Warfarin vs. Asprin in Reduced Ejection Fraction

WARFARIN vs. ASPIRIN in REDUCED
CARDIAC EJECTION FRACTION
Trial
(WARCEF)
Principal Investigators:
Shunichi Homma, MD* JLP Thompson, PhD † *
Clinical Statistical
Columbia University
*College of Physicians and Surgeons and
† Mailman School of Public Health, New York, NY

Financial Support Disclosures
• National Institute of Neurological Disorders and Stroke
U01-NS-043975 (S. Homma)
U01-NS-039143 (J.L.P. Thompson)
• No other disclosures
• Warfarin, warfarin placebo provided by Taro
Pharmaceuticals U.S.A.
• Aspirin, aspirin placebo provided by Bayer HealthCare

Background
• Heart failure patients are at an increased risk
of death and stroke due to thromboembolic
events
• Warfarin and aspirin are often given to heart
failure patients in sinus rhythm but they have
not been compared to each other in a large
group of heart failure patients

Primary Aim
To determine if warfarin or aspirin is superior for
preventing combined outcome of death, ischemic
stroke, or intracerebral hemorrhage in patients with
LVEF ≤ 35% in sinus rhythm
Main Secondary Aim
To determine if warfarin or aspirin is superior for
preventing combined outcome of death, ischemic
stroke, intracerebral hemorrhage, MI, or heart
failure hospitalization in patients with LVEF ≤ 35%
in sinus rhythm

Key Inclusion Criteria
1. Normal sinus rhythm
2. LVEF35%
3. No defined cardioembolic source
4. On optimum heart failure regimen

• Double-Blind Multicenter Study
Warfarin (INR 2 – 3.5) vs. ASA (325mg)
• Echo Core Lab to confirm site determined
LVEF
• Timeline
Study Design
Recruitment: October 2002 to January 2010
Follow-up ended: July 2011

Statistical Design
• Primary null hypothesis
No overall difference between warfarin (target
INR 2.75) and aspirin (325 mg/day) in time to first
to occur of ischemic stroke, intracerebral
hemorrhage, or death.
• = 0.05 two-sided for superiority
• Power 80% for 17.8% HR reduction.
(achieved 67% after recruitment curtailed)
• Given long follow-up (6 yrs maximum),
prespecified analysis provides for a time-varying
treatment effect (treatment by time interaction) if
hazards are nonproportional

Enrollment: 11 countries, 176 sites, 2,305 patients
Canada: 216
United States: 903
United Kingdom: 41
Germany: 134
Czech Republic: 173
Slovakia: 27
Hungary: 152
Argentina: 92
Netherlands: 189
Poland: 263
Ukraine: 115

Randomized, n
Lost to Follow-up, n
Withdrew Consent, n
Mean Follow-up (range)
Total Patient Years
Enrolled Patients
Warfarin Aspirin
1142
17
14
3.54 (1-6) yrs
4045
1163
18
20
3.47 (1-6) yrs
4033

Baseline Findings
Warfarin
(N=1142)
Aspirin
(N=1163)
Age 61 ± 11.6 yrs 61 ± 11.1 yrs
Male sex (%) 904 (79.3 %) 936 (80.7 %)
Prior stroke/ TIA (% ) 155 (13.6 %) 139 (12.0 %)
NYHA Classification (%)
I 150 (13.2 %) 165 (14.3 %)
II 621 (54.6 %) 646 (56 %)
III 351 (30.9 %) 329 (28.5 %)
IV 15 (1.3 %) 13 (1.1 %)
Ejection Fraction 25 ± 7.5 % 25 ± 7.5 %

Baseline Medication
Time in Therapeutic Range
Warfarin
(N=1142)
Aspirin
(N=1163)
Aspirin /Other Antiplatelet 65.9 % 67.7 %
Warfarin/other OAC 7.9 % 7.7 %
ACE Inhibitor/ARB 98.4 % 98.4 %
Beta Blocker 90.3 % 89.5 %
Aldosterone Blocker 61.0 % 59.9 %
Nitrate 25 % 22.4 %
Diuretic 81.4 % 80.3 %
Statin 83.4 % 82.7 %
Defibrillator 18.6 % 17.8 %
Mean INR 2.5 ± 0.95
Time in Therapeutic Range (2-3.5) 63%

No. at Risk
Primary Outcome
Aspirin 4,033 patient years (320 endpoints; 7.93% per year)
Warfarin 4,045 patient years (302 endpoints; 7.47% per year)
Overall HR = 0.93 (0.79-1.10) p=0.40
Proportional Hazards
assumption violated
Primary Analysis: Tx by Time Interaction
Aspirin 1163 1073 860 658 508 329 94
Warfarin 1142 1049 852 653 525 363 115
aspirin
warfarin

