Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

Background: the optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation.Methods: we performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7–14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. Findings: between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI –0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (p non-inferiority=0·0003). Superiority was not identified (p superiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, –0·004 to 0·006; p=0·78). Interpretation: Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. Funding: British Heart Foundation.</p

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) : Protocol for a randomized controlled trial

Rationale: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. Aim: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. Methods and design: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. Study outcomes: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. Sample size target: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. Discussion: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke. Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT0375993

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial

RATIONALE: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. AIM: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. METHODS AND DESIGN: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. STUDY OUTCOMES: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. SAMPLE SIZE TARGET: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. DISCUSSION: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke.Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published version, accepted version, submitted versio

Anticoagulation Timing in Acute Stroke With Atrial Fibrillation According to Chronic Kidney Disease: The OPTIMAS Trial

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of ischemic stroke (IS) and intracerebral hemorrhage, so the safety and efficacy of early direct oral anticoagulant (DOAC) initiation in those with CKD are of clinical relevance. METHODS: OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke With Atrial Fibrillation) was a multicenter, randomized, parallel-group, open-label trial with blinded outcome assessment, recruiting patients with IS and atrial fibrillation from 100 UK hospitals between 2019 and 2024. Participants were randomized 1:1, stratified by stroke severity, to early (within 4 days of onset) or delayed (at days 7-14) DOAC initiation. CKD was defined as a past medical history of known CKD, collected according to trial protocol as part of the case report form. For this prespecified subgroup analysis, the trial cohorts were classified according to the presence or absence of CKD. Whether CKD modified the treatment effect of early DOAC initiation was determined by fitting mixed effects logistic regression models with interaction terms between CKD and treatment group. The primary outcome was a composite outcome of recurrent IS, symptomatic intracranial hemorrhage, and systemic arterial embolism. Key secondary outcomes included the individual components of the primary outcome and all-cause mortality. RESULTS: We included 3601 patients (mean age, 78±10 years; 45% female), 543 with CKD. There were 116 primary outcome events: 97 (3.2%) in the normal kidney function group and 19 (3.5%) in the CKD group. There was no difference between early and delayed DOAC initiation for the primary outcome in either the normal kidney function group (odds ratio, 1.01 [95% CI, 0.67-1.51]) or the CKD group (odds ratio, 0.90 [95% CI, 0.36-2.25]; Pinteraction=0.822). Similarly, for the secondary outcomes, we detected no modification of the treatment effect according to CKD (Pinteraction values of 0.637, 0.386, and 0.107 for IS, symptomatic intracranial hemorrhage, and all-cause mortality, respectively). CONCLUSIONS: Our findings suggest that CKD does not modify the effects of early versus delayed DOAC initiation after acute IS. Based on these results, early DOAC initiation should not be withheld in patients with CKD