Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial (WARCEF)

• ClinicalTrials.gov Identifier: NCT00041938
• Recruitment Status: Completed
• First Posted: July 22, 2002
• Results First Posted: May 14, 2013
• Last Update Posted: September 5, 2014
• Sponsor: Columbia University
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Shunichi Homma, Columbia University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Conditions: Heart Disease; Stroke; Ischemic Heart Disease; Myocardial Infarction
• Interventions: Drug: aspirin; Drug: Warfarin
• Enrollment: 2305

Participant Flow

Recruitment Details	Recruited 2305 patients at 176 sites in 11 countries, between 10/1/2002 and 1/31/2010.
Pre-assignment Details	Intent-to-treat trial - all randomized patients followed and analyzed.

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description	Aspirin : 325 mg per day	Warfarin : International Normalized Ratio (INR) 2.5-3.0; target INR 2.75
Period Title: Overall Study
Started	1163	1142
Completed Follow-up	761	745
Primary Endpoint	320	302
Only Vital Status Known	44	46
Lost to Follow-up	18	17
Withdrew Consent	20	14
Completed	1125	1111
Not Completed	38	31

Baseline Characteristics

Arm/Group Title		Aspirin	Warfarin	Total
Arm/Group Description		Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75	Total of all reporting groups
Overall Number of Baseline Participants		1163	1142	2305
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1163 participants	1142 participants	2305 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	732 62.9%	706 61.8%	1438 62.4%
	>=65 years	431 37.1%	436 38.2%	867 37.6%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1163 participants	1142 participants	2305 participants
		61 (11.1)	61 (11.6)	61 (11.3)
Sex/Gender, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1163 participants	1142 participants	2305 participants
Male		936	904	1840
Female		224	236	460
Unknown		3	2	5
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1163 participants	1142 participants	2305 participants
North America		546	573	1119
Europe		567	527	1094
Argentina		50	42	92

Outcome Measures

1. Primary Outcome

Title	Event Rate Per 100 Patient Years for Composite Endpoint of Ischemic Stroke, Intracerebral Hemorrhage, or Death
Description	The time, in years, from randomization to the first to occur of ischemic stroke, intracerebral hemorrhage, or death, up to a maximum of 6 years. Event rate per 100 patient years = 100*(number of subjects with event)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization until the date of the first to occur of ischemic stroke, intracerebral hemorrhage, or death, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis: all enrolled patients were analyzed.

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient-years
	7.93	7.47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	The primary null hypothesis: time to first event in the composite primary endpoint does not differ significantly between warfarin and aspirin. The original target sample size was 2860, providing 89% power for a log-rank test with two-sided alpha .05, assuming a hazard rate reduction of 17.82% in either group compared with the other, after adjustment for use of beta-blockers and allowance for discontinuation of therapy, dropout, and crossover. The final sample of 2305 patients yielded 69% power.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.40
	Comments	The primary null hypotheses was tested at two-tailed alpha=0.05. A Haybittle-Peto interim monitoring procedure was performed with stopping boundaries for the interim analyses corresponding to a nominal two-tailed P value of 0.001.
	Method	Regression, Cox
	Comments	Cox models stratified by site, New York Heart Association class (I vs. II-IV), and status w/ respect to recent stroke or Transient Ischemic Attack.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.10
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

2. Secondary Outcome

Title	Event Rate Per 100 Patient-years for Composite Endpoint of Hospitalization for Heart Failure, Myocardial Infarction, Ischemic Stroke, Intracerebral Hemorrhage, or Death.
Description	The time, in years, from date of randomization to the date of the first to occur of hospitalization for heart failure, myocardial infarction, ischemic stroke, intracerebral hemorrhage, or death, up to 6 years. Event rate per 100 patient years = 100*(number of subjects with event)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From randomization to the first to occur of hospitalization for heart failure, myocardial infarction, ischemic stroke, intracerebral hemorrhage, or death, up to a maximum of 6 years.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis: all enrolled patients were analyzed.