Warfarin vs. Aspirin Hazard Ratios by Year of Follow-up*
(Prespecified Time-Varying Analysis)
Hazard Ratio for Warfarin versus Aspirin
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Aspirin
better
Warfarin
better
Significant Treatment by Time Interaction:
HR multiplier per year: 0.894 (0.800, 0.998), p=0.046.
0 1 2 3 4 5 6
Year
Aspirin 1073 860 658 508 329 94
Warfarin 1049 852 653 525 363 115
*Estimated from time-varying model in continuous time

Death
Components of Primary Outcome
Warfarin (N=1142)
4,045 yrs
Aspirin (N=1163)
4,033 yrs
n Rate/yr n Rate/yr
268 6.63% 263 6.52%
Ischemic
stroke 29 0.72% 55 1.36%
Intracerebral
hemorrhage 5 0.12% 2 0.05%
Hazard Ratio†
(95% CI)
1.01 (0.85-1.21)
0.52 (0.33 - 0.82)
2.22 (0.43 - 11.66)
P-
Value
0.91
0.005
0.35

No. at risk
Main Secondary Outcome
Warfarin 3,519 patient years 447 endpoints
Aspirin 3,582 patient years 435 endpoints
Warfarin
(12.70% per year)
Aspirin
(12.15% per year)
Overall HR 1.07 = (093,1.23) p=0.33
Aspirin 1163 1004 750 554 419 270 75
Warfarin 1142 954 735 541 426 291 88

Major Hemorrhage
(Frequencies* : Rate /yr)
Warfarin Aspirin Rate P
Ratio
Overall 72 (1.78%) 35 (0.87%) 2.05

Conclusions
• No overall difference for Primary Outcome
• Suggestive benefit of warfarin for Primary
Outcome at 4 years and beyond
• Warfarin reduces ischemic stroke risk
throughout follow-up
• More major hemorrhage with warfarin, but
intracerebral and intracranial hemorrhage similar
• No difference for the Main Secondary Outcome
(Primary Outcome + MI and HFH)

CLINICAL IMPLICATIONS
• Given no overall benefit of warfarin and
increased risk of bleeding, in spite of
suggestive benefit at 4 years and beyond,
there is no compelling evidence to use
warfarin or aspirin for all patients.
• Given effectiveness in preventing stroke,
and possible benefit of warfarin after 4
years, analyses being performed to identify
groups that will benefit from warfarin or
aspirin.

STUDY ORGANIZATION
Sponsor – the National Institute of Neurological
Disorders and Stroke.U01-NS-043975 (S.
Homma), and U01-NS-039143 (J.L.P.
Thompson)
Executive Committee – S. Homma, J.L.P
Thompson, P. Pullicino, R. Freudenberger, S.
Graham, J. Teerlink, S. Ammon, D. Mann, J.P.
Mohr, R.L. Sacco, B. Massie, S. Anker, A.
Labovitz, and C. Moy (NIH project scientist)
Clinical Coordinating Center – S. Homma,V.
Mejia, A. Gabriel, S. Borden, E. Peña, C. Harris,
R. Khadouri, D. Gohs, M. Brown, G. Berry, D.
Disantis, M. Scullin, P. Smith, S. Kohsaka, W.
Watson, and L. Guillory.
Statistical Analysis Center – J. L. P. Thompson,
B. Levin, R. Buchsbaum, M. Del Valle, A.
Sanford, G. Levy, K. Tea, J. Grier, L. Swydan, B.
O’Hare, R. Prodhan, R. Arbing, E. Flanagan, E.
Duverger, A. Peljto, W. Lo, A. Tierney, A.
Henriquez, and J. Keen.
CEC – J.R. Teerlink, S. Ammon, S. Slomiak, and
L. Cape. Neurology Adjudicators – H.J.M.
Barnett, A. Bruno, J.D. Easton, S. Levine, and
D. Sahlas; Cardiology Adjudicators – F. Bleyer,
P. Carson, A. Ellis, A. Miller, and S.T. Palmeri;
Hemorrhage adjudicator – R. Hart.
Core Echo Lab: A. Labovitz, M. Di Tullio,
M.Bierig, R. Liu, and C. Donato.
DSMB – G.J. del Zoppo, G.W. Albers, M.
Eliasziw, J.A. Hinchey, K.C. Johnston, A.M.
Lowe, I.L. Piña, J.A. Swain, and P. Gilbert (NIH
liaison)

Thank you to:
• Site investigators and
coordinators
• CCC and SAC team members
• CEC Committee members
• DSMB members
• NINDS
• All study volunteers