Combination antithrombotic and antiplatelet therapy for preventing thromboembolic complications in patients with atrial fibrillation

Few medical treatment goals are more important yet more troublesome than the prevention of thromboembolic complications in patients with atrial fibrillation (AF). Anticoagulation with warfarin (Coumadin) has been the mainstay of therapy. Over the past 2 decades, many large, pro­spective, randomized trials have been conducted to evaluate the risks and benefits of this and other pharmacologic agents. Recom­men­d­ations have been developed based on analysis of risk factors.^1-3 Most trials have favored warfarin, with a target international normalized ratio (INR) between 2.0 and 3.0. War­farin has been compared with aspirin, both alone and in combination. Aspirin alone and in combination with low-intensity anticoagulation has shown disappointing results.

Perez-Gomez and Fernández compare standard anticoagulation therapy and combination therapy with acenocumarol and triflusal (Disgren), which is an antiplatelet agent. Patients with mitral stenosis and with nonvalvular AF who had a history of em­bolism were considered high risk and were randomized to receive either standard anticoagulation (INR 2.0-3.0) or combination therapy with anticoagulation (INR 1.4-2.4) and triflusal. Patients with nonvalvular AF and no history of embolism were considered intermediate risk and randomized to receive either standard anticoagulation, combination therapy (INR 1.25-2.0), or triflusal alone. The primary end point was a composite of systemic embolization, stroke, or cardiovascular death.

The study by Perez-Gomez and Fernández showed a significantly lower primary outcome rate in the combined therapy arm as compared with the anticoagulation arm. This was seen in both the intermediate- and high-risk groups. The authors report a 61% relative reduction in primary outcome and severe bleeding in the intermediate-risk group, and a 49% reduction in primary outcome in the high-risk group. In the intermediate-risk group, antiplatelet therapy alone was less effective than either combined or anticoagulation therapy.

Two additional observations were made in this study. First, patients with AF and mitral stenosis and those with nonvalvular AF had similar embolic event rates. This was attributed to the counterbalancing of factors such as left atrial size and lower flow velocities in the mitral stenosis group, and to older age, hypertension, diabetes, and peripheral vascular disease in the nonvalvular group. Second, there was a significantly higher rate of events in the patient with previous embolism who received standard anticoagulation therapy.

The findings in this study are in contrast to previous studies of combination therapy with warfarin and aspirin, which used a lower intensity of anticoagulation than the present study, with either an adjusted dose (INR 1.2-1.5) or a fixed dose of 1.25 mg daily.^4,5 In addition, while numerous other studies evaluated the efficacy of aspirin, triflusal was used in this study and it is important to note the differences. Similar to aspirin, triflusal irreversibly inhibits platelet cyclooxygenase. In contrast, however, only min­imal inhibition of endothelial cyclo­oxygenase is observed and pro­stacyclin synthesis is not reduced significantly. Platelet phosphodiesterase is inhibited by triflusal, with an in­crease in platelet cAMP levels, which can inhibit platelet activation; this effect is negligible with aspirin.⁶ Triflusal may also stimulate nitric oxide release and inhibit superoxide anion release in neutrophils, yielding an in-direct vasodilating effect.⁷ The active metabolite of triflusal, HTB (3-hydroxy-4-trifluoromethyl benzoic acid), has the same properties as its parent compound and potentiates its effect, whereas the metabolite of as­pirin, salicylic acid, has negligible antiplatelet activity.⁸ These differences may explain the potential advantage of triflusal over aspirin. Triflusal also has a lesser effect on bleeding time than aspirin, hence its lower reported incidence of bleeding complications.⁹

Perez-Gomez and Fernández show promising results using combination anticoagulation and antithrombotic therapy. Caution must be exercised, however, before broad application of these findings because of the relatively small sample size, the limited clinical experience with triflusal, and the unavailability of this drug in the United States. With warfarin being used for over half a century, this study illuminates the path that has already been forged towards finding safer and more effective agents for the prevention of thromboembolic complications of AF.