Atherothrombosis and Atrial Fibrillation: Mixing Treatments to Match Pathophysiology

Abstract & Commentary

Synopsis: Current clinical trial evidence favors the use of aspirin or clopidogrel as first-line agents for the majority of patients with vascular disease.

Sources: Tran H, et al. JAMA. 2004;292:1867-1874; Shireman TI, et al. Stroke. 2004;35:2362-2367.

Atherothrombosis, namely the superimposition of thrombus on preexisting atherosclerosis, is a pathophysiologic process that affects the cerebral, coronary, and peripheral arterial circulations. Oral antiplatelet drugs, because they prevent initiation and propagation of thrombus formation, are the drugs of choice to prevent ischemic events in patients with vascular disease. There is controversy, however, regarding the choice of oral antiplatelet therapy in patients with cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral arterial disease (PAD). Clinicians believe that each vascular condition is different: Neurologists tend to use aspirin (ASA) combined with extended-release dipyridamole (ER-DP) for patients with CVD. Cardiologists prefer ASA, clopidogrel, or their combination for patients with CAD, and the optimal antiplatelet treatment for PAD is uncertain.

Tran and Anand have summarized the current state of evidence regarding oral antiplatelet treatment in various subgroups of patients with vascular disease. They searched the Medline database and the Cochrane Groups’ trial register to identify studies published between 1960 and August 2004. They concluded that the weight of current evidence supports the use of ASA or clopidogrel as first line therapy to prevent recurrent TIA or stroke. ER-DP combined with ASA is only a possible alternative because the evidence supporting its use comes from a single trial, The European Stroke Prevention Study 2 (ESPS 2)1, and because dipyridamole has the potential to cause coronary artery dilatation that can divert blood flow away from stenosed coronary arteries and produce myocardial ischemia during exercise. Therefore, current ACC/AHA guidelines recommend that dipyridamole not be used in patients with stable angina.2 This recommendation, however, was based on the short-acting form not ER-DP.3 No increase in cardiac events from the use of ER-DP was observed in ESPS 2.4

Appropriate oral antiplatelet therapy is ASA for patients with ST-segment elevation myocardial infarction ASA, clopidogrel for those with chronic stable angina or peripheral arterial disease, and ASA plus clopidogrel for those with non-ST-segment elevation acute coronary syndrome.

Anticoagulation with warfarin is the most effective agent for stroke prophylaxis in elderly patients with atrial fibrillation (AF). Patients on warfarin commonly have concomitant conditions such as CAD, CVD, or PAD, for which antiplatelet drugs are indicated. Therefore, combined warfarin-antiplatelet therapy is common clinical practice.

Shireman and colleagues retrospectively studied elderly AF patients to determine the influence of patient-specific factors on concomitant warfarin-antiplatelet therapy, and the impact of combined therapy on major bleeding risk. They identified more than 10,000 patients, who were older than 65 years, in the National Stroke Project database, that had been discharged from hospital on warfarin. The cohort was divided evenly between men and women, and the mean age was 77 years. Approximately 20% of AF patients discharged on warfarin were simultaneously on an antiplatelet agent, principally ASA alone (90%), ASA plus clopridogrel or ticlopidine (6%), or clopidogrel or ticlopidine alone (4%). Antiplatelet use was less common among women, older persons, patients with terminal illness, cancer, dementia, and a history of bleeding. Patients with CAD were more likely to receive an antiplatelet agent. At 90 days after discharge, antiplatelet drugs increased major bleeding rates from 1.3% in the warfarin-only group to 1.9% in the combined therapy group (OR = 1.5, P = 0.052). Intracerebral hemorrhage was 3 times more frequent in the combined group, but the rates were 0.9% in the combined group vs 0.3% in the warfarin-only group.

After accounting for other risk factors, Shireman et al concluded that combined warfarin-antiplatelet therapy increased the risk of a major bleeding event by 50% during the 90-day follow-up period.

Comment by John J. Caronna, MD

Tran and Anand summarized and critically reviewed the current evidence from clinical trials of antiplatelet drugs alone or in combination in patients with atherosclerosis of brain, heart, and limb arteries. On the basis of their analysis, they recommend ASA or clopidogrel for the majority of patients with vascular disease regardless of site. For patients who develop recurrent TIA or stroke while taking ASA or clopidogrel, an option for second-line therapy can be ASA combined with ER-DP, but only in the absence of symptomatic CAD.

Antiplatelet therapy remains central to the treatment of CAD because the pathophysiology of acute coronary artery occlusion often involves plaque rupture or fissure with platelet aggregation.5 Therefore, it is not surprising that Shireman et al found that one-fifth of AF patients were discharged on combined warfarin-antiplatelet therapy, usually because of concomitant CAD. The bad news is that combined therapy resulted in an increase in major bleeding risks, especially for ICH. The good news is that the absolute rates remained low. Therefore, the clinician must carefully consider both the potential cardiac benefit and the bleeding risk in a particular elderly patient with AF before recommending combined warfarin-antiplatelet therapy.

Dr. Caronna is Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, NY, NY.


1. European Stroke Prevention Study 2. J Neurol Sci. 1997;151:Suppl:S1-77.

2. ACC/AHA Task Force on Practice Guidelines. Circulation. 2003;107:149-158.

3. Tsuya, T et al. Am J. Cardiol. 1990;66:275-278.

4. Diener HC, et al. Int J. Clin Pract. 2001;55:162-163.

5. Schulman S. JAMA. 2004;292:1875-1882.