Abstract & Commentary
Synopsis: The addition of antiplatelet therapy to reduced intensity anticoagulation in atrial fibrillation patients reduces death and embolic events without increasing bleeding.
Source: Perez-Gomez F, et al. J Am Coll Cardiol. 2004;44: 1557-1566.
In this study, Perez-Gomez and colleagues report the results of the National Study for Prevention of Embolism in Atrial Fibrillation (NASPEAF) trial. The hypothesis for this trial was that the addition of an antiplatelet agent to a moderate intensity anticoagulant regimen would improve mortality and embolic events in atrial fibrillation patients at intermediate or high risk for such events. Patients were eligible for the study if they had either intermittent or persistent atrial fibrillation and were either older than age 60 or had other risk factors for embolic events. The high-risk group consisted of 495 patients with a history of prior embolism and/or mitral stenosis. The intermediate group consisted of 714 patients without mitral stenosis or prior embolism. Patients with prosthetic valves, a stroke in the previous 6 months, renal insufficiency, uncontrolled hypertension, or other indications for nonsteroidal, inflammatory, antiplatelet drugs or anticoagulants were excluded.
The antiplatelet agent used in the study was triflusal, a drug structurally similar to acetylsalicylic acid. Triflusal was administered at a dose of 600 mg per day, the equivalent of 300 mg of aspirin per day. The anticoagulant used was acenocumarol, the coumarin derivative most commonly used in Spain. In the intermediate risk group, patients were randomized between antiplatelet therapy only, anticoagulant therapy with a target INR of 2-3, and combination therapy with triflusal and acenocumarol, with a target INR of 1.25-2. In the high-risk group, patients were randomized to either anticoagulant therapy with a target INR of 2-3 or combination therapy with triflusal and an INR range of 1.4-2.4.
The primary outcome was a composite of vascular death, transient ischemic attack, nonfatal stroke, and systemic embolism. Secondary end points were severe bleeding, myocardial infarction, nonvascular death, and minor bleeding.
In the intermediate risk group, the annual event rates for the combined primary end points were 3.82% in the triflusal group, 2.70% in the anticoagulant group, and 0.92% in the combined therapy group. In the high-risk group, the annual event rates for the composite end point were 4.76% in the anticoagulant only group and 2.44% in the combined triflusal-anticoagulant group. Among the intermediate risk patients, the annual rates for severe bleeding were 0.35% in the triflusal group, 1.8% in the anticoagulant group, and 0.9% in the combined therapy group. In the high-risk group, the annual rate for severe bleeding was 2.1% in the anticoagulant group and 2.1% in the combined therapy group.
Actuarial analysis of the primary composite end point showed that combined therapy was superior to the other treatment modalities in both the intermediate and high-risk patients.
Perez-Gomez et al concluded that addition of antiplatelet therapy to reduced intensity anticoagulation in atrial fibrillation patients reduces death and embolic events without increasing bleeding.
Comment by John P. DiMarco, MD, PhD
Numerous studies have established the value of warfarin anticoagulation in patients with valvular and nonvalvular atrial fibrillation. When warfarin is used alone, the optimal target INR appears to be 2-3. Attempts to use warfarin at a dose that would produce only minimal or no changes in the INR in combination with antiplatelet therapy have been unsuccessful. In this paper, Perez-Gomez et al attempted to use a moderate reduction in target INR in association with antiplatelet therapy in both a very high risk group and an intermediate risk group.
Although the study group is relatively small, the data do suggest that this approach may be effective. The key difference between this and prior studies is that the reduction in anticoagulation target intensity was only moderate.
In the intermediate group, the median INR was 1.93 vs 2.47 in the anticoagulant group. Adherence to this target was quite good. Two-thirds of the INR values were within the prescribed range in both groups. In the high-risk group, the median INR in the combined therapy group was 2.17 and in the anticoagulant group it was 2.50. By lowering the target INR, Perez-Gomez et al were able to add an antiplatelet agent without increasing bleeding or losing the benefits of anticoagulation.
These data suggest that very careful monitoring of INR during warfarin therapy, plus the addition of an antiplatelet agent, can allow lower targets to be used without detrimental effects. This approach may be of benefit for patients who have a perceived increased risk for bleeding, in whom physicians might otherwise be reluctant to use standard anticoagulant therapy, despite the presence of atrial fibrillation.
Dr. DiMarco is Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, VA.