Safety of Single, Dual, and Triple Therapy in Atrial Fibrillation and the Risk of Bleeding

Patients with atrial fibrillation (AF) usually require long-term oral anticoagulation and platelet inhibition, which is indicated by coexisting vascular disease, such as ischemic heart disease. Thromboembolic events are more likely when a patient with AF is on platelet inhibitor therapy; physicians often choose to combine clopidogrel or aspirin with a standard anticoagulant, or they utilize triple therapy with an oral anticoagulant, aspirin, or clopidogrel. The safety of this treatment is poorly documented, according to the authors of a recent study designed to analyze the risk of bleeding after treatment with warfarin, clopidogrel, aspirin, and combinations of these agents. They reported study results in Archives of Internal Medicine [2010;170(16):1450-1455]. The researchers used data from the Danish National Patient Registry, choosing all patients ≥30 years of age who were discharged from hospitals between January 1, 1997, and December 31, 2006. These patients must have had a first-time primary or secondary diagnosis of AF. The exposure groups were monotherapy with clopidogrel, aspirin, or warfarin; dual therapy with aspirin-clopidogrel, warfarin-aspirin, and warfarin-clopidogrel; and triple therapy with warfarin-aspirin-clopidogrel. The primary end point was bleeding, defined as admission to the hospital with a bleeding diagnosis, a diagnosis of bleeding as the cause of death, or a nonfatal bleeding episode. Of the 126,837 patients meeting the above criteria, 118,606 (93.5%) were alive at discharge and were included in this study. After discharge, 82,854 patients (69.9%) had at least 1 prescription filled for aspirin, warfarin, clopidogrel, or combinations of these drugs. The combined end point of bleeding occurred in 13,573 patients (11.4%). Of these patients, 12,191 (10.3%) experienced nonfatal bleeding while 1381 (1.2%) experienced fatal bleeding. Most of the bleeding events were gastrointestinal, and the incidence rate of combined nonfatal and fatal bleeding was the highest in the initial period following discharge. In patients with AF, the risk of bleeding increased in proportion to the number of antithrombotic agents used. There was a 3-fold higher risk of bleeding in patients who received dual therapy with clopidogrel and warfarin and those who received triple therapy with clopidogrel, aspirin, and warfarin. The importance of this finding, according to the authors, is highlighted by a nonbeneficial effect in terms of ischemic stroke prevention and the significantly increased risk of death after a nonfatal bleeding episode. The authors found that aspirin monotherapy was a risk factor in particular for gastrointestinal bleeding. The perception is that aspirin monotherapy is less risky in patients with AF considered at high risk for bleeding, compared with oral anticoagulant therapy. There was comparable bleeding risk but superiority of warfarin over aspirin for preventing ischemic stroke. Clopidogrel monotherapy had a risk of bleeding similar to that of aspirin monotherapy, and warfarin monotherapy was superior to clopidogrel monotherapy in the prevention of ischemic stroke. For patients receiving combined aspirin and warfarin therapy, the risk of bleeding was almost twice as high as those receiving warfarin monotherapy. This raises safety concerns, according to the authors, because the present study did not show superiority of combined therapy over traditional anticoagulant monotherapy. Dual aspirin and clopidogrel therapy, compared with warfarin monotherapy, was associated with an increased risk of bleeding and ischemic stroke. The highest risk of bleeding was in patients receiving dual clopidogrel and warfarin therapy and in those patients receiving triple therapy. The authors concluded that appropriate selection of patients for these therapies is crucial, and physicians should weigh the risks and benefits carefully before prescribing combination therapy.