Antithrombotic Therapy for Nonvalvular Atrial Fibrillation

Abstract & Commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.
This article originally appeared in the August 2007 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Rakesh Mishra, MD.

Source: Hart RG, et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.

In this paper, Hart and colleagues report the results of a meta-analysis of antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF). Hart et al identified and included in their database 29 randomized trials that tested various forms of antithrombotic therapy in patients with NVAF. The trials included in the meta-analysis had a total follow-up exposure of 42,450 patient years. The patients had an average age of 71 years and a male to female ratio of 65:35. Results were reported for adjusted dose warfarin compared to placebo or no therapy, antiplatelet therapy compared with placebo or no therapy, and adjusted dose warfarin compared with antiplatelet therapy.

There were 6 randomized trials that compared adjusted dose warfarin to placebo or no therapy. These trials included 2,900 participants who had 186 strokes during a mean follow-up of 1.6 years per participant. Adjusted dose warfarin was associated with a 64% reduction in stroke with similar reductions seen for both disabling and nondisabling strokes. The absolute risk reduction in all strokes was 2.7% per year in the 8 primary prevention trials and 8.4% per year in a single secondary prevention trial. When only ischemic strokes were considered, there was a 67% relative risk reduction associated with adjusted dose warfarin.

There were 8 trials that compared antiplatelet therapy with placebo. These trials involved 4,876 participants who had 488 strokes. When aspirin alone was compared to placebo or no treatment, aspirin was associated with a 19% reduced incidence of stroke. The absolute risk reduction was 0.8% per year for primary prevention trials and 2.5% per year for secondary prevention trials. There were 9 randomized trials that compared warfarin with various doses of aspirin, 3 other trials in which warfarin was compared with other antiplatelet agents and 2 trials where adjusted dose warfarin was compared to low fixed and ineffective doses of warfarin plus aspirin. When adjusted warfarin was compared with antiplatelet therapy alone, warfarin was associated with a 37% reduction in strokes. Among all patients, there was a 52% reduction in ischemic stroke.

The authors also examined several randomized trials that compared adjusted dose warfarin to other antithrombotic agents. There were 3 randomized trials in NVAF involving ximelagatran. There was an 8% reduction in stroke risk with ximelagatran compared to adjusted dose warfarin. Although 19 trials with other agents have been reported, the authors considered that the available data were insufficient for analysis.

The authors also examined major extracranial and intracranial bleeding events and total mortality. Even with the meta-analysis of this size, the frequency of these events is lower than that for ischemic strokes, so that the estimates of the effects of antithrombotic therapies are less precise. Two conclusions were, however, reached. The risk for intracranial hemorrhage was doubled with adjusted dose warfarin but the absolute risk increase was small (0.2% per patient per year) and all-cause mortality was substantially reduced by adjusted dose warfarin vs placebo.

The authors conclude that in patients with NVAF, warfarin reduces stroke by approximately 60% and death by 25% compared with no antithrombotic therapy. Antiplatelet therapy reduces stroke by approximately 20%. The data support the current guideline recommendations.

Commentary

This meta-analysis of a large number of studies involving antithrombotic therapy in patients with nonvalvular atrial fibrillation provides a useful resource for physicians making decisions about anticoagulation in patients with NVAF. The data clearly show that warfarin should be the gold standard against which new therapies are compared, but also indicate that alternative therapies may be appropriate in patients with few or no risk factors for stroke. The problems and complications for warfarin therapy are well summarized. Unfortunately, it appears that the bleeding complications, the major complication associated with warfarin therapy, are strongly related to the intensity of antithrombotic therapy, and safer yet equally effective alternatives to warfarin have not yet been identified.

In 2006, the guidelines for anticoagulation in patients with nonvalvular atrial fibrillation were revised. They recommend oral anticoagulation for all patients with atrial fibrillation unless there are contraindications or the patient is under age 60 without any heart disease or risk factors for atrial fibrillation (lone atrial fibrillation). For the latter patients the benefits of aspirin vs the risk of bleeding has not been established. The results of this meta-analysis can be used as a reference for the recommendations made in these guidelines.