Corey Diamond, PharmD
The optimum time to resume or initiate direct oral anticoagulants (DOAC) after an acute ischemic stroke in patients with AFib remains unclear. Starting too soon may risk bleeding complications, while starting too late may risk a recurrent stroke. Currently, guidance is derived solely from expert consensus rather than from clinical data. However, findings from a new study published in the June 29, 2023, issue of NEJM by Fischer and colleagues suggested that it may be safe to resume DOACs earlier rather than later for select patients with AFib after an acute ischemic stroke.
Comparing timing
The ELAN trial was a randomized controlled trial that included data from over 2,000 patients who had experienced an acute ischemic stroke and AFib. Patients in the comparator groups received either early anticoagulation with a DOAC—defined as 48 hours after a minor or moderate stroke—or late DOAC anticoagulation, which was defined at day 6 or 7 after a major stroke.
An additional comparator group received DOAC anticoagulation that was consistent with the expert consensus opinion “1-3-6-12–day rule” from the European Heart Rhythm Association’s (EHRA) 2013 guidelines (i.e., receiving DOAC therapy on day 1, 3, 6, or 12 after a transient ischemic attack or after a minor, moderate, or severe stroke, respectively).
The study’s 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. Additionally, secondary outcomes included the individual components of the composite outcome within 30 and 90 days after randomization.
The study found no significant difference between the treatment outcomes of the early DOAC treatment group compared to the late DOAC treatment group in the primary composite outcome or its individual component outcomes.
Notably, findings revealed a trend toward a slight benefit of early DOAC initiation for both the composite primary outcomes and the rates of recurrent stroke at 30 and 90 days. A caveat to these results, however, was that the trial was not designed to test for superiority or noninferiority.
Practice comparisons
Current clinical practice entails delaying the initiation or resumption of DOAC therapy for patients with AFib following an acute ischemic stroke.
This recommendation comes from multiple guidelines that are based on expert opinion. For instance, EHRA recommends delayed DOAC initiation based on their “1-3-6-12–day rule.” Conversely, the American Heart Association makes a general recommendation of delaying DOAC initiation to 14 days after an ischemic stroke if there is a “high risk” of hemorrhagic transformation, versus 2 to 14 days if there is a “low risk.”
Two other notable studies have investigated the timing of DOAC initiation after a cardioembolic stroke in AFib. Results of the TIMING trial, published in Circulation in 2022, suggested noninferiority of early DOAC therapy following ischemic stroke in addition to demonstrating no cases of symptomatic intracranial hemorrhage.
Similarly, findings from a cohort study using a “1-2-3-4–day rule” published in Stroke in 2022 found data supporting earlier initiation of DOACs for AFib following an ischemic stroke.
Regardless, clear outcome data remain elusive.
Considerations for clinicians
According to the study authors, the ELAN trial was “designed to estimate the treatment effects of early initiation and later initiation of DOACs and the degree of precision of this estimate.” However, no definitive conclusions regarding the safety and efficacy of early DOAC treatment after a cardioembolic ischemic stroke can be made regarding the results.
“No statistical hypothesis was tested for superiority or noninferiority, and the results are intended to provide qualitative data that may be of use to clinicians,” the authors stated in the article.
They continued, “the components of the primary outcome that are probably of most interest to clinicians are recurrent ischemic strokes, systemic embolism, and symptomatic intracranial hemorrhage.
“By day 30, recurrent ischemic strokes had occurred in 1.4% of the participants in the early-treatment group and 2.5% of the participants in the later-treatment group; systemic embolism had occurred in 0.4% and 0.9%, respectively; and the incidence of symptomatic intracranial hemorrhage was low, approximately 0.2% in both treatment groups.” ■