By Alan Z. Segal, MD
In ischemic stroke associated with atrial fibrillation, early restart of anticoagulation with apixaban one to three days after ischemic stroke, compared to late restart (seven to 14 days), there were no significant differences between the groups in the primary outcome — a composite endpoint including recurrent ischemic stroke, symptomatic intracranial hemorrhage, and systemic embolism.
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;404(10464):1731-1741.
As the population ages and atherosclerotic disease is aggressively treated, the role of atrial fibrillation (AF) as a risk factor for ischemic stroke has become even more prominent. Although the optimal management of stroke subtypes has been the subject of ongoing research, such as comparing dual vs. mono antiplatelet therapy, it has been long-established that patients with strokes caused by AF should be treated with anticoagulation (AC). However, it has been a matter of debate as to exactly when this AC should be initiated. The goal is to balance the risk of recurrent ischemic events with that of hemorrhagic transformation, especially in large hemispheric events prone to bleeding.
Historically, warfarin was the primary agent used for AC. Typically, it would take many days of warfarin dosing to load up to therapeutic levels. With warfarin, initiation of AC was imprecise and, by necessity, could not be achieved immediately. With the introduction of direct oral anticoagulant drugs (DOACs), AC could be accomplished timely and more safely than with warfarin. Typically, initiation of DOACs has been done according to a “1-3-6-12” rule. It is recommended to wait one day after a transient ischemic attack (TIA), three days after a mild stroke, six days after a moderate stroke, and 12 days after a large stroke.
Generally, the “size” of a stroke was determined by its geographic extent rather than by clinical severity as measured by the National Institutes of Health Stroke Scale (NIHSS). Depending on the location, small strokes, such as in the internal capsule, could produce high NIHSS scores, but would be safe for AC. Conversely, larger strokes, such as in the cerebral cortex, might produce milder clinical deficits, but be more prone to hemorrhage.
The current trial (OPTIMAS) builds on three recent similar trials: Early versus Late AC for Stroke with AF (ELAN), Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With AF (TIMING), and Optimal Time Delay to Initiate AC After Ischemic Stroke in AF (START).1-4 Review of the strengths and weaknesses of each of these investigations (study size, crossover rates, lack of follow-up) is beyond the scope of this review. More importantly, a collaborative analysis of individual data from all these studies, in the form of a pooled meta-analysis, is soon to be published.
Specifically, in OPTIMAS, patients were started on a DOAC early (≤ 4 days) after stroke (n = 1,814) or were started late (seven to 14 days) after stroke (n = 1,807). On average, early DOAC initiation occurred after 3.1 days, and late initiation occurred after 8.3 days. Very few “late” patients were enrolled beyond 10 days. The primary outcome variable was a composite endpoint including recurrent ischemic stroke, symptomatic intracranial hemorrhage, and systemic embolism. This endpoint occurred in 59 (3.3%) patients in the early group compared with an exactly equal 3.3% in the delayed group. This “difference” was not significant (confidence interval [CI], -0.011 to 0.012), but met the study’s strict ± 2% margin for noninferiority (P = 0.0003).
Similarly equal, the risk comparing early to late DOAC administration was comparable for recurrent ischemic stroke (2.4% vs. 2.3%) and for symptomatic intracerebral hemorrhage (ICH) (0.6% vs. 0.7%). The vast majority of strokes in OPTIMAS were on the milder side, equally balanced between the early and late therapy groups. Patients with an NIHSS score of 0-4 comprised 41% of the population and patients with an NIHSS score of 5-10 comprised 34%. Patients with an NIHSS score of 11-15, 16-21, or > 21 comprised 12%, 9%, and 4%, respectively. When participants were dichotomized to an NIHSS score < 10 vs. > 10, there was no difference in outcome. There also was no difference based on the choice of DOAC (apixaban, dagibatran, edoxaban, or rivaroxaban) and no difference if patients were treated with intravenous thrombolysis or embolectomy.
Commentary
As with many trials exploring secondary stroke prevention, rates of recurrent events in OPTIMAS were extremely low. Given this limitation, it could not be shown that late initiation of DOACs put patients at risk for recurrent ischemic stroke or that early initiation produced a higher rate of symptomatic intracranial hemorrhage. However, importantly, this equivalency provides reassurance that initiation of a DOAC at any point within the first two weeks after stroke with AF is safe and effective.
This finding is novel because prior studies of DOACs in stroke and AF, such as ARISTOTLE (apixaban vs. warfarin for secondary stroke prevention), excluded subjects with strokes occurring within 30 days of study enrollment. OPTIMAS also provides confirmation that the current “1-3-6-12” rule remains reasonable and comports with newly available data.
Unlike prior studies, OPTIMAS classified patients based on their NIHSS scores rather than infarct volume, which, as stated previously, may be a better predictor of hemorrhage risk. Conducted in the United Kingdom, OPTIMAS required computed tomography or magnetic resonance imaging to exclude hemorrhage, but did not require an imaging diagnosis of the stroke itself. Fortuitously, because of this design, there was a subset of patients in OPTIMAS who were anticoagulated despite findings of confluent areas of hematoma within the infarcted tissue. Such patients were ineligible for inclusion in prior studies (such as ELAN) and would be considered high-risk, but they actually were treated safely with DOACS in OPTIMAS at both the early and late timepoints.
Alan Z. Segal, MD, is Associate Professor of Neurology, Weill Cornell Medicine.
References
- Goeldlin MB, Hakim A, Branca M, et al. Early vs late anticoagulation in minor, moderate, and major ischemic stroke with atrial fibrillation: Post hoc analysis of the ELAN randomized clinical trial. JAMA Neurol. 2024;81(7):693-702.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
- Healey JS, Lopes RD, Granger CB, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N Engl J Med. 2024;390(2):107-117.
- Alrohimi A, Buck B, Jickling G, et al. Early apixaban therapy after ischemic stroke in patients with atrial fibrillation. J Neurol. 2021;268(5):1837-1846.
