ABU DHABI, UAE — The long-standing debate as to when to start anticoagulation in patients with an acute ischemic stroke and atrial fibrillation (AF) looks as though it’s settled.
Results of the OPTIMAS trial, the largest trial to address this question, showed that 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 (5 days and up) on its primary endpoint of new ischemic stroke, symptomatic intracerebral hemorrhage, and unclassified stroke at 30 days.
The results of the OPTIMAS trial and the meta-analysis were both presented at the 16th World Stroke Congress (WSC) 2024. The OPTIMAS trial was also simultaneously 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, PhD, University College London in England.
Presenting the meta-analysis, Signild Åsberg, MD, Uppsala University, Uppsala, Sweden, said his group’s findings “support the early start of DOACs (within 4 days) in clinical practice.”
Werring pointed out that starting anticoagulation early also had important logistical advantages.
“This means we can start anticoagulation before patients are discharged from hospital, thus ensuring that this important secondary prevention medication is always prescribed, when appropriate. That’s going to be a key benefit in the real world.”
Clinical Dilemma
Werring noted that AF accounts for 20%-30% of ischemic strokes, which tend to be more severe than other stroke types. The pivotal trials of DOACs did not include patients within 30 days of an acute ischemic stroke, creating a clinical dilemma on when to start this treatment.
“On the one hand, we wish 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 the acute infarct. Guidelines on this issue are inconsistent and have called for randomized control trials in this area,” he noted.
So far, three randomized trials on DOAC timing have been conducted, which Werring said suggested early DOAC treatment is safe. However, these trials have 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 trial included a broad population of patients with acute ischemic stroke associated with AF including these critical subgroups.
The trial, conducted at 100 hospitals in the United Kingdom, included 3648 patients with AF and acute ischemic stroke who were randomly assigned to early (≤ 4 days from stroke symptom onset) or delayed (7-14 days) anticoagulation initiation with any DOAC.
There was no restriction on stroke severity, and patients with hemorrhagic transformation were allowed, with the exception of parenchymal hematoma type 2, a rare and severe type of hemorrhagic transformation.
Approximately 35% of patients had been taking an oral anticoagulant, mainly DOACs, prior to their stroke, and about 30% had revascularization with thrombolysis, thrombectomy, or both. Nearly 900 participants (25%) had 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 systemic embolism incidence at 90 days. The initial analysis aimed to show noninferiority of early DOAC initiation, with a noninferiority margin of 2 percentage points, followed by testing for superiority.
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 fulfilled. Superiority was not achieved.
Symptomatic intracranial hemorrhage occurred in 0.6% of patients in the early DOAC initiation group vs 0.7% of those in the delayed group — a nonsignificant difference.