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient-years
	12.15	12.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Secondary null hypothesis: time to first event in the composite secondary endpoint does not differ significantly between warfarin and aspirin. This was tested at prespecified alpha = 0.05 level, two-tailed.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.33
	Comments	Secondary null hypothesis was tested at two-tailed alpha = 0.05.
	Method	Regression, Cox
	Comments	Cox models stratified by site, New York Heart Association class (I vs. II-IV), and status w/ respect to recent stroke or Transient Ischemic Attack.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.93 to 1.23
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

3. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient-years for Ischemic Stroke
Description	Time, in years, from date of randomization to date of ischemic stroke component of primary composite outcome, up to 6 years. Event rate per 100 patient years = 100*(number of subjects with ischemic stroke)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of ischemic stroke component of primary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: rate per 100 patient years
	1.36	0.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to ischemic stroke, adjusting for competing risks of death and intracerebral hemorrhage.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.005
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.82
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

4. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient-years for Intracerebral Hemorrhage
Description	Time, in years, from date of randomization to date of intracerebral hemorrhage component of primary composite outcome. Event rate per 100 patient years = 100*(number of subjects with intracerebral hemorrhage)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of intracerebral hemorrhage component of primary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: rate per 100 patient years
	0.05	0.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to intracerebral hemorrhage, adjusting for competing risks of death and ischemic stroke.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.35
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.22
	Confidence Interval	95%; 0.43 to 11.66
	Estimation Comments	[Not Specified]

5. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient-years for Death
Description	Time, in years, from date of randomization to date of death component of primary composite outcome. Event rate per 100 patient years = 100*(number of subjects who died)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of death component of primary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient-years
	6.52	6.63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.91
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.20
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

6. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient Years of Myocardial Infarction Component of Secondary Composite Outcome
Description	Time, in years, from date of randomization to date of myocardial infarction, up to 6 years. Includes only myocardial infarctions that occurred during follow-up, before any heart failure hospitalization. Event rate per 100 patient years = 100*(number of subjects with myocardial infarction)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of myocardial infarction component of secondary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	0.87	0.80

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to myocardial infarction, adjusting for competing risks of heart failure hospitalization, ischemic stroke, intracerebral hemorrhage, and death.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.93
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.64
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

7. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient Years of Heart Failure Hospitalization Component of Secondary Composite Outcome.
Description	Time, in years, from date of randomization to date of heart failure hospitalization, up to 6 years. Includes hospitalizations for heart failure during follow-up that were not preceded by myocardial infarction. Event rate per 100 patient years = 100*(number of subjects with heart failure hospitalization)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of heart failure hospitalization component of secondary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat.

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	5.67	6.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to heart failure hospitalization, adjusting for competing risks of myocardial infarction, ischemic stroke, intracerebral hemorrhage, and death.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.053
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.998 to 1.47
	Estimation Comments	[Not Specified]

8. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient Years of Ischemic Stroke Component of Secondary Composite Outcome
Description	Ischemic stroke component of secondary composite endpoint. Includes only ischemic strokes that were not preceded by a myocardial infarction or heart failure hospitalization. The number of ischemic strokes that are components of the secondary outcome does not therefore match the number of ischemic strokes that are components of the primary outcome. Event rate per 100 patient years = 100*(number of subjects with ischemic stroke)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1)of all randomized patients / 365.25.
Time Frame	From date of randomization to date of ischemic stroke component of secondary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat.

