From Pages to Practice

By Suellen Li, MD

Published August 2, 2023


Mr. Wang is a 73-year-old male with a history of atrial fibrillation (AF) and diabetes who presented with left-sided weakness. Head imaging showed an ischemic stroke affecting the superficial cortical branch of the right middle cerebral artery. When should he restart oral anticoagulation?

Initiation of oral anticoagulation after ischemic stroke is often delayed to reduce the risk of hemorrhagic transformation in the immediate post-stroke period. However, this delay may increase the risk of recurrent ischemic events. The “1-3-6-12-day rule” is commonly used to guide timing of anticoagulation initiation after stroke based on stroke severity (1 day for transient ischemic attack [TIA], and 3, 6, or 12 days for mild, moderate, or severe stroke). However, recent studies suggest that earlier anticoagulation may be better.

In 2022, researchers of a prospective cohort study in Japan reported no difference in major bleeding events between early and later initiation of anticoagulation. Later that year, the randomized TIMING trial in Sweden showed that early (<4 days) initiation of anticoagulation was noninferior to delayed (5–10 days) initiation. Both studies found that early anticoagulation was associated with numerically lower rates of recurrent stroke, but the first study was not randomized, the second was based on a smaller-than-planned sample size, and both reflected homogeneous populations.

Enter the international ELAN trial published in NEJM in 2023. Investigators randomized more than 2000 patients with mild, moderate, or severe strokes and AF in 15 countries to receive early or later initiation of anticoagulation. Early was defined as within 48 hours after mild or moderate stroke or on day 6–7 after severe stroke. Later initiation was based on the 1-3-6-12- day rule and defined as 3–4 days, 6–7 days, or 12–14 days after minor, moderate, or severe stroke. At 30 days, no significant increase in symptomatic intracranial bleeding was reported (only 2 participants in each group experienced bleeding). Fewer participants in the early group versus the later group experienced recurrent ischemic stroke (1.4% vs. 2.5%). Although the trial was not designed to test superiority or noninferiority, the results provide reassurance that early initiation of anticoagulation likely does not cause harm and may reduce risk of recurrent stroke.

In the clinical scenario described above of a patient with moderate stroke and AF, Mr. Wang can restart anticoagulation within 48 hours rather than wait 6 days as previously recommended. Keep an eye out for the ongoing OPTIMAS (NCT03759938) and START (NCT03021928) trial results for further clarification of optimal timing of anticoagulation initiation after ischemic stroke due to AF.

Read the following NEJM Journal Watch summary for more details of this study.

Timing of Oral Anticoagulation After Stroke due to Atrial Fibrillation

Seemant Chaturvedi, MD, reviewing Fischer U et al. N Engl J Med 2023 May 24

The timing of initiation of oral anticoagulation after an ischemic stroke due to atrial fibrillation needs to balance the risk for recurrent ischemic events with the risk for hemorrhagic transformation. Few randomized trials have examined different strategies in this scenario. Now, investigators have performed a randomized trial comparing a strategy of early direct oral anticoagulant (DOAC) initiation or a later-initiation strategy. The early-initiation group started a DOAC within 48 hours after a mild or moderate stroke or on day 6 to 7 after a severe stroke. The later-initiation group started medication on days 3–4, 6–7, or 12–14 for a mild, moderate, or severe stroke. The primary study outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days of randomization.

The study enrolled 2013 patients (median age, 78 years; 45% women) from 15 countries. Stroke severity ranged from mild (37%), to moderate (40%), to severe (23%). The median NIH stroke scale score at the time of randomization was 3. A primary outcome event occurred in 2.9% of the early group and 4.1% of the later group. Recurrent ischemic stroke occurred in 1.4% of the early group and 2.5% of the later group within 30 days. Symptomatic intracranial hemorrhage within 30 days was uncommon in both groups (0.2%).

Comment: This trial provides important information in that early introduction of DOACs appears to provide advantages in preventing recurrent ischemic events. Symptomatic intracranial hemorrhage was reassuringly low in both groups. One caveat is that the neurologic deficit at the time of randomization was mild. In patients with moderate or severe neurologic deficits, delayed DOAC initiation could still be reasonable.

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Suellen Li, MD, is a 2023–2024 NEJM Editorial Fellow. She is a hospitalist at Massachusetts General Hospital, where she also completed her internal medicine residency.