Early versus delayed DOAC treatment in acute ischemic stroke with AF

In OPTIMAS among patients with acute ischemic stroke associated with AF, early DOAC initiation (≤4 days) was noninferior to delayed initiation (7–14 days) for the composite outcome, including ischemic stroke and intracranial hemorrhage, at 90 days.

This summary is based on the publication of Werring DJ, Dehbi HM, Ahmed N, et al. - Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial. Lancet. 2024 Oct 23:S0140-6736(24)02197-4 [Online ahead of print]. doi: 10.1016/S0140-6736(24)02197-4

Introduction and methods

Background

As large RCTs of DOAC treatment in AF excluded patients with acute ischemic stroke [1,2], the optimal timing of anticoagulation soon after acute ischemic stroke associated with AF is unclear. Some clinical guidelines recommend early initiation, while others advise delaying anticoagulation in certain patient groups [3,4]. More recent randomized and observational studies suggested that early anticoagulation reduces the risk of ischemic stroke with no increase in intracranial hemorrhage but could not conclusively demonstrate the safety of early anticoagulation and whether it is superior to delayed initiation [5,6].

Aim of the study

The study aim was to investigate the efficacy and safety of early versus delayed initiation of DOACs in patients with acute ischemic stroke associated with AF.

Methods

The OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischaemic Stroke) trial is an ongoing multicenter, open-label, blinded-endpoint, parallel-group, phase 4 RCT performed at 100 UK hospitals. In total, 3648 adults with AF and a clinical diagnosis of acute ischemic stroke whose treating physician was uncertain of the optimal timing of DOAC initiation were randomized to early (i.e., ≤4 days after onset of stroke symptoms) or delayed (i.e., 7–14 days after stroke symptom onset) initiation of DOAC therapy, stratified by stroke severity at randomization. Exclusion criteria included coagulopathy and a contraindication to DOAC use. Of the randomized participants, 27 were excluded because of ineligibility after randomization or withdrawal of consent. The authors used a hierarchical gatekeeper approach by first testing for noninferiority, followed by testing for superiority.

Outcomes

The primary endpoint was a composite outcome of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke syndromes, or systemic embolism at 90 days in the modified intention-to-treat population (n=3621). Secondary efficacy endpoints included the incidence of the individual components of the primary endpoint at 90 days and all-cause mortality at 90 days. Safety endpoints included symptomatic intracranial hemorrhage, major extracranial bleeding, clinically relevant nonmajor extracranial bleeding, and all major bleeding events at 90 days.

Main results

Efficacy

• The primary endpoint occurred in 59 of 1814 patients (3.3%) in the early DOAC initiation group and 59 of 1807 participants (3.3%) in the delayed DOAC initiation group (adjusted risk difference: 0.000; 95%CI: –0.011 to 0.012). The upper limit of the 95%CI (1.2 percentage points) was less than the noninferiority margin of 2 percentage points (P for noninferiority=0.0003). Superiority was not identified (P for superiority=0.96).

• The time-to-event analysis for the primary endpoint showed an HR of 0.98 (95%CI: 0.68–1.41; log-rank P=0.93).

• For the secondary efficacy endpoints, no differences were observed between the early and late DOAC initiation groups (all P>0.05).

• Subgroup analysis showed generally consistent results across prespecified subgroups stratified by age, sex, clinical stroke severity, reperfusion therapy, or previous anticoagulation treatment (all P>0.05).

Safety

• Symptomatic intracranial hemorrhage occurred in 11 participants (0.6%) randomized to early DOAC initiation, compared with 12 (0.7%) in the delayed DOAC initiation group (adjusted risk difference: 0.001; 95%CI: –0.004 to 0.006; P=0.78).

• The rates of the other safety endpoints also did not differ between the treatment groups (all P>0.05).

Conclusion

In the OPTIMAS trial among patients with acute ischemic stroke associated with AF, early DOAC initiation (≤4 days after stroke symptom onset) was noninferior to delayed initiation (7–14 days) for the composite outcome of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Few patients (0.6%) had a symptomatic intracranial hemorrhage, and this safety endpoint was not influenced by the timing of anticoagulation initiation. The authors believe their “findings do not support delaying initiation of a DOAC because of concerns about the risk of early intracranial hemorrhage, particularly in people with moderate-to-severe stroke, as guidelines recommend.”

Find this article online at Lancet.

References

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