Warfarin vs Clopidogrel Plus Aspirin for Atrial Fibrillation

Abstract & Commentary

By John P. DiMarco, MD, PhD Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville This abstract first appeared in the January edition of Clinical Cardiology Alert. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.

Source: Hohnloser SH, et al. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: An ACTIVE W substudy. J Am Coll Cardiol. 2007;50:2156-2161.

The atrial fibrillation clopidogrel trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) is a noninferiority trial comparing anticoagulation with warfarin to therapy with aspirin plus clopidogrel for stroke prevention in patients with atrial fibrillation. ACTIVE W enrolled 6706 patients and is the largest atrial fibrillation anticoagulation trial completed to date. Patients in ACTIVE W could have either paroxysmal atrial fibrillation or sustained (ie, persistent or permanent) atrial fibrillation. ACTIVE W was halted when warfarin anticoagulation was observed to be superior to aspirin and clopidogrel. In this paper, Hohnloser and colleagues look at the stroke rates in paroxysmal vs other types of atrial fibrillation and examine the effects of anticoagulation in these subsets.

In ACTIVE W, 1202 patients had paroxysmal atrial fibrillation, 891 patients had persistent atrial fibrillation, and 4604 had permanent atrial fibrillation. In this paper, the patients with persistent or permanent atrial fibrillation were analyzed together as a sustained atrial fibrillation group. Patients with paroxysmal atrial fibrillation were slightly younger, had a shorter history of atrial fibrillation, more commonly had hypertension as their primary cardiac diagnosis, and had less valvular disease, heart failure, and diabetes compared to ACTIVE W patients with sustained atrial fibrillation. Their mean CHADS 2 risk score was also lower (1.79 ± 1.03 vs 2.04 ± 1.12).

During a median follow-up of 1.3 years, there were 25 strokes and 4 non-CNS systemic embolic events among the 1202 patients with paroxysmal atrial fibrillation, compared with 136 strokes and 20 non-CNS systemic embolic events in the 5495 patients with sustained atrial fibrillation. This yields an embolic event rate of 2.0 per 100 patient years in patients with paroxysmal atrial fibrillation compared with 2.2 in patients with sustained atrial fibrillation (relative risk 0.87, 95% confidence interval 0.59 to 1.30, P = 0.50). After adjusting for baseline variables, the relative risk was 0.94. There was no difference in the incidence of stroke and non-CNS systemic embolism according to treatment allocation, based on the type of atrial fibrillation. Oral anticoagulation was superior to clopidogrel plus aspirin for the prevention of stroke and non-CNS embolism in both types of atrial fibrillation. The relative risk for stroke or non-CNS systemic embolism was 2.09 in the aspirin plus clopidogrel group among those with sustained atrial fibrillation and 1.61 among those with paroxysmal atrial fibrillation. Bleeding rates were higher on clopidogrel and aspirin, but there was no difference in bleeding rates based on the pattern of atrial fibrillation.

Hohnloser et al concluded that patients with paroxysmal and sustained atrial fibrillation have similar risks for stroke and non-CNS embolism, and that oral anticoagulation is more effective than antiplatelet therapy in both types of atrial fibrillation.


The prior evidence for recommendations of anticoagulation in patients with paroxysmal, as opposed to sustained, atrial fibrillation are based on only a small number of patients in randomized clinical trials. These trials used an older definition of paroxysmal atrial fibrillation and were conducted almost 20 years ago. Since then, stroke rates in all patients with atrial fibrillation have declined, with the decline possibly due to better therapy of hypertension and associated conditions. In this paper, however, Hohnloser et al show that paroxysmal atrial fibrillation, using a current definition, carries the same risk for stroke as does sustained atrial fibrillation, at least in patients with enough atrial fibrillation to warrant entry into the trial.

The major questions in dealing with patients with paroxysmal atrial fibrillation is the lower limit of frequency or duration of atrial fibrillation that is required to increase the risk of stroke. This paper shows that paroxysmal or self-terminating episodes have approximately the same prognostic significance as sustained episodes, but the paper does not provide a true estimate of atrial fibrillation burden in these patients. It is still unknown whether patients with only rare or very short episodes are also at increased risk. In clinical practice, an estimate of total atrial fibrillation burden is impossible in most patients since it is well recognized that silent episodes of atrial fibrillation are frequent. There is, however, a study ongoing that is using pacemaker memory to document the prevalence of symptomatic and asymptomatic runs of atrial fibrillation (correlating this with the risk for stroke).