Abu Dhabi, United Arab Emirates — The long-standing debate about when to start anticoagulation in patients with acute ischemic stroke and atrial fibrillation (AF) appears to have been resolved.

The results of the OPTIMAS trial, the largest trial to address this question, showed that initiation of a direct oral anticoagulant (DOAC) within 4 days after ischemic stroke associated with AF was noninferior to delayed initiation (7–14 days) for composite outcome of ischemic stroke, intracranial hemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Importantly, early DOAC initiation was safe, with a low rate of symptomatic hemorrhage regardless of stroke severity.

In addition, a new meta-analysis, known as CATALYST, which included all four randomized trials now available on this issue, showed a clear benefit of earlier initiation (within 4 days) versus later ( from 5 days and more) in terms of its main evaluation objective. New ischemic stroke, symptomatic intracerebral hemorrhage, and unclassified stroke at 30 days.

The results of the OPTIMAS study and the meta-analysis were both presented on October 24 at 16th World Stroke Congress (WSC) 2024. The OPTIMAS trial was also simultaneous published online in The Lancet.

“Our findings do not support the guideline-recommended practice of delaying DOAC initiation after ischemic stroke with AF, regardless of clinical stroke severity, reperfusion, or prior anticoagulation,” said OPTIMAS investigator David Werring, MD, PhD. University College London, London, England.

Presenting the meta-analysis, Signild Åsberg, MD, Uppsala University, Uppsala, Sweden, said her group’s findings “support early initiation of DOACs (within 4 days) in clinical practice.”

Werring pointed out that early initiation of anticoagulation also had important logistical advantages.

“This means we can start anticoagulation before patients are discharged from hospital, ensuring that this important secondary prevention drug is always prescribed when appropriate. This will be a key benefit in the real world.”

Clinical dilemma

Werring noted that AF accounts for 20% to 30% of ischemic strokes, which tend to be more severe than other types of stroke. The pivotal studies of AOD did not include patients within 30 days of an acute ischemic stroke, creating a clinical dilemma about when to start this treatment.

“On the one hand, we want to start anticoagulation early to reduce early recurrence of ischemic stroke. But on the other hand, there are concerns that if we start anticoagulation early, it could cause intracranial bleeding, including hemorrhagic transformation of acute infarction. Guidelines on this issue are inconsistent and have called for randomized control trials in this area,” he noted.

So far, there have been three randomized trials of DOAC timing, which Werring said early DOAC treatment is safe. However, these studies provided limited data on moderate-to-severe stroke, patients with hemorrhagic transformation, or those already taking oral anticoagulants—subgroups in which there are particular concerns about early oral anticoagulation.

The OPTIMAS study included a broad population of patients with acute ischemic stroke associated with AF, including these critical subgroups.

The study, conducted at 100 UK hospitals, included 3648 patients with AF and acute ischemic stroke who were randomized to early (≤ 4 days from stroke symptom onset) or delayed (7–14 days) with any AOD.

There was no stroke severity restriction, and patients with hemorrhagic transformation were allowed, except for type 2 parenchymal hematoma, a rare and severe type of hemorrhagic transformation.

About 35% of patients had taken an oral anticoagulant, mainly DAO, before stroke, and about 30% had revascularization with thrombolysis, thrombectomy, or both. Almost 900 participants (25%) had a moderate to severe stroke (National Institutes of Health Stroke Scale (NIHSS) score ≥ 11).

The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or incidence of systemic embolism at 90 days. The initial analysis aimed to show non-inferiority of early DOAC initiation with a non-inferiority margin of 2 percentage points, followed by superiority testing.

Results showed that the primary outcome occurred in 3.3% of both groups (adjusted risk difference, 0.000; 95% CI, −0.011 to 0.012), with noninferiority criteria met. Superiority was not achieved.

Symptomatic intracranial hemorrhage occurred in 0.6% of patients in the early DOAC initiation group versus 0.7% of those in the delayed group—a nonsignificant difference.

Applicable to real-world practice

A time-to-event analysis of the primary outcome showed that there were fewer outcomes in the first 30 days in the early DOAC initiation group, but the curves converged thereafter.

Subgroup analysis showed consistent results across the entire study population, with no change in the effect of early DOAC initiation by stroke severity, reperfusion treatment, or prior anticoagulation.

Werring said strengths of the OPTIMAS trial included a large sample size, a large population with the possibility of generalization to real-world practice, and the inclusion of patients at higher bleeding risk than those included in previous studies.

