Warfarin and Antiplatelet Trial in Chronic Heart Failure - WATCH
The goal of the trial was to evaluate the use of warfarin, aspirin, or clopidogrel for death, nonfatal myocardial infarction (MI), or stroke in patients with chronic heart failure (CHF), and normal sinus rhythm.
Treatment with warfarin or clopidogrel would be associated with a reduction in death, MI, or stroke compared with treatment with aspirin among patients with CHF.
Patients Enrolled: 1,587
NYHA Class: II (44%), III (54%), IV (2%)
Mean Follow Up: 23 months
Mean Patient Age: 63 years
Mean Ejection Fraction: baseline, 25%
Age >18 years, symptomatic CHF (NYHA class II-IV) for >3 months, an ejection fraction ≤35%, sinus rhythm, and treatment with an ACE inhibitor (unless not tolerated) and diuretic for at least 60 days
Definite indications or contraindications for one of the study agents, imminent procedures necessitating withdrawal, CHF not attributable to ischemic or nonischemic dilated cardiomyopathy, severe comorbid conditions, and other factors that might preclude protocol adherence
- Efficacy: Composite of all-cause mortality and nonfatal MI or stroke
- Safety: Major bleeding episodes
Primary endpoint events plus hospitalizations for CHF, unstable angina, transient ischemic attacks, and systemic or pulmonary arterial embolic events
The trial was conducted with the Veterans Affairs Cooperative Studies Program. Patients were randomized to either: 1) open-label warfarin (international normalized ratio [INR] target of 2.5-3.0), 2) double-blind antiplatelet therapy with aspirin (162 mg), or 3) double-blind antiplatelet therapy with clopidogrel (75 mg). No loading dose was given for either aspirin or clopidogrel.
Angiotensin-converting enzyme (ACE) inhibitors (88%), beta-blockers (70%), and loop diuretics (99%)
The trial was designed to enroll 4,500 patients, but was discontinued early due to slow enrollment after 1,587 patients were enrolled. Baseline characteristics were fairly similar between the three arms. About 73% had an ischemic cardiomyopathy, and the majority of patients had CHF (duration ≥2 years, as well as New York Heart Association (NYHA) class III or IV heart failure (56%). Mean INR in the warfarin group was 2.6, with 31% of INR measures in the target INR range of 2.5-3.0.
For the comparison of aspirin and warfarin, there was no difference in the primary composite endpoint of death, MI, or stroke (20.7% with aspirin vs. 19.6% with warfarin, hazard ratio 0.98, 95% confidence interval 0.86-1.12, p = 0.77) or the individual endpoints of the composite: death (18.0% vs. 17.0%, p = 0.69) or MI (2.7% vs. 3.9%, p = 0.27); the incidence of all strokes was higher in the aspirin arm (2.3% vs. 0.6%, respectively, p = 0.01). Hospitalizations for heart failure were lower in the warfarin arm (16.5% vs. 22.2%, p = 0.019). The incidence of major bleeds, including central nervous system bleeds, was similar between the two arms; however, minor bleeding was more common in the warfarin arm (p = 0.05).
For the comparison of aspirin and clopidogrel, there was no difference in the primary composite endpoint of death, MI, or stroke (20.7% with aspirin vs. 21.6% with clopidogrel, p = 0.72). All other endpoints, including mortality (18.0% vs. 18.3%), strokes (2.3% vs. 2.3%), as well as major and minor bleeding episodes were similar between the two arms (p > 0.05).
For the comparison of clopidogrel and warfarin, there was again no difference in the incidence of the primary endpoint (21.6% vs. 19.6%, p = 0.44). Strokes (2.3% vs. 0.6%, p = 0.017) were more common in the clopidogrel arm, whereas both major (2.1% vs. 5.2%, p = 0.007) and minor bleeding (22.7% vs. 28.7%, p = 0.025) were more common in the warfarin arm.
Among patients with CHF and normal sinus rhythm, antithrombotic treatment with warfarin or clopidogrel was not associated with a reduction in the composite of death, MI, or stroke compared with aspirin. There seemed to be a lower incidence of strokes in the warfarin arm, compared with both clopidogrel and aspirin, which was tempered by a significantly higher risk of bleeding in the warfarin arm. The power to detect a difference for the primary outcome in this trial was lower because the trial was discontinued after only one-third of patients were enrolled.
The ongoing Warfarin Versus Aspirin With Reduced Ejection Fraction (WARCEF) trial will further explore the use of antithrombotic therapy in patients with heart failure.
Massie BM, Collins JF, Ammon SE, et al., on behalf of the WATCH trial investigators. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009;119:1616-24.
Presented by Dr. Barry M. Massie at the American College of Cardiology Annual Scientific Session, March 2004.
Keywords: Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Diuretics, Warfarin, Ticlopidine, Fibrinolytic Agents, Purinergic P2Y Receptor Antagonists, International Normalized Ratio, Veterans, Cardiomyopathies, Heart Failure, Confidence Intervals
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