Two Antithrombotics for One Patient?

Darrell Hulisz, PharmD
Associate Professor, Department of Family Medicine, Case Western Reserve University, Cleveland, Ohio; Clinical Pharmacist, University Hospitals, Case Medical Center, Cleveland, Ohio

Warfarin and aspirin are occasionally used concomitantly for primary or secondary prevention of thrombotic disorders. Their respective antithrombotic mechanisms are in theory complementary; however, combined use can increase the risk for bleeding. About 40% of patients receiving long-term warfarin are estimated to receive concomitant aspirin, although this practice is not always based on compelling evidence of a net therapeutic benefit.^[1] The combination may seem logical for patients with concurrent diseases in which both drugs are indicated (eg, advanced coronary artery disease [CAD] and chronic atrial fibrillation [AF]). In many cases, the harm-to-benefit ratio must be considered, particularly in patients at risk for bleeding.

A retrospective analysis evaluated patients’ risk for bleeding in after myocardial infarction (MI) treated with combinations of aspirin, clopidogrel, and warfarin. The only treatment that did not increase fatal or nonfatal bleeding was warfarin monotherapy. Compared with aspirin monotherapy, the hazard ratio (HR) for nonfatal and fatal bleeding for warfarin was 1.23 (95% CI, 0.94-1.61); the HR for warfarin with aspirin was 1.84 (95% CI, 1.51-2.23). With aspirin as the reference treatment, warfarin monotherapy also had the lowest HR for all-cause mortality (0.65 [95% CI, 0.56-0.76]); the HR for combination therapy was 0.87 (95% CI, 0.77-0.98). This data suggest that patients who have had MI may benefit the most from warfarin monotherapy because it has a lower risk for bleeding, proven efficacy, and a lower risk for all-cause mortality.^[2]

The multicenter, randomized SPORTIF (Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation) trials^[3] examined the combination of aspirin and warfarin in patients with AF and at least 1 of the following conditions: history of stroke or transient ischemic attack, CAD, and diabetes mellitus. Patients given both agents were deemed high risk, usually owing to CAD. There were no statistically significant differences in stroke, stroke/systemic embolism, MI, or death between the warfarin monotherapy group and the dual-treatment group (P = .71, .78, .40, and .84, respectively). Risk for major bleeding was 3.9% with dual therapy vs 2.3% with warfarin monotherapy (P = .01). Because dual therapy conferred no additional stroke risk reduction but was associated with an increase in bleeding risk, it does not seem to be of benefit for patients with AF.

In a study conducted at 78 US Veterans Affairs medical centers, 5059 patients who had had MI within the previous 14 days were randomly assigned to receive warfarin plus aspirin (81 mg/day) or aspirin alone (162 mg/day); the median duration of follow-up was 2.7 years. The primary outcome was all-cause mortality, and secondary outcomes included recurrent MI, stroke, and major hemorrhage. More major bleeding episodes occurred in the warfarin plus aspirin group than in the aspirin-alone group (1.28 vs 0.72 event per 100 person-years of follow-up; P < .001). Groups did not differ for all-cause mortality, recurrent MI, or stroke. The investigators concluded that the combination of warfarin and aspirin did not provide a clinical benefit greater than that of aspirin monotherapy.^[4]

A meta-analysis of randomized, controlled trials examined warfarin plus aspirin vs warfarin alone in patients at risk for cardiovascular disease. The intensity of warfarin was the same in both treatment arms. Ten studies were identified, including 5 in patients with mechanical heart valves, 2 in patients with chronic AF, 2 in patients with CAD, and 1 of patients at high risk for cardiovascular disease. Combined therapy significantly reduced the risk for thromboembolic events (odds ratio, 0.66 [95% CI, 0.52-0.84]). However, this therapeutic benefit was almost completely driven by the 5 studies involving patients with mechanical heart valves; no statistical benefit was found in the other studies.^[5]

Other randomized clinical trials using more complex methods have examined the use of warfarin, aspirin, or the combination after acute coronary syndrome.^[6,7] Primary outcomes, such as mortality, reinfarction, and stroke, were improved in the combination therapy groups vs the monotherapy groups, but combination therapy increased bleeding complications.

A joint consensus statement on management of AF published by the American College of Cardiology, American Heart Association, and European Society of Cardiology (ACC/AHA/ESC) in 2006^[8] states that dual therapy has a high risk for intracranial hemorrhage, especially in the elderly population. Thus, for most patients, warfarin monotherapy should be adequate to prevent ischemic events. In patients with AF requiring percutaneous coronary intervention, clopidogrel plus warfarin should be used for 9 to 12 months, followed by continuation of warfarin monotherapy.

In patients with mechanical heart valves, however, the ACC/AHA guidelines recommend warfarin treatment plus aspirin 75 mg/day to 100 mg/day. This dual therapy is also recommended in patients with biological valves and the following risk factors: AF, previous thromboembolism, left ventricular dysfunction, and hypercoagulable conditions. These guidelines state that the further reduction of thromboembolism risk with dual therapy is also associated with a reduction in mortality from other cardiovascular conditions. This combination therapy is especially recommended in patients who developed thromboembolism while receiving warfarin, patients with known vascular disease, and patients with hypercoagulable conditions.^[9]

Conclusion

The widespread use of warfarin plus aspirin is often due to the simultaneous treatment of chronic AF and advanced CAD (eg, after MI). However, with except for patients with mechanical heart valves, evidence that combination therapy provides a therapeutic benefit over warfarin monotherapy is limited. Sufficient evidence demonstrates that warfarin plus aspirin increases the risk for major bleeding complications. This would most likely pose more of a problem in patients with a recent history of gastrointestinal bleeding, thrombocytopenia, uremia, or other risk factors for bleeding.

Some clinical scenarios in which combination warfarin and aspirin may be recommended with caution include patients with acute coronary syndromes after percutaneous coronary intervention or coronary artery bypass graft (CABG) surgery. In these situations, aspirin (or other antiplatelet drugs) may help prevent post-stent or post-CABG thrombosis, although use of an antiplatelet drug should probably not be continued indefinitely.

The author wishes to acknowledge Leslie Bonsall, PharmD candidate, for providing technical assistance.