Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction - WARCEF

Description:

Chronic systolic heart failure (CHF) is associated with a hypercoagulable state. Earlier trials on the use of warfarin in patients with CHF had included patients with atrial fibrillation (AF) and valvular heart disease, and thus, the true value of anticoagulation in patients with CHF but no other obvious cause for anticoagulation is unknown. Accordingly, the WARCEF trial sought to compare outcomes between the use of warfarin and aspirin in patients with CHF and normal sinus rhythm (NSR).

Hypothesis:

The trial sought to compare the safety and efficacy of warfarin and aspirin for preventing thromboembolic events in patients with CHF and NSR.

Study Design

  • Blinded
  • Parallel
  • Randomized

Patient Populations:

  • Age ≥18 years
  • NSR
  • No contraindication to warfarin
  • LVEF ≤35% within 3 months of randomization
  • Modified Rankin score ≤4
  • Planned treatment with ACEI/ARB, beta-blockers, or hydralazine and nitrates

    Number of enrollees: 2,305
    Duration of follow-up: 3.5 years
    Mean patient age: 61 years
    Percentage female: 20%
    Ejection fraction: 25%
    NYHA class: I (14%), II (55%), III (30%), IV (1%)

Exclusions:

  • Conditions conferring high risk of cardiac embolism, such as AF, mechanical cardiac valve, endocarditis, intracardiac mobile or pedunculated thrombus

Primary Endpoints:

  • Composite of death, ischemic stroke, or intracerebral hemorrhage

Secondary Endpoints:

  • Composite of primary outcome, MI, or CHF hospitalization

Drug/Procedures Used:

Patients without a clear indication for aspirin or warfarin therapy were randomized in a double-dummy fashion to receive either warfarin + aspirin placebo or aspirin 325 mg daily + warfarin placebo. Goal international normalized ratio [INR] in the warfarin arm was 2-3.5. Patients in the aspirin arm had sham INR results generated.

Concomitant Medications:

Angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) (98%), beta-blockers (90%), diuretics (81%), statins (83%), aldosterone antagonists (61%)

Principal Findings:

A total of 2,305 patients were randomized at 168 centers in 11 countries: 1,142 to warfarin and 1,163 to aspirin. Baseline characteristics were fairly similar between the two arms. The mean left ventricular ejection fraction (LVEF) was about 25%, with ischemic cardiomyopathy accounting for 43% of the patients; the majority of patients (85%) had New York Heart Association (NYHA) class II or III symptoms. AF was present in 3.8%, pulmonary embolism/venous thromboembolism in 2.3%, and prior stroke/transient ischemic attack in 13%. An implantable cardioverter-defibrillator was present in 18% of patients. Time in therapeutic range was 62.6% in the warfarin arm.

The primary endpoint of death, ischemic stroke, or intracerebral hemorrhage was similar between the warfarin and aspirin arms (7.47 events/100 patient-years [P-Y] vs. 7.93/100 P-Y, hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.79-1.10, p = 0.40). On time-varying analysis, the HR for warfarin decreased by 0.89/year, and a benefit was noted after the fourth year of therapy. Of the individual endpoints, there was a significant reduction in ischemic stroke with warfarin (0.72/100 P-Y vs. 1.36/100 P-Y, p = 0.005), with no difference in death (6.63/100 P-Y vs. 6.52/100 P-Y, p = 0.91) and intracerebral hemorrhage (0.12/100 P-Y vs. 0.05/100 P-Y, p = 0.35). The main secondary outcome of death, ischemic stroke, intracerebral hemorrhage, myocardial infarction, or CHF rehospitalization was similar (12.7/100 P-Y vs. 12.15/100 P-Y, p = 0.33). CHF hospitalization was borderline reduced in patients on aspirin (6.79/100 P-Y vs. 5.67/100 P-Y, p = 0.053).

Major hemorrhage was significantly higher in the warfarin arm (1.78 events/100 P-Y vs. 0.87/100 P-Y, relative risk 2.21, 95% CI 1.42-3.47, p < 0.001). This was mostly due to an increase in gastrointestinal and other bleeding; intracerebral hemorrhage and intracerebral bleeding were similar. Minor hemorrhage was similarly higher in the warfarin arm.

Interpretation:

The results of this trial indicate that warfarin is not superior to aspirin in patients with CHF and NSR for the overall primary endpoint, although there appeared to be a benefit with sustained use beyond 4 years. Further, warfarin appeared to be superior to aspirin for a reduction in ischemic strokes, although this was tempered by a twofold increase in major bleeding. Aspirin on the other hand was associated with a trend toward reduction in CHF hospitalization as compared with warfarin.

The reduction in ischemic stroke with warfarin noted in this trial confirms earlier similar findings from the WATCH trial. Overall stroke rates in this trial are lower than those noted in patients with AF. It is unclear if newer anticoagulants such as oral direct thrombin inhibitors (such as dabigatran) and factor Xa antagonists (such as apixaban and rivaroxaban) would be beneficial since they appear to have the same efficacy as warfarin for preventing thromboembolic events (for example, in patients with AF), with a superior bleeding profile.

References:

Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;May 2:[Epub ahead of print].

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Novel Agents, Acute Heart Failure, Chronic Heart Failure

Keywords: Risk, Follow-Up Studies, Ischemic Attack, Transient, Morpholines, Warfarin, Venous Thromboembolism, International Normalized Ratio, Hydralazine, beta-Alanine, Benzimidazoles, Nitrates, Cardiomyopathies, Stroke Volume, Factor Xa, Confidence Intervals, Pyridones, Myocardial Infarction, Pulmonary Embolism, Pyrazoles, Heart Failure, Systolic, Heart Valve Diseases, Defibrillators, Implantable, Cerebral Hemorrhage


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