Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischemic Stroke Patients With Atrial Fibrillation - ELAN

May 24, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Amit Saha, MD
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Swiss National Science Foundation, Swiss Heart Foundation, Stroke Association in the United Kingdom, and Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, Japan.
Date Presented:
05/24/2023
Date Published:
05/24/2023
Original Posted Date:
05/24/2023
References

Contribution To Literature:

The ELAN trial demonstrated similar safety and efficacy with early versus later DOAC initiation in patients with nonvalvular AF and acute ischemic stroke.

Description:

The goal of the trial was to compare the therapeutic effect(s) and safety profile of early versus later initiation of direct oral anticoagulant (DOAC) therapy in patients presenting with acute ischemic stroke and nonvalvular atrial fibrillation (AF) not on therapeutic anticoagulation.

Study Design

  • Randomized
  • Open-label
  • International, multicenter

Eligible patients were randomized in a 1:1 fashion to either early (≤48 hours for minor/moderate stroke, ≤7 days for major stroke; n = 1,006) or later (≤4 days for minor stroke, ≤7 days for moderate stroke, ≤14 days for major stroke; n = 1,007) initiation of DOAC therapy. Choice of therapy was per clinician discretion at the appropriate dose of any DOAC with an indication for prevention of stroke and systemic embolism.

  • Total number screened: 36,643
  • Total number of enrollees: 2,013
  • Duration of follow-up: 90 days
  • Median patient age: 77 years
  • Percentage female: 45%
  • Percentage with prior ischemic stroke: 13.3%
  • Median CHA2DS2-VASc score: 5
  • Baseline aspirin use: 50%

Inclusion criteria:

  • Age ≥18 years
  • Acute ischemic stroke confirmed by computed tomography (CT) or magnetic resonance imaging or with normal CT and focal neurologic deficit ≥24 hours suspected due to ischemic stroke
  • Permanent, persistent, or paroxysmal AF, previously known or diagnosed during admission
  • Not on therapeutic anticoagulation at time of stroke

Exclusion criteria:

  • Mechanical valve prosthesis
  • Moderate to severe rheumatic mitral stenosis
  • Other indication for anticoagulation
  • Contraindication to DOAC
  • Baseline anticoagulation (international normalized ratio [INR] ≥1.7, anti-IIa ≥100 ng/mL, aPTT >1.5x upper limit of normal, or anti-Xa ≥0.7 U/mL)
  • Serious bleeding in the last 6 months or high risk of bleeding (e.g., platelet count <100,000 mm3, hemoglobin <10 g/dL, INR ≥1.7)
  • Severe renal impairment (creatinine clearance <15 mL/min for rivaroxaban, apixaban, and edoxaban and <30 mL/min for dabigatran)
  • Intracranial parenchymal hemorrhage

Other salient features/characteristics:

  • Pre-randomization stroke treatment: systemic thrombolysis (38.9%), endovascular revascularization (22.2%)
  • Stroke size and distribution:
  • Minor, ≤1.5 cm: 37.4%
  • Moderate, cortical superficial branch of anterior, middle, or posterior cerebral artery: 39.5%
  • Major, larger cerebral artery infarct or brainstem/cerebellar infarct ≥1.5 cm: 23.1%

Principal Findings:

The primary outcome, a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days of randomization for early vs. later anticoagulation, was: 2.9% vs. 4.1% (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.44-1.14).

Secondary outcomes for early vs. later anticoagulation:

  • Recurrent ischemic stroke at 30 days: 1.4% vs. 2.5% (OR 0.57, 95% CI 0.29-1.07)
  • Systemic embolism at 30 days: 0.4% vs. 0.9% (OR 0.48, 95% CI 0.14-1.42)
  • Major extracranial bleeding at 30 days: 0.3% vs. 0.5% (OR 0.63, 95% CI 0.15-2.38)
  • Symptomatic intracranial hemorrhage at 30 days: 0.2% vs. 0.2% (OR 1.02, 95% CI 0.16-6.59)
  • Modified Rankin scale score ≤2 at 30 days: 62.6% vs. 62.6% (OR 0.93, 95% CI 0.79-1.09)
  • Primary outcome at 90 days: 3.7% vs. 5.6% (OR 0.65, 95% CI 0.42-0.99)

Interpretation:

Among patients with acute ischemic stroke with concomitant nonvalvular AF who were not on therapeutic anticoagulation at the time of stroke, early versus later DOAC initiation resulted in similar rates of the composite primary outcome at 30 days. Individual components of the primary outcome as well as per-protocol and prespecified subgroup analyses were likewise similar between the early and later cohorts. There was a benefit noted at 90 days with early initiation, but it was not prespecified or adjusted for multiple testing, and can therefore be considered hypothesis generating.

Current guidelines from the European Stroke Organization and the American Heart Association/American Stroke Association recommend delaying anticoagulation after ischemic stroke for ≥48 hours and up to 14 days depending on infarct severity and risk of hemorrhagic conversion. The TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) trial demonstrated noninferiority with DOAC initiation at ≤4 days post-stroke, a time point also being studied in the ongoing OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke) trial. ELAN shortens this to ≤48 hours from stroke onset and provides further data that may support earlier initiation of DOAC therapy for nonvalvular AF after acute ischemic stroke if desired or indicated.

References:

Fischer U, Koga M, Strbian D, et al., on behalf of the ELAN Investigators. Early Versus Later Anticoagulation for Stroke With Atrial Fibrillation. N Engl J Med 2023;May 24:[Epub ahead of print].

Presented at the 9th European Stroke Organization Conference, Munich, Germany, May 24, 2023.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Embolism, Hemorrhage, Intracranial Hemorrhage, Traumatic, Infarction, Ischemic Stroke, Stroke, Thrombolytic Therapy, Secondary Prevention, Vascular Diseases


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