Early vs. Delayed NOAC Therapy After Ischemic Stroke in Atrial Fibrillation

Quick Takes

  • Patients suffering ischemic stroke associated with AF had noninferior outcomes with early (≤4 days) vs. delayed (5-10 days) anticoagulation initiation.
  • Early initiation of anticoagulation had numerically lower rates of ischemic stroke and all-cause mortality than delayed anticoagulation initiation.
  • Among almost 900 patients with AF-associated ischemic stroke, none experienced an intracranial hemorrhage with NOAC initiation.

Study Questions:

What is the efficacy and safety of early versus delayed non–vitamin K antagonist oral anticoagulant (NOAC) therapy in patients with acute ischemic stroke associated with atrial fibrillation (AF)?


The TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) study is a registry-based, randomized, noninferiority, open-label, blinded endpoint adjudicated study. Patients were identified from the Swedish Stroke Register for enrollment and follow-up at 34 centers in Sweden. Within 72 hours of stroke onset, patients were randomized to receive NOAC therapy early (≤4 days) or delayed (5-10 days), with the choice of NOAC at the investigator’s discretion. The primary endpoint was a composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, and all-cause mortality assessed through 90 days. The prespecified noninferiority margin was 3%.


Between April 2017–December 2020, 888 patients were randomized to either early (n = 450) or delayed (n = 438) NOAC therapy. There was no loss to follow-up over the initial 90-day follow-up period. Mean age was 78.3 years (standard deviation, 9.9 years) and 46.2% were women; 49.1% of patients had known prior AF and 17.5% had a history of prior stroke. The primary composite outcome occurred in 31 patients (6.9%) in the early NOAC therapy group versus 38 patients (8.7%) in the delayed NOAC initiation group (absolute risk difference, -1.8%; 95% confidence interval [CI], -5.3% to 1.7%; p for noninferiority = 0.004). Ischemic stroke rates were 3.1% and 4.6% (risk difference, -1.5%; 95% CI, -4.0% to 1.1%) and all-cause mortality rates were 4.7% and 5.7% (risk difference, -1.0%; 95% CI, -4.0% to 1.9%) in the early and delayed groups, respectively. No patients in either group experienced a symptomatic intracerebral hemorrhage.


The authors concluded that early initiation of NOAC therapy was noninferior to a delayed start for patients with acute ischemic stroke and AF.


AF is a leading cause of ischemic stroke. When detected, guidelines recommend prompt initiation of oral anticoagulation therapy to help prevent future thromboembolic events. However, given the risk of hemorrhagic conversion shortly after an ischemic stroke, the optimal timing of oral anticoagulation initiation has not been identified through prospective, randomized trials. The TIMING study used a registry-based randomized approach to enroll almost 900 patients with an early (≤4 days) or delayed (5-10 days) initiation of NOAC (also known as direct oral anticoagulant [DOAC]) therapy. While the primary composite endpoint showed noninferiority between the two initiation timepoints, there was a numerically (but not statistically) significant reduction in both ischemic stroke and all-cause mortality with early anticoagulant initiation.

Importantly, there were no intracranial hemorrhage events in the first 90 days, providing a degree of safety reassurance. This finding differs from older studies conducted primarily using vitamin K antagonists, which are known to have higher rates of intracranial hemorrhage than NOAC therapy. Patients who present with ischemic stroke associated with AF benefit from anticoagulation initiation, in accordance with guideline recommendations. The TIMING study tells us that anticoagulation should be initiated within the first 4 days after ischemic stroke presentation.

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

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Cerebral Hemorrhage, Geriatrics, Intracranial Hemorrhages, Ischemic Stroke, Secondary Prevention, Stroke, Thromboembolism, Vascular Diseases, Vitamin K

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