The Lancet · 1996 · 1.1K citations · 26 references
MedicinePharmacologyPharmacotherapyCardiovascular PharmacotherapyClinical PharmacologyPreventive CardiologyAnticoagulant TherapyAnticoagulation TherapyAntithrombotic TherapyAtrial FibrillationStrokeThrombosisAtrial Fibrillation MonitoringAtrial Fibrillation Risk AssessmentAtrial Fibrillation-related ThromboembolismBleeding Risk ReductionFixed-dose DosingMonitoring Of Anticoagulant TherapyPrimary Stroke PreventionStroke Embolism
Adjusted‑dose warfarin effectively prevents ischemic stroke in atrial fibrillation but carries significant bleeding risk and requires frequent monitoring. The study aimed to evaluate a simpler, safer regimen—low‑intensity fixed‑dose warfarin plus aspirin—for high‑risk AF patients. In a randomized, open‑label trial, 1,067 high‑risk AF patients were assigned to either low‑intensity warfarin (INR 1.2‑1.5) plus aspirin or adjusted‑dose warfarin (INR 2.0‑3.0), with mean INRs of 1.3 and 2.4, respectively. Adjusted‑dose warfarin reduced the annual rate of ischemic stroke and systemic embolism from 7.9% to 1.9% (absolute reduction 6.0%) and lowered disabling stroke and composite vascular events, while major bleeding rates were comparable between groups.
Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism.1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled.The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups.Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.
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