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	1.14	0.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to ischemic stroke, adjusting for competing risks of myocardial infarction, heart failure hospitalization, death and intracerebral hemorrhage.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.03
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.32 to 0.96
	Estimation Comments	[Not Specified]

9. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient Years of Intracerebral Hemorrhage Component of Secondary Composite Outcome
Description	Time, in years, from date of randomization to date of intracerebral hemorrhage component of secondary composite outcome. Includes only intracerebral hemorrhages not preceded by myocardial infarction or heart failure hospitalization. Event rate per 100 patient years = 100*(number of subjects with intracerebral hemorrhage)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of intracerebral hemorrhage component of secondary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	0.06	0.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	Null hypothesis: there is no difference between warfarin and aspirin in time to intracerebral hemorrhage, adjusting for competing risks of myocardial infarction, heart failure hospitalization, ischemic stroke, and death.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.51
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 0.32 to 9.88
	Estimation Comments	Hazard ratio is for comparison of warfarin vs. aspirin. Warfarin represents the numerator and aspirin represents the denominator of the hazard ratio.

10. Other Pre-specified Outcome

Title	Event Rate Per 100 Patient Years of Death Component of Secondary Composite Outcome
Description	Time, in years, from randomization to death component of secondary composite outcome. This measure counts only deaths that were not preceded by heart failure hospitalization, myocardial infarction, ischemic stroke, or intracerebral hemorrhage. Event rate per 100 patient years = 100*(number of subjects who died)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization to date of death component of secondary composite outcome, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	4.41	4.43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.83
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	Cause-specific Cox model, stratified by site, NYHA class (I vs. II, III, or IV), and prior stroke or TIA status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	95%; 0.81 to 1.30
	Estimation Comments	[Not Specified]

11. Other Pre-specified Outcome

Title	Rate Per 100 Patient Years of Major Hemorrhage
Description	Rate/100 patient-years of major hemorrhage. Includes all major hemorrhages in any patient. Major hemorrhage was defined as intracerebral, epidural, subdural, subarachnoid, spinal intramedullary, or retinal hemorrhage; any other bleeding causing a decline in the hemoglobin level of more than 2 g per deciliter in 48 hours; or bleeding requiring transfusion of 2 or more units of whole blood, hospitalization, or surgical intervention. Event rate per 100 patient years = 100*(number of major hemorrhage events)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1) of all randomized patients / 365.25.
Time Frame	From date of randomization until end of scheduled follow-up, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient years
	0.87	1.78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Regression, Poisson
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	2.05
	Confidence Interval	(2-Sided) 95%; 1.36 to 3.12
	Estimation Comments	The warfarin arm represents the numerator and the aspirin arm represents the denominator of the rate ratio.

12. Other Pre-specified Outcome

Title	Rate Per 100 Patient-years of Minor Hemorrhage.
Description	Rate per 100 patient years of minor hemorrhage. Includes all minor hemorrhages. Minor hemorrhage was defined as any non-major hemorrhage. Event rate per 100 patient years = 100*(number of minor hemorrhage events)/patient-years of follow-up. Patient years of follow-up = sum(date of conclusion of follow-up - date of randomization + 1)of all randomized patients / 365.25.
Time Frame	From date of randomization until the end of scheduled follow-up, up to 6 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Aspirin	Warfarin
Arm/Group Description:	Aspirin : 325 mg per day	Warfarin : INR 2.5-3.0; target INR 2.75
Overall Number of Participants Analyzed	1163	1142
Measure Type: Number; Unit of Measure: events per 100 patient-years
	7.34	11.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aspirin, Warfarin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Regression, Poisson
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.56
	Confidence Interval	95%; 1.34 to 1.81
	Estimation Comments	Warfarin group represents the numerator and aspirin group represents denominator of rate ratio.

