PDF: WARCEF
(2012)Objective
Warfarin versus aspirin for preventing ischemic stroke, or intracerebral hemorrhage in patients with heart failure and reduced ejection fraction who are in sinus rhythm.
Study Summary
• In patients with heart failure (LVEF ≤35%) in sinus rhythm, there was no significant difference in the composite primary outcome. Warfarin significantly reduced the risk of ischemic stroke but increased the risk of major hemorrhage. The benefit in stroke reduction did not translate to overall survival benefit.
Intervention
Randomized, double-blind, double-dummy trial of 2,305 patients with LVEF ≤35% and sinus rhythm assigned to: • Warfarin (INR target 2.75, range 2.0–3.5) • Aspirin 325 mg daily Follow-up: mean 3.5 years, maximum 6 years.
Study Design
Arms: Array
Outcome
• Primary outcome: 7.47 vs. 7.93 events/100 patient-years (HR 0.93; 95% CI 0.79–1.10; p=0.40)
• Ischemic stroke: 0.72 vs. 1.36 events/100 patient-years (HR 0.52; 95% CI 0.33–0.82; p=0.005)
• Major hemorrhage: 1.78 vs. 0.87 events/100 patient-years (Rate Ratio 2.05; p<0.001)
• No significant difference in all-cause death, intracerebral hemorrhage, or secondary composite outcomes.
• Stroke reduction benefit of warfarin emerged after 4 years but was borderline in significance.
• Ischemic stroke: 0.72 vs. 1.36 events/100 patient-years (HR 0.52; 95% CI 0.33–0.82; p=0.005)
• Major hemorrhage: 1.78 vs. 0.87 events/100 patient-years (Rate Ratio 2.05; p<0.001)
• No significant difference in all-cause death, intracerebral hemorrhage, or secondary composite outcomes.
• Stroke reduction benefit of warfarin emerged after 4 years but was borderline in significance.
Bottom Line
In patients with reduced LVEF and sinus rhythm, there was no significant overall difference between warfarin and aspirin in preventing the composite of ischemic stroke, intracerebral hemorrhage, or death. Warfarin significantly reduced ischemic stroke risk but at an increased risk of major hemorrhage. The choice between therapies should be individualized.
Major Points
- 2305 patients with heart failure, sinus rhythm, and LVEF ≤35% were followed for up to 6 years (mean 3.5 years).
- Primary outcome (composite of ischemic stroke, intracerebral hemorrhage, or death from any cause) rates were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (HR 0.93; 95% CI, 0.79 to 1.10; P=0.40). No significant overall difference.
- Time-varying analysis showed a hazard ratio slightly favoring warfarin over aspirin by the fourth year (P=0.046).
- Warfarin significantly reduced ischemic stroke throughout follow-up (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; HR 0.52; 95% CI, 0.33 to 0.82; P=0.005).
- The rate of major hemorrhage was significantly higher with warfarin (1.78 events per 100 patient-years vs. 0.87; P<0.001).
- Rates of intracerebral and intracranial hemorrhage did not differ significantly (0.27 events per 100 patient-years with warfarin vs. 0.22 with aspirin, P=0.82).
- Myocardial infarction and hospitalization for heart failure rates did not differ significantly between groups.
Study Design
- Study Type
- Cooperative, double-blind, multicenter clinical trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy design with fabricated INR results for aspirin group to maintain blinding; end-point adjudication committee was blinded.
- Sample Size
- 2305
- Follow-up
- Up to 6 years (mean 3.5±1.8 years)
- Centers
- 168
- Countries
- 11 countries (North America, Europe, Argentina)
Primary Outcome
Definition: Time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 320 patients (27.5%); 7.93 events per 100 patient-years | 302 patients (26.4%); 7.47 events per 100 patient-years | 0.93 (0.79 to 1.10) | 0.40 |
Limitations & Criticisms
- The study enrolled fewer patients (2305 vs 2860 planned) and had less power (69% for primary hypothesis vs 89% planned) than originally anticipated due to slow recruitment, potentially affecting the ability to detect smaller, but clinically relevant, differences.
- Although the study was double-blind, patients in the warfarin group had their INR results provided to sites, while aspirin patients received fabricated INR results, which means investigators and patients were aware of what 'active' treatment looked like, potentially introducing a subtle unblinding bias.
- The time in the therapeutic range for INR in the warfarin group was relatively low at 63%, which might have impacted the effectiveness of warfarin.
- A substantial portion of follow-up time in both groups (34% for warfarin, 32% for aspirin) involved patients not receiving the assigned study treatment, although this duration was similar in both groups.
- The benefit with warfarin in preventing ischemic stroke was offset by an increased incidence of major bleeding, presenting a clinical dilemma without a clear superior choice.
- There was a trend toward an increased rate of hospitalization for heart failure in the warfarin group, which contrasts with previous trials and warrants further investigation.
Citation
N Engl J Med 2012;366:1859-69.