

Study Synopsis and Perspective

Patients presenting with an acute ischemic stroke and found to have AF can be safely started on a DOAC much earlier than starting generally occurs in current clinical practice, a new study suggests.

The ELAN trial found that starting DOAC treatment earlier was not associated with an increased risk for intracranial hemorrhage (ICH), but rather was linked to a lower rate of ischemic events.

“We conclude that there is no reason to delay DOAC treatment in these patients. Our results suggest that early DOAC treatment is reasonable; it is unlikely to cause harm, and it is probably better at reducing ischemic events,” lead investigator of the study, Urs Fischer, MD, professor of neurology at University Hospital Basel, Switzerland, commented to | Medscape Cardiology.

Senior investigator Jesse Dawson, MD, professor of stroke medicine at Queen Elizabeth University Hospital, Glasgow, United Kingdom, added: “This issue of timing of DOAC treatment causes a lot of anxiety in our daily workload. Clinicians are scared of causing an ICH, so they tend to wait. These results will ease a lot of that anxiety.”

Dr Fischer presented the results of the ELAN trial at the European Stroke Organisation Conference (ESOC) in Munich, Germany, on May 24, 2023. The trial was also simultaneously published online in the New England Journal of Medicine.[2]

He explained that patients presenting with acute ischemic stroke who are found to have AF need to be started on anticoagulation to reduce the risk for a recurrent stroke. But there are no clear guidelines on when to start anticoagulation in these patients at present, with concerns that starting very early may increase the risk for hemorrhagic transformation and ICH.

On the basis of observations that patients with larger strokes have a higher risk for ICH in the early poststroke period, some guidelines advise different times for starting anticoagulation for different stroke severities: 1 day for a transient ischemic attack, 3 days for a minor stroke, 6 days for a moderate stroke, and 12 days for a severe stroke, known as the 1-, 3-, 6-, 12-day rule.

“But this is not based on evidence, just on expert opinion,” Dr Fischer noted. “The ELAN trial was conducted to obtain more solid information on optimal timing for starting anticoagulation and whether we can safely start a DOAC earlier than these guidelines currently advise.”

For the trial, which was conducted in 15 countries, 2013 patients with an acute ischemic stroke and found to have AF were randomly selected to start DOAC treatment earlier or later.

The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.

“The most important finding was that among 2000 patients randomized, there was a very low rate of bleeding complications, and no increase in any bleeding complication in the early DOAC group. This has been a major worry about starting anticoagulation early,” Dr Fischer commented.

“These are very practical findings, in that we can keep things simple,” Dr Dawson added. “If the patient has a big stroke, anticoagulation with a DOAC can now be started at 6 days. For everyone else, we can start DOAC treatment as soon as possible without fear of causing harm. So, we can now confidently give patients with a minor or moderate stroke, as defined by imaging, a beneficial treatment as soon as we establish they are having an ischemic stroke and have AF.”

Dr Dawson pointed out that about 25% of patients with ischemic stroke are found to have AF on admission electrocardiogram, and in another 4% to 5%, AF is found in the first 48 hours. “These are the patients we are targeting in this study.”

The researchers note that the trial did not have a statistical superiority or noninferiority design, but rather is aimed to estimate the treatment effects of early initiation vs later initiation of DOACs.

“This trial was slightly different, in that we weren’t testing a strict statistical hypothesis because we didn’t have any data with which to formulate what sort of effect size to aim for, so we performed a qualitative trial to look at what the event rates were with the 2 approaches,” Dr Fischer explained.

Dr Dawson added: “We can say from these results that there is a high level of probability that early DOAC treatment does not cause harm and a reasonable probability that it reduces risks of a recurrent stroke or other ischemic event.”

The researchers give an estimate of the effect size for the primary composite endpoint, which combines the major ischemic and bleeding events, ranging from a 2.8 lower risk to a 0.5% higher risk with early DOAC treatment.

“So, it is very likely that the composite endpoint would be lower,” Dr Dawson said.

