Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study

Abstract

Background: There are no evidence-based recommendations on the optimal time point to initiate non–vitamin K antagonist oral anticoagulants (NOACs) after acute ischemic stroke in patients with atrial fibrillation. We aimed to investigate the efficacy and safety of early versus delayed initiation of NOAC in these patients. Methods: TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) was a registry-based, randomized, noninferiority, open-label, blinded end-point study at 34 stroke units using the Swedish Stroke Register for enrollment and follow-up. Within 72 hours from stroke onset, patients were randomized to early (≤4 days) or delayed (5–10 days) NOAC initiation, with choice of NOAC at the investigators’ discretion. The primary outcome was the composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days. The prespecified noninferiority margin was 3%. Secondary outcomes included the individual components of the primary outcome. Results: Between April 2, 2017, and December 30, 2020, 888 patients were randomized to either early (n=450) or delayed (n=438) initiation of NOAC. No patient was lost to 90-day follow-up. Mean age was 78.3 years (SD, 9.9 years); 46.2% were women; 49.1% had previously known atrial fibrillation; and 17.5% prior stroke. The primary outcome occurred in 31 patients (6.89%) assigned to early initiation and in 38 patients (8.68%) assigned to delayed NOAC initiation (absolute risk difference, −1.79% [95% CI, −5.31% to 1.74%]; P noninferiority =0.004). Ischemic stroke rates were 3.11% and 4.57% (risk difference, −1.46% [95% CI, −3.98% to 1.07%]) and all-cause mortality rates were 4.67% and 5.71% (risk difference, −1.04% [95% CI, −3.96% to 1.88%]) in the early and delayed groups, respectively. No patient in either group experienced symptomatic intracerebral hemorrhage. Conclusions: Early initiation was noninferior to delayed start of NOAC after acute ischemic stroke in patients with atrial fibrillation. Numerically lower rates of ischemic stroke and death and the absence of symptomatic intracerebral hemorrhages implied that the early start of NOAC was safe and should be considered for acute secondary stroke prevention in patients eligible for NOAC treatment. Registration: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT02961348.

Risk of hemorrhagic transformation with early use of direct oral anticoagulants after acute ischemic stroke: A pooled analysis of prospective studies and randomized trials

“…In the TIMING trial, 33 patients with AF-related stroke randomized within 72 h to early (⩽4 days) DOAC was noninferior to delayed (5–10 days) DOAC, with 1.79% absolute risk difference of composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days. Symptomatic HT rates in the TIMING trial and our study were both zero.…”

Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study

“…22 The recently published Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation ( TIMING ) study was the first RCT on this topic and showed that early initiation of anticoagulation was noninferior to delayed initiation concerning a composite endpoint of ischemic stroke, death, and ICH. 2 The results of other currently ongoing RCTs, that is, ELAN, 5 OPTIMAS, 4 and START, 3 are eagerly awaited. Real-world evidence reflecting the initiation or resumption of anticoagulants in daily practice is crucial as a complement to data derived from RCTs.…”

“…Delaying the initiation of anticoagulation, however, may enhance the risk of recurrent ischemic events. 1 With one exception, 2 results from randomized controlled trials (RCTs) on the timing of anticoagulation [3][4][5] are not yet available and guidelines are currently based on expert opinion. [6][7][8] Surveys among stroke practitioners on timing of anticoagulation following AIS or TIA have shown no consensus in decision-making.…”

Early Diagnosis of Atrial Fibrillation and Stroke Incidence in Primary Care: Translating Measurements into Actions—A Retrospective Cohort Study

“…Although the clinical benefits of early anticoagulation are widely recognized and safe, 26.9% did not achieve appropriate control objectives [ 18 , 38 , 39 , 40 , 41 , 42 , 43 ]. This fact increases the impact of the unknown AF ( Table S1 ).…”