COPENHAGEN, DENMARK. Atrial fibrillation patients with risk factors for ischemic stroke are usually prescribed aspirin or warfarin. In some cases, particularly in patients with coexisting cardiovascular disease, an antiplatelet agent such as aspirin or clopidogrel are added to warfarin in the belief that this will further reduce stroke risk. Danish researchers now report that the practice of combining antiplatelet and anticoagulation therapy in the same patients is associated with a substantially higher risk of fatal or non-fatal internal bleeding.

Their study included 118,606 patients who were discharged from hospital between January 1, 1997 and December 31, 2006 with a diagnosis of atrial fibrillation (AF). The mean age of the patients was 74 years and 52% were male. Many had comorbidities such as hypertension (16%), heart failure (18%) or ischemic heart disease (16%), while 7% had suffered a previous ischemic stroke. About 77% were taking antiarrhythmic drugs and 27% were being treated with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor antagonists. About 70% of the patients were discharged with a prescription for antiplatelet agents and/or warfarin. The pattern of prescriptions was as follows:

• Warfarin – 42.9%
• Aspirin – 40.1%
• Clopidogrel – 3.1%
• Clopidogrel + aspirin – 2.4%
• Warfarin + aspirin – 15.5%
• Warfarin + clopidogrel – 1.2%
• Warfarin + aspirin + clopidogrel – 1.1%

Patients treated only with aspirin were older and more often female than were those in the other treatment groups. During the 10-year follow-up period, 1381 patients (1.2%) experienced a fatal bleeding, while 12,191 (10.3%) were hospitalized as the result of a non-fatal internal bleeding. Using warfarin as a reference point, aspirin-treated patients had a 4% reduced risk of experiencing a bleeding event but all combination treatments were associated with a substantial increase in risk.

• Clopidogrel monotherapy – 45% increased risk
• Aspirin + clopidogrel – 91% increased risk
• Aspirin + warfarin – 75% increased risk
• Clopidogrel + warfarin – 257% increased risk
• Clopidogrel + aspirin + warfarin – 303% increased risk

The use of clopidogrel either alone or in combination was primarily associated with an increased risk of gastrointestinal bleeding. Patients who had experienced a non-fatal bleeding event during therapy had a 145% increased risk of dying during the follow-up period. It is also worth noting that the 3.9% annual bleeding incidence observed in this "real world" study is substantially higher than that found in closely controlled clinical trials. Also, the bleeding incidence during the first year of warfarin therapy is 7% among elderly patients. Perhaps most surprising, there was no indication that combining warfarin with an antiplatelet agent (aspirin, clopidogrel or both) reduced the risk of ischemic stroke.

The article concludes with the following note from the editor, "They [the Danish researchers] find that adding clopidogrel or aspirin to warfarin monotherapy greatly increases the fatal and non-fatal bleeding risk while showing no benefit to prevention of ischemic stroke."

Hansen, ML, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Archives of Internal Medicine, Vol. 170, No. 16, September 13, 2010, pp. 1433-41

Editor's comment: This study clearly shows that there is no advantage and much potential risk in using combined antiplatelet/anticoagulation therapy in atrial fibrillation patients needing stroke prevention therapy. It is unfortunate that the authors did not include actual data on the incidence of stroke in the different treatment groups and compared it to a group receiving no treatment.