During the discussion, it was noted that the study included few (about 3%) patients — about 3% — with very severe stroke (NIHSS score > 21), questioning whether the results could be applied to this group.

Werring noted that there was no evidence of heterogeneity, and if anything, patients with more severe strokes may have benefited slightly from earlier DOAC initiation. “So my feeling is that these results probably generalize to more severe patients,” he said.

One “Comment” accompanying The Lancet Publishing the OPTIMAS trial, Else Charlotte Sandset, MD, University of Oslo, Oslo, Norway, and Diana Aguiar de Sousa, MD, Central Lisbon University Hospital Center, Lisbon, Portugal, noted that “the growing body of evidence strongly supports the message that early initiation of anticoagulation for ischemic stroke patients is safe. The consistent absence of heterogeneity in safety outcomes suggests that the risk of symptomatic intracranial hemorrhage is not a major concern, even in patients with large infarcts.

Regardless of the size of the treatment effect, early initiation of anticoagulation makes sense when it can be done safely, as it helps prevent recurrent ischemic strokes and other embolic events. Early intervention reduces the risk of embolization, especially in high-risk patients, and allows secondary prevention measures to be started while patients are still hospitalized, they added.

CATALYST Findings

The CATALYST meta-analysis included four studies, namely, TIMING, ELAN, OPTIMAS and START, of early versus late DOAC administration in a total of 5411 patients with acute ischemic stroke and AF. In this meta-analysis, early was defined as within 4 days of stroke and later as 5 days or more.

The primary outcome was a composite of ischemic stroke, symptomatic intracerebral hemorrhage, or unclassified stroke at 30 days. This was significantly reduced in the early group (2.12%) versus 3.02% in the later group, giving an odds ratio of 0.70 (95% CI, 0.50–0.98; p =.04).

Results were consistent across subgroups, all suggesting an advantage for early DOAC.

Further analysis showed a clear benefit of early DOAC initiation in ischemic stroke, the curves separating early.

The rate of symptomatic intracerebral hemorrhage was low in both groups (0.45% in the early group and 0.40% in the later group), as was extracranial hemorrhage (0.45% vs. 0.55%).

At 90 days, there were still lower event rates in the early group than in the late group, but the difference was no longer statistically significant.

“Changing Practice” results.

Commenting on both studies for Medscape Medical Newschair of the WSC session where the results of both the OPTIMAS study and the meta-analysis were presented, Craig Anderson, MD, George Institute for Global Health, Sydney, Australia, described these latest results as “practice changing.”

“When to start anticoagulation in patients with acute ischemic stroke with AF has long been uncertain. The dogma has always been that we should wait. Over the years, we’ve become a little more confident, but now we have good data from randomized trials showing that early initiation is safe, with meta-analysis showing benefit,” he said.

“These new data from OPTIMAS will reassure clinicians that there is no excessive harm and, more importantly, no excessive harm in all patient groups. And the meta-analysis clearly showed an initial benefit of early anticoagulation. This is a very convincing result,” he added.

Anderson cautioned that there may still be concerns about starting AOD early in some groups, including Asian populations who have a higher risk of bleeding (those studies included predominantly white patients) and people who are older or frail, who they may have extensive small vessel disease.

During the discussion, several questions focused on the lack of imaging data available on patients in the studies. Anderson said the imaging data would help reassure doctors about the safety of early anticoagulation in patients with large heart attacks.

“Stroke clinicians make decisions based on the patient and the brain, and right now we only have information about the patient. We don’t have information about the brain – that comes from imaging.”

However, he believes this new data will lead to a change in practice. “But maybe it won’t be as dramatic as we would hope because I think some clinicians may still be hesitant to apply these results to patients at high risk of bleeding. With imaging data from studies that may change.”

The OPTIMAS study was funded by University College London and the British Heart Foundation. Werring reported consulting fees from Novo Nordisk, the National Institute for Health and Care Excellence, and Alnylam; payments or speaker fees from Novo Nordisk, Bayer and AstraZeneca/Alexion; participation in a data safety monitoring board for the OXHARP study; and participation as steering committee chair for the MACE-ICH and PLINTH trials. Åsberg has received institutional research grants and lecture fees for his institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Institut Produits Synthése. Sandset and de Sousa were both members of the steering committee of the ELAN process. Anderson reported funding from Penumbra and Takeda China.