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Aspirin		Warfarin
Arm/Group Description	Aspirin : 325 mg per day		Warfarin : INR 2.5-3.0; target INR 2.75
All-Cause Mortality
	Aspirin		Warfarin
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Aspirin		Warfarin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	617/1163 (53.05%)		632/1142 (55.34%)
Blood and lymphatic system disorders
Blood dyscrasia †	3/1163 (0.26%)	3	4/1142 (0.35%)	4
BLOOD/BONE MARROW: Other †	1/1163 (0.09%)	1	3/1142 (0.26%)	4
Thrombocytopenia/Anemia/Leukopenia †	1/1163 (0.09%)	1	12/1142 (1.05%)	12
Hemorrhage/Bleeding †	0/1163 (0.00%)	0	1/1142 (0.09%)	1
LYMPHATICS: Other †	1/1163 (0.09%)	1	0/1142 (0.00%)	0
Peripheral edema †	4/1163 (0.34%)	4	4/1142 (0.35%)	4
Cardiac disorders
Atrial fibrillation/Atrial flutter/Supraventricular tachycardia †	56/1163 (4.82%)	67	35/1142 (3.06%)	45
Bradycardia †	6/1163 (0.52%)	6	6/1142 (0.53%)	6
CARDIAC ARRHYTHMIA: Other †	7/1163 (0.60%)	7	3/1142 (0.26%)	3
Ventricular fibrillation †	7/1163 (0.60%)	8	15/1142 (1.31%)	17
Ventricular tachycardia †	24/1163 (2.06%)	33	39/1142 (3.42%)	46
Acute cardiac failure/CHF/Pulmonary edema †	209/1163 (17.97%)	432	243/1142 (21.28%)	506
AICD firing/discharge †	16/1163 (1.38%)	21	20/1142 (1.75%)	21
Angina/Chest pain †	70/1163 (6.02%)	105	88/1142 (7.71%)	148
CARDIAC GENERAL: Other †	16/1163 (1.38%)	18	16/1142 (1.40%)	19
Malignant hypertension †	3/1163 (0.26%)	3	7/1142 (0.61%)	7
Myocardial infarction/Acute Coronary Syndrome †	48/1163 (4.13%)	60	50/1142 (4.38%)	59
Pulmonary embolism †	6/1163 (0.52%)	6	5/1142 (0.44%)	5
Endocrine disorders
Diabetes mellitus and its complications †	26/1163 (2.24%)	35	22/1142 (1.93%)	35
ENDOCRINE: Other †	2/1163 (0.17%)	2	1/1142 (0.09%)	1
Eye disorders
OCULAR/VISUAL: Other †	5/1163 (0.43%)	7	3/1142 (0.26%)	5
Gastrointestinal disorders
Gastrointestinal disturbance/Diarrhea/Jaundice/Nausea/Stomach pain/Etc. †	54/1163 (4.64%)	70	66/1142 (5.78%)	82
GASTROINTESTINAL: Other †	25/1163 (2.15%)	31	17/1142 (1.49%)	18
General disorders
ALLERGY/IMMUNOLOGY: Other †	1/1163 (0.09%)	1	1/1142 (0.09%)	1
Laryngeal edema/Allergic reaction/Anaphylaxis/Angioedema/Rash †	4/1163 (0.34%)	4	2/1142 (0.18%)	2
CONSTITUTIONAL SYMPTOMS: Other †	7/1163 (0.60%)	7	1/1142 (0.09%)	1
Drug abuse †	3/1163 (0.26%)	3	1/1142 (0.09%)	1
OTHER: Other †	19/1163 (1.63%)	23	32/1142 (2.80%)	33
Pregnancy †	0/1163 (0.00%)	0	1/1142 (0.09%)	1
Suicide attempt/Psychiatric disorder †	16/1163 (1.38%)	16	10/1142 (0.88%)	10
PAIN: Other †	14/1163 (1.20%)	15	13/1142 (1.14%)	20
Hepatobiliary disorders
Acute hepatic failure †	3/1163 (0.26%)	3	3/1142 (0.26%)	3
HEPATOBILIARY/PANCREAS: Other †	3/1163 (0.26%)	3	5/1142 (0.44%)	7
Infections and infestations
Infection/Sepsis/Fever †	66/1163 (5.67%)	79	79/1142 (6.92%)	97
Metabolism and nutrition disorders
Metabolic disturbance/Gout †	14/1163 (1.20%)	15	16/1142 (1.40%)	17
