Initiation of Warfarin in Patients With Atrial Fibrillation: Early Effects on Ischemic Strokes

Study Questions:

Is the initiation of warfarin associated with an increased risk of ischemic stroke in patients with atrial fibrillation (AF)?


Patients from a large British primary care database with incident AF were identified. Patients who experienced an ischemic stroke were matched with controls in a nested case-control analysis. Conditional logistic regression was used to estimate the adjusted rate ratios (RRs) of ischemic stroke associated with current use of warfarin, categorized with respect to the initiation of warfarin (≤30 days, 31-90 days, or >90 days), when compared with non-use of any antithrombotic therapy.


Among the cohort of 70,766 patients (56% with CHADS2 ≤1), 5,519 developed an ischemic stroke during follow-up. During the first 30 days after initiation of warfarin, there was a 71% increased risk of ischemic stroke, as compared to no therapy (RR, 1.71; 95% confidence interval, 1.39-2.12). The risk was highest in the first week, peaking at 3 days after initiation. The risk was significantly lower beyond 30 days after initiation.


In this large population-based study, initiation of warfarin in patients with AF was associated with an increased risk of ischemic stroke.


These findings are consistent with those of the ROCKET-AF and ARISTOTLE studies, which reported an increased risk of early (within 30 days) thromboembolic events in patients who were transitioned from rivaroxaban and apixaban, respectively, to warfarin at the conclusion of the study period. No increased risk was observed in patients who discontinued rivaroxaban during the study. Warfarin not only inhibits the activation of coagulation factors II, VII, IX and X, but also results in decreased production of protein C. Due to its short half-life (8 hours, as compared with factor II, with a half-life of 42-72 hours), warfarin may lead to rapid depletion of protein C, contributing to an initial hypercoagulable state before its anticoagulant effect becomes manifest. It may then be reasonable to bridge high-risk AF patients with heparin during this vulnerable period or alternatively, prescribe one of the novel oral anticoagulants.

Keywords: Protein C, Risk, Follow-Up Studies, Morpholines, Thiophenes, Pyrazoles, Pyridones, Primary Health Care

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