Prompt DOAC therapy after stroke safe for AF patients

Initiating direct oral anticoagulants (DOACs) within 4 days after an ischaemic stroke in patients with atrial fibrillation (AF) is safe and yields similar outcomes as delayed initiation, as shown in the phase 4 OPTIMAS trial.

In a modified intention-to-treat analysis, the primary outcome of a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days did not differ by the timing of DOAC initiation. The primary composite outcome occurred in 3.3 percent of patients in the early arm (≤4 days) vs 3.3 percent in the delayed arm (7–14 days), with the noninferiority criterion met (adjusted risk difference [RD], 0.000, 95 percent confidence interval [CI], –0.011 to 0.012; p=0.0003 for noninferiority). [Lancet 2024;404:1731-1741]

Fewer than 1 percent of patients overall had symptomatic intracranial haemorrhage, without significant difference between the early and the delayed arms (0.6 percent vs 0.7 percent; adjusted RD, 0.001, –0.004 to 0.006; p=0.78).

Additionally, the effect of early DOAC initiation was consistent across subgroups defined by stroke severity (NIHSS score 0–10 vs NIHSS score >10), reperfusion treatment (intravenous thrombolysis, mechanical thrombectomy, or both), and previous anticoagulation. This indicates that starting DOAC early does not carry a heightened risk of symptomatic intracranial haemorrhage in these patient groups, according to the investigators.

“Our findings are consistent with other trials of early DOAC initiation, including the TIMING, ELAN, and START trials, and taken together with the results of these trials, provide reassurance for the safety of early anticoagulation with a DOAC and do not support the common current guideline-supported practice of delaying oral anticoagulation … for up to 14 days after moderate-to-severe acute stroke,” they said. [Circulation 2022;146:1056-1066; N Engl J Med 2023;388:2411-2421; Int J Stroke 2019;14:977-982]

“Early DOAC initiation also has the potential practical advantage of improving the proportion of patients who start secondary prevention treatment before hospital discharge, although this is not shown by our data and should be investigated in further studies,” they added.

OPTIMAS was a multicentre, open-label, blinded-endpoint, parallel-group randomized controlled trial conducted at 100 hospitals in the UK. The modified intention-to-treat population comprised 3,621 adult AF patients (mean age 78.5 years, 54.7 percent male, 93.7 percent White) who had sustained an acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation. These patients were randomly allocated to the early arm (n=1,814) or the delayed arm (n=1,807).

The investigators emphasized that the population is likely representative of those with acute stroke and AF, including those with severe stroke. In OPTIMAS, the median NIHSS score on admission of the patients was 5, which is higher than the score of 4 reported in a large, multicentre, observational study of patients with ischaemic stroke associated with AF treated with DOACs. Furthermore, the proportion of patients taking an anticoagulant at the time of their stroke was higher than in previous trials (DOACS, 32.2 percent; vitamin K antagonist, 3.1 percent), providing important evidence on the safety of restarting a DOAC within the first 4 days in this patient group. [Ann Neurol 2019;85:823-834]

“The larger size of OPTIMAS than previous trials has allowed more precise and reliable estimates of the influence of DOAC timing on recurrent ischaemic stroke or intracranial haemorrhage. Our broad eligibility criteria were intended to give a representative study sample and provide results that are readily applicable to clinical practice,” the investigators said.