Anticoagulation Timing in Cardioembolic Stroke and Recurrent Event Risk

Abstract

Objective: Guidelines recommend initiating anticoagulation within 4 to 14 days after cardioembolic stroke. Data supporting this did not account for key factors potentially affecting the decision to initiate anticoagulation, such as infarct size, hemorrhagic transformation, or high-risk features on echocardiography. Methods: We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with ischemic stroke and atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0-3 days, 4-14 days, or >14 days), and outcomes were recurrent stroke/transient ischemic attack/systemic embolism, symptomatic intracerebral hemorrhage (sICH), and major extracranial hemorrhage (ECH) within 90 days. Results: Among 2,084 patients, 1,289 met the inclusion criteria. The combined endpoint occurred in 10.1% (n = 130) subjects (87 ischemic events, 20 sICH, and 29 ECH). Overall, there was no significant difference in the composite endpoint between the 3 groups (0-3 days: 10.3%, 64/617; 4-14 days: 9.7%, 52/535; >14 days: 10.2%, 14/137; p = 0.933). In adjusted models, patients started on anticoagulation between 4 and 14 days did not have a lower rate of sICH (vs 0-3 days; odds ratio [OR] = 1.49, 95% confidence interval [CI] = 0.50-4.43), nor did they have a lower rate of recurrent ischemic events (vs >14 days; OR = 0.76, 95% CI = 0.36-1.62, p = 0.482). Interpretation: In this multicenter real-world cohort, the recommended (4-14 days) time frame to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required to determine the optimal timing of anticoagulation initiation.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study

“…According to more recent results from the ‘Initiation of Anticoagulation after Cardioembolic stroke’ (IAC) study (n = 1,289), however, no relevant differences in occurrence of ischaemic or haemorrhagic events were found when comparing the starting interval of 4–14 days with earlier or later administration of anticoagulation. 16 In accordance, neither the ‘Clinical relevance of Microbleeds in Stroke’ (CROMIS-2) study 24 (n = 1,355) showed a difference between an early (≤ 4d) or later (> 4d) start of anticoagulation in regard to outcome measures, nor did the ‘Stroke Acute Management with Urgent Risk-factor Assessment and Improvement’ (SAMURAI-NVAF) study (n = 499; ≤ 3d vs. > 3d). 25 Other smaller studies were conducted yielding heterogeneous findings.…”

“… 15 However, this finding could not be confirmed in a more recent study. 16 Previous studies are limited by sample size, confounding and especially confounding by indication. Therefore, the recommendations for the ideal timing of anticoagulation after acute IS are still conflicting.…”

Antithrombotic dilemmas in stroke medicine: new data, unsolved challenges

“…Several observational studies have also reported outcomes according to anticoagulation timing (Supplementary Table 1). Collectively, these studies suggest that early anticoagulation with a NOAC is not associated with a high risk of intracranial haemorrhage, and that this risk is low compared to that of recurrent ischaemic stroke (77)(78)(79)(80)(81)(82)(83). Unexpectedly, several studies of these studies found numerically higher intracranial haemorrhage rates with more delayed anticoagulation, or similar or higher rates of recurrent ischaemia in early treatment groups (80)(81)(82)(83).…”

“…Collectively, these studies suggest that early anticoagulation with a NOAC is not associated with a high risk of intracranial haemorrhage, and that this risk is low compared to that of recurrent ischaemic stroke (77)(78)(79)(80)(81)(82)(83). Unexpectedly, several studies of these studies found numerically higher intracranial haemorrhage rates with more delayed anticoagulation, or similar or higher rates of recurrent ischaemia in early treatment groups (80)(81)(82)(83). Given substantial imbalances in stroke severity, size and the presence of haemorrhagic transformation between groups, these results are likely to be confounded by treatment bias.…”

Anticoagulation after stroke: persistent uncertainties

“…They recommend to start anticoagulation within 3-4 days after mild and small strokes (<1.5 cm), after 7 days for moderate and after 14 days for large strokes. The aforementioned approaches have been tested in observational studies with inherent limitations [19]. Most recently, first results of the TIMING trial (NCT02961348; Sweden) were presented at the 7th European Stroke Conference (ESOC) 2021.…”