Aspirin, Warfarin, or Both for Primary Prevention of Cardiovascular Disease?

The use of aspirin therapy for the primary prevention of cardiovascular disease (CVD) has become commonplace in the United States. Clinical trials have demonstrated that the use of aspirin in high-risk patients may be associated with fewer coronary events in men and fewer strokes in women.¹ Additionally, the US Preventive Services Task Force recommends the use of aspirin for the primary prevention of CVD in at-risk patients aged 50 years and older.²

For patients receiving aspirin for primary prevention who suddenly require short-term anticoagulation with warfarin for deep vein thrombosis (DVT) or pulmonary embolism (PE), a difficult clinical decision is required of their primary care provider: continue both agents at the risk of increased bleeding, or discontinue aspirin and assume that warfarin will provide sufficient cardioprotection.

Is there evidence supporting the use of warfarin in the primary prevention of CVD?

Patient Case

JJ is a 63-year-old man with a history of type 2 diabetes mellitus, hypertension, and dyslipidemia. He is a current smoker with a 40 pack-year history. He is taking 500 mg of metformin twice daily for his diabetes; 40 mg of lisinopril daily and 25 mg of chlorthalidone daily for his hypertension; 40 mg of atorvastatin daily for his dyslipidemia and diabetes; and 81 mg of aspirin daily for primary prevention of CVD.

JJ presents today after having recently been hospitalized for a PE. He had been discharged from the hospital on 5 mg of warfarin once daily, and his international normalized ratio (INR) is currently 2.2. You have decided that JJ will complete a 6-month course of anticoagulation therapy with warfarin.

After being informed of this decision, JJ expresses some concerns about his anticoagulant/antiplatelet therapy. He asks whether he still needs to take his daily aspirin since he will be taking warfarin for the next 6 months. He expresses further concern about the possibility of having a bleeding event, given the fact that he already bruises easily with his aspirin therapy. How do you respond?

The Evidence

The use of warfarin has been evaluated for both primary and secondary prevention of CVD. The Thrombosis Prevention Trial³ evaluated the effect of warfarin with and without aspirin in 5499 men in the United Kingdom aged 45 to 69 years who were considered at high risk for the development of ischemic heart disease (IHD) (top 20% of risk score distribution or top 25% in areas with high IHD mortality rates). Participants were randomly assigned to receive warfarin only, warfarin and aspirin, aspirin only, or placebo; warfarin was initiated at 2.5 mg titrated to an INR of 1.5. The researchers found that the use of warfarin was associated with a 21% reduction (95% CI, 4-35; P=.02) in the rate of IHD, which was defined as fatal and nonfatal coronary death and myocardial infarction (MI). This end point was driven by a 39% reduction (95% CI 15-57; P=.003) in fatal coronary death and MI. Furthermore, warfarin was associated with a 17% reduction (95% CI, 1-30; P=.04) in all-cause mortality. Warfarin was not associated with a significant reduction in the rate of overall stroke. Aspirin was associated with a 32% reduction (95% CI, 12-48; P=.004) in the rate of nonfatal IHD events; however, unlike warfarin, it was not associated with a significant reduction in the rate of fatal events. When comparing aspirin with warfarin, there was no difference in the rate of IHD.

The benefit of warfarin for the prevention of major cardiovascular (CV) events was further elucidated in the study by Hurlen and colleagues,⁴ which evaluated its use in patients with acute MI. Following hospitalization for MI, participants were randomly assigned to receive warfarin (INR 2.8-4.2), aspirin 160 mg daily, or warfarin (INR 2.0-2.5) and aspirin 75 mg. Patients receiving warfarin alone were found to have a significantly lower rate of mortality, thrombotic cerebral stroke, or reinfarction compared with patients on aspirin monotherapy (16.7% vs 20%; 95% CI, 0.69-0.95; P=.03).

The benefits of reducing CV events must be weighed carefully against the risks of bleeding. In the Thrombosis Prevention Trial, the use of warfarin and aspirin was associated with significantly more intermediate and minor bleeding events compared with the use of warfarin alone or aspirin alone (intermediate bleeding: 80 vs 53 vs 48, respectively; P<.01; minor bleeding: 621 vs 496 vs 484, respectively; P<.001).³ Another study⁵ showed that the rate of clinically relevant bleeding more than doubled in patients on anticoagulation plus aspirin compared with patients on anticoagulation alone (36.6 vs 16.9 events per 100 patient-years, respectively); the absolute rates of major bleeding were also increased with anticoagulation plus aspirin (4.8 events per 100 patient-years) compared with anticoagulation alone (2.2 events per 100 patient-years), although the difference was not statistically significant (95% CI, 0.86-2.62).

Clinical Application

Taken together, the available evidence suggests at least a similar, if not improved, cardioprotective effect of warfarin monotherapy compared with aspirin, but a dramatic increase in the rate of bleeding when aspirin is combined with therapeutic anticoagulation. While the Thrombosis Prevention Trial used an INR goal of 1.5, JJ would have an INR goal of 2.0 to 3.0; it seems unlikely that at this higher goal the benefits of warfarin in the setting of cardioprotection would be reduced, although the risks for bleeding may increase.

If the available evidence were to be interpreted that warfarin is as effective as aspirin for the primary prevention of CV events, given that the warfarin in JJ’s scenario would used for 2 indications (PE prevention and CVD prevention) it represents a better choice. Aspirin would be useful only for reducing the rate of CV events; 1 drug for 2 indications is certainly more advantageous than 2 drugs for 2 indications due to the increased risk of adverse effects with multiple medications.

Given the magnitude of the increased risk of bleeding shown with combination therapy, it seems unlikely that there would be a comparable offset in the reduction in CV events if aspirin were added to anticoagulation. The rate of clinically relevant bleeding more than doubled, and while the increased rate of major bleeding was not statistically significant, it seems more likely that there is a chance for harm as opposed to no additional harm from the combination.

If JJ were to have a history of MI with stent placement, it would lead to a different risk-to-benefit equation, but since his aspirin is for primary prevention—an indication for which the data showing benefit is equivocal—it is unlikely that the relative benefits of aspirin plus anticoagulation outweigh the risks of bleeding during the acute treatment of a PE.

Outcome of the Case

JJ should be counseled that due to his indication for aspirin (primary prevention of CVD) and the short-term indication for his warfarin (acute PE), the risks of bleeding with combined therapy outweigh the benefits given that warfarin monotherapy has been shown to provide better protection than aspirin monotherapy for the primary prevention of CV events. Furthermore, the addition of aspirin to warfarin would not confer any substantial benefit for reducing JJ’s risk of future DVTs or PEs in the acute treatment period. However, this combination would significantly increase his chances for bleeding.

JJ should continue to have his INR monitored at regular intervals and be counseled to avoid the use of aspirin and nonsteroidal anti-inflammatory drugs while he is on warfarin therapy. Once his 6-month treatment with warfarin is complete, a discussion on the risks and benefits of indefinite anticoagulation should be undertaken to determine his future treatment needs with anticoagulation or a return to aspirin monotherapy.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

1. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860.
2. Bibbins-Domingo K; US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(12):836-845.
3. Medical Research Council’s General Practice Research Framework. Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet. 1998;351(9098):233-241.
4. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974.
5. Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-953.