METABOLIC/LABORATORY: Other †	12/1163 (1.03%)	14	10/1142 (0.88%)	11
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL/SOFT TISSUE: Other †	39/1163 (3.35%)	43	29/1142 (2.54%)	32
Visceral necrosis †	0/1163 (0.00%)	0	4/1142 (0.35%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANCY: Other †	22/1163 (1.89%)	24	20/1142 (1.75%)	24
Nervous system disorders
Convulsions/Seizures †	6/1163 (0.52%)	6	5/1142 (0.44%)	10
NEUROLOGY: Other †	8/1163 (0.69%)	8	7/1142 (0.61%)	7
Stroke or TIA †	13/1163 (1.12%)	16	15/1142 (1.31%)	16
Syncope/Pre-syncope †	41/1163 (3.53%)	48	68/1142 (5.95%)	83
Renal and urinary disorders
Acute renal failure/Proteinuria †	28/1163 (2.41%)	32	33/1142 (2.89%)	36
RENAL/GENITOURINARY: Other †	7/1163 (0.60%)	7	7/1142 (0.61%)	7
Reproductive system and breast disorders
SEXUAL/REPRODUCTIVE FUNCTION: Other †	2/1163 (0.17%)	2	6/1142 (0.53%)	6
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure †	7/1163 (0.60%)	8	9/1142 (0.79%)	9
Pulmonary disease/Pneumonia/Bronchitis/Asthma/Breathing difficulties †	87/1163 (7.48%)	133	79/1142 (6.92%)	100
PULMONARY/UPPER RESPIRATORY: Other †	7/1163 (0.60%)	7	3/1142 (0.26%)	3
Skin and subcutaneous tissue disorders
DERMATOLOGY/SKIN: Other †	1/1163 (0.09%)	1	0/1142 (0.00%)	0
Grade 4 dermatologic manifestations †	1/1163 (0.09%)	2	1/1142 (0.09%)	1
Surgical and medical procedures
"Cardiac device implantation (pacemaker, defibrillator, etc.)" †	123/1163 (10.58%)	133	109/1142 (9.54%)	118
"Cardiac procedure (stent, catheterization, EP study, ablation, etc.)" †	62/1163 (5.33%)	76	66/1142 (5.78%)	82
Cardiac surgery †	28/1163 (2.41%)	28	23/1142 (2.01%)	25
Non-cardiac surgery/Diagnostic surgery †	75/1163 (6.45%)	102	57/1142 (4.99%)	67
SURGERY/INTRA-OPERATIVE INJURY: Other †	4/1163 (0.34%)	4	8/1142 (0.70%)	8
Vascular disorders
Systemic embolism †	3/1163 (0.26%)	3	5/1142 (0.44%)	5
VASCULAR: Other †	16/1163 (1.38%)	17	13/1142 (1.14%)	13
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Aspirin		Warfarin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	749/1163 (64.40%)		799/1142 (69.96%)
General disorders
All non-serious adverse events *	749/1163 (64.40%)	4483	799/1142 (69.96%)	4895
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. J.L.P. (Seamus) Thompson
• Organization: Columbia University
• Phone: 212-342-1252
• EMail: jlt12@columbia.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lee TC, Qian M, Liu Y, Graham S, Mann DL, Nakanishi K, Teerlink JR, Lip GYH, Freudenberger RS, Sacco RL, Mohr JP, Labovitz AJ, Ponikowski P, Lok DJ, Matsumoto K, Estol C, Anker SD, Pullicino PM, Buchsbaum R, Levin B, Thompson JLP, Homma S, Di Tullio MR; WARCEF Investigators. Cognitive Decline Over Time in Patients With Systolic Heart Failure: Insights From WARCEF. JACC Heart Fail. 2019 Dec;7(12):1042-1053. doi: 10.1016/j.jchf.2019.09.003.

