Exploring the OPTIMAS Trial: A New Perspective on Anticoagulation Timing for Acute Ischemic Stroke Patients with Atrial Fibrillation

For years, physicians treating patients with atrial fibrillation (AF) who suffer from acute ischemic strokes have faced a dilemma: balancing the risk of hemorrhage with the need to prevent further strokes. Current guidelines typically advise delaying oral anticoagulation for up to two weeks following a stroke. However, the recently published OPTIMAS trial, a large multicenter study, challenges this long-standing approach by suggesting that starting direct oral anticoagulants (DOACs) within four days may be as safe and effective as waiting.¹

The OPTIMAS trial sought to explore whether initiating DOACs within four days of an acute ischemic stroke among patients with AF might reduce the risk of recurrent ischemic strokes without significantly raising hemorrhage risk. With a sample size of 3,621 patients and a rigorously controlled design, the trial aimed to determine if early initiation of anticoagulation is indeed non-inferior to the current guideline-supported practice of delaying DOAC initiation by one to two weeks. Conducted at 96 sites, the OPTIMAS trial randomly assigned participants to either an early DOAC initiation group (within four days of stroke onset) or a delayed group (7–14 days post-stroke). The study’s primary outcome was a composite measure of recurrent ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days following initiation. Additionally, the trial evaluated secondary outcomes, including all-cause mortality, recurrent ischemic events, and major extracranial bleeding events.

The findings from OPTIMAS are both groundbreaking and clinically significant. The trial demonstrated that early initiation of DOACs is non-inferior to delayed initiation when measured against the composite primary outcome. In other words, starting DOAC therapy within four days did not increase the overall risk of recurrent stroke, intracranial hemorrhage, or systemic embolism compared to starting one to two weeks later. One of the most reassuring results from OPTIMAS was the low rate of symptomatic intracranial hemorrhage in both groups, a factor that often contributes to caution in clinical practice. Specifically, only 23 out of 3,621 participants (0.6%) experienced symptomatic intracranial hemorrhage, with no significant difference observed between the early and delayed initiation groups. This finding suggests that, in the absence of contraindications, early anticoagulation initiation may be a safe approach for a broad range of stroke patients. Secondary analyses from OPTIMAS showed consistency across patient subgroups, including those with varying stroke severities, those with or without a prior history of anticoagulant use, and those who received reperfusion therapies. This homogeneity in safety and efficacy signals that early DOAC initiation may be viable across a diverse patient population, expanding the applicability of the results to clinical practice.

The OPTIMAS findings challenge the traditional caution surrounding early anticoagulation post-stroke. Current practice guidelines often recommend waiting up to two weeks before starting DOAC therapy, especially in patients with moderate-to-severe stroke, due to concerns about intracranial hemorrhage. However, by showing non-inferiority of early initiation in preventing recurrent ischemic strokes without increasing the risk of bleeding, OPTIMAS questions whether this delay is necessary. Immediate clinical implications include the potential for early DOAC initiation to become a standard approach for secondary stroke prevention in AF patients. Early initiation could simplify hospital discharge planning, reducing the need for interim antiplatelet bridging therapies (e.g., aspirin) and ensuring that patients begin anticoagulation therapy before leaving the hospital. This streamlined approach may improve adherence to secondary prevention protocols and, ultimately, patient outcomes.

Despite its strengths, the OPTIMAS trial does have limitations. The study excluded patients starting anticoagulation between days 4 and 7 post-stroke, creating a time gap between the early and delayed groups that may leave room for additional exploration. Additionally, the trial included only a small number of patients with very severe strokes or extensive hemorrhagic transformations, leaving some uncertainty about the safety of early DOAC use in these high-risk populations. Another point of consideration is that the trial had relatively few cases of symptomatic intracranial hemorrhage (23 events), which may limit the statistical power for assessing this risk. Therefore, while the findings are promising, more data—particularly in high-risk subgroups—will help further refine and validate the safety profile of early DOAC initiation. Future studies will likely focus on determining the optimal timing of DOAC initiation in the first week post-stroke. Planned meta-analyses, such as the CATALYST collaboration, aim to pool individual participant data from the trials OPTIMAS, TIMING, START, and ELAN to provide even more comprehensive insights into the nuanced relationships between DOAC timing, stroke severity, and risk of complications.

In conclusion, OPTIMAS has opened a new chapter in stroke management by challenging the status quo. While more research is needed to confirm these findings in specific patient subgroups, the trial underscores the potential benefits of early DOAC initiation, moving clinical practice toward more timely, efficient, and patient-centered stroke care.

---

References

1. Werring DJ, Dehbi H-M, 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. The Lancet. doi: 10.1016/S0140-6736(24)02197-4.

---