Dr Fischer noted that a previous study (TIMING) tried to address the issue of earlier vs later anticoagulation in these patients but was stopped early after 880 patients had been enrolled because of slow recruitment.[3]

“Results from this study failed to show superiority of early vs late DOAC treatment, but they did suggest noninferiority, and they also found no increase in major bleeding complications, which is an added reassurance,” he commented.

Another trial looking at early vs late anticoagulation in these patients, OPTIMAS, is ongoing in the United Kingdom and is aiming to randomize 3500 patients.

Imaging-Based Assessment of Stroke Severity

In the ELAN trial, the definition of stroke severity was based on imaging rather than on the National Institutes of Health Stroke Scale (NIHSS).

He noted that although clinicians tend to use the NIHSS clinical symptom score to define mild, moderate, and severe stroke, the imaging approach is actually more accurate when determining the risk for bleeding and ICH. And though imaging results often correlate with NIHSS scores, there can be some exceptions.

Commenting on the ELAN trial results at the ESOC meeting, Georgios Tsivgoulis, MD, professor of neurology, University of Athens, Greece, said that the trial showed that early administration of DOACs in these patients was safe and did not increase the rate of ICH.

But he highlighted 1 important caveat: that the majority of patients had mild or moderate stroke.

European Stroke Organisation Conference 2023. Presented May 24.

N Eng J Med. Published online May 24, 2023.

Study Highlights

  • The trial was conducted at 103 stroke centers in Europe, the Middle East, and Asia. Participants all had a history of AF and acute ischemic stroke.
  • Intravenous thrombolysis or thrombectomy was allowed at the time of presentation for stroke, but therapeutic anticoagulation was not. Intracranial hemorrhage at presentation beyond petechial hemorrhage at the site of infarct disqualified patients from study participation.
  • Participants were randomly assigned to 1 of 2 treatment groups for DOACs:
    • Early treatment: initiation of DOACs within 48 hours for minor or moderate stroke or 6 or 7 days for severe stroke.
    • Late treatment: initiation of DOACs within 3 to 4 days for minor stroke; 6 or 7 days for moderate stroke; and 12 to 14 days for severe stroke.
  • The primary study outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Researchers also examined these outcomes at 90 days after randomization and included secondary outcomes of nonmajor bleeding and overall mortality.
  • 2013 patients underwent randomization. The median age of participants was 77 years, and 45% were female. A total of 37% of the cohort had minor stroke, whereas 40% had moderate stroke and 23% of participants had a major stroke.
  • 39% of the study cohort received thrombolysis for acute stroke, and 22% received thrombectomy.
  • The vast majority of participants received their DOAC per study protocol.
  • The primary outcome event occurred in 2.9% of participants in the early-treatment group and 4.1% of participants in the late-treatment group. The odds ratio (OR) for the primary outcome in comparing the early- vs late-treatment groups was 0.70 (95% CI, 0.44-1.14).
  • ORs for specific outcomes in the early-treatment vs late-treatment groups within 30 days were as follows:
    • Major extracranial bleeding: 0.63 (95% CI, 0.15-2.38)
    • Symptomatic intracranial hemorrhage: 1.02 (95% CI, 0.16-6.59)
    • Recurrent ischemic stroke: 0.57 (95% CI, 0.29-1.07)
  • At 90 days, the OR for the composite outcome significantly favored the early- vs late-treatment group (OR, 0.65; 95% CI, 0.42-0.99), but this was not a prespecified study outcome.
  • There was no significant difference between treatment groups in the outcomes of recurrent ischemic stroke or intracranial hemorrhage at 90 days.
  • The 90-day rates of serious adverse events in the early- and late-treatment groups were 13.9% and 15.8%, respectively.

Implications for the healthcare team

  • In a previous study comparing DOACs with warfarin after stroke among patients with AF, DOACs were associated with lower rates of intracerebral hemorrhage, but not recurrent stroke or mortality.
  • The current study finds similar outcomes for the early vs late initiation of DOACs after ischemic stroke among patients with AF.
  • The healthcare team may choose early vs late treatment with direct oral anticoagulants after stroke related to atrial fibrillation at their discretion.

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