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Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial
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Design
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Cooperative, double-blind, randomized, multicenter clinical trial
N= 2305
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Objective
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To determine incident ischemic stroke (IIS) rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified |
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Study Groups
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IIS (n= 84)
No IIS (n= 2221)
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Inclusion Criteria
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Age 18 years or older, normal sinus rhythm, no contraindication to warfarin therapy, left ventricular ejection fraction (LVEF) 35% or less |
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Exclusion Criteria
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Clear indication for warfarin or aspirin treatment, high risk of cardiac embolism (e.g., atrial fibrillation), mechanical heart valve, endocarditis, intracardiac mobile or pedunculated thrombus |
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Methods
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In the WARSAW study, patients were randomized to receive warfarin (target international normalized ratio [INR] 2.0 to 3.5) or aspirin 325 mg/day, with matching placebo agents to facilitate blinding. Clinically plausible INR results were fabricated for the aspirin group to maintain blinding.
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Duration
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Up to 6 years (mean follow-up: 3.5 ± 1.8 years) |
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Outcome Measures
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Risk of IIS calculated as the number of events per 100 patient-years in patients with or without baseline stroke, and EF of < 15% or ≥ 15%
Risk of IIS by baseline stroke and EF categories
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Baseline Characteristics
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IIS (n= 84)
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No IIS (n= 2221)
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Age 60 years and older
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54.8% |
55.3% |
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Male
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78.6% |
80.1% |
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White
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76.2% |
75.3% |
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Systolic blood pressure ≥ 119.5
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60.7% |
62.0% |
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Ejection fraction < 15%
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16.7% |
9.3% |
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New York Heart Association Class III or IV
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32.1% |
30.9% |
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Already on warfarin
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9.5% |
7.7% |
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Baseline stroke
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23.8% |
10.3% |
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In the WARSAW study, the mean LVEF was 24.7 ± 7.5%
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Results
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Endpoint
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Rate ratio (p-Value)
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Warfarin
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Aspirin
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With baseline stroke
Number of events (number/100 patient-years)
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N= 128
8 (1.80)
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N= 120
12 (3.00)
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0.60 (0.262)
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Without baseline stroke
Number of events (number/100 patient-years)
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N= 1014
21 (0.58)
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N= 1043
43 (1.18)
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0.49 (0.008)
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EF < 15%
Number of events (number/100 patient-years)
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N= 110
8 (2.34)
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N= 109
6 (1.74)
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1.35 (0.580)
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EF ≥ 15%
Number of events (number/100 patient-years)
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N= 1032
21 (0.57)
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N= 1054
49 (1.33)
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0.43 (0.001)
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EF < 15%
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EF ≥ 15%
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With baseline stroke
Number of events (number/100 patient-years)
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N= 21
3 (5.88)
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N= 227
17 (2.14)
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2.75 (0.107)
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Without baseline stroke
Number of events (number/100 patient-years)
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N= 198
11 (1.73)
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N= 1859
53 (0.80)
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2.15 (0.021)
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Study Author Conclusions
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In a WARCEF exploratory analysis, prior stroke and EF< 15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF.
We found a rate of IIS of 5.88/100 patient-years in patients with both prior stroke and EF< 15% which is a rate similar to that of patients with AF with a moderate stroke risk, who are routinely anticoagulated. This suggests that there are subgroups of patients with HF with a high enough stroke rate to have a clinically relevant benefit from anticoagulation.
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InpharmD Researcher Critique
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Unfortunately, the results are not conclusive as to whether warfarin exhibits a benefit in patients with prior stroke and reduced ejection fraction < 30%, although the mean LVEF was 24.7 ± 7.5% in the WARSAW study. The subanalysis indicates that warfarin may be less effective in those with baseline stroke and lower EF, but the only comparator is with aspirin. Bleeding risk was not assessed. |