Teerlink JR, Qian M, Bello NA, Freudenberger RS, Levin B, Di Tullio MR, Graham S, Mann DL, Sacco RL, Mohr JP, Lip GYH, Labovitz AJ, Lee SC, Ponikowski P, Lok DJ, Anker SD, Thompson JLP, Homma S; WARCEF Investigators. Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial. JACC Heart Fail. 2017 Aug;5(8):603-610. doi: 10.1016/j.jchf.2017.04.011.

Di Tullio MR, Qian M, Thompson JL, Labovitz AJ, Mann DL, Sacco RL, Pullicino PM, Freudenberger RS, Teerlink JR, Graham S, Lip GY, Levin B, Mohr JP, Buchsbaum R, Estol CJ, Lok DJ, Ponikowski P, Anker SD, Homma S; WARCEF Investigators. Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure: Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial. Stroke. 2016 Aug;47(8):2031-7. doi: 10.1161/STROKEAHA.116.013679. Epub 2016 Jun 28.

Freudenberger RS, Cheng B, Mann DL, Thompson JL, Sacco RL, Buchsbaum R, Sanford A, Pullicino PM, Levin B, Teerlink JR, Graham S, Mohr JP, Labovitz AJ, Di Tullio MR, Lip GY, Estol CJ, Lok DJ, Ponikowski P, Anker SD, Homma S; WARCEF Investigators. The first prognostic model for stroke and death in patients with systolic heart failure. J Cardiol. 2016 Aug;68(2):100-3. doi: 10.1016/j.jjcc.2015.09.014. Epub 2015 Nov 6.

Homma S, Thompson JL, Qian M, Ye S, Di Tullio MR, Lip GY, Mann DL, Sacco RL, Levin B, Pullicino PM, Freudenberger RS, Teerlink JR, Graham S, Mohr JP, Labovitz AJ, Buchsbaum R, Estol CJ, Lok DJ, Ponikowski P, Anker SD; WARCEF Investigators. Quality of anticoagulation control in preventing adverse events in patients with heart failure in sinus rhythm: Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial substudy. Circ Heart Fail. 2015 May;8(3):504-9. doi: 10.1161/CIRCHEARTFAILURE.114.001725. Epub 2015 Apr 7.

Shaffer JA, Thompson JL, Cheng B, Ye S, Lip GY, Mann DL, Sacco RL, Pullicino PM, Freudenberger RS, Graham S, Mohr JP, Labovitz AJ, Estol CJ, Lok DJ, Ponikowski P, Anker SD, Di Tullio MR, Homma S; WARCEF Investigators. Association of quality of life with anticoagulant control in patients with heart failure: the Warfarin and Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. Int J Cardiol. 2014 Dec 15;177(2):715-7.

Homma S, Thompson JL, Sanford AR, Mann DL, Sacco RL, Levin B, Pullicino PM, Freudenberger RS, Teerlink JR, Graham S, Mohr JP, Massie BM, Labovitz AJ, Di Tullio MR, Gabriel AP, Lip GY, Estol CJ, Lok DJ, Ponikowski P, Anker SD; WARCEF Investigators. Benefit of warfarin compared with aspirin in patients with heart failure in sinus rhythm: a subgroup analysis of WARCEF, a randomized controlled trial. Circ Heart Fail. 2013 Sep 1;6(5):988-97. doi: 10.1161/CIRCHEARTFAILURE.113.000372. Epub 2013 Jul 23.

Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GY, Di Tullio MR, Sanford AR, Mejia V, Gabriel AP, del Valle ML, Buchsbaum R; WARCEF Investigators. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012 May 17;366(20):1859-69. doi: 10.1056/NEJMoa1202299. Epub 2012 May 2.

• Responsible Party: Shunichi Homma, Columbia University
• ClinicalTrials.gov Identifier: NCT00041938
• Other Study ID Numbers: AAAC1093; U01NS039143-01 ( U.S. NIH Grant/Contract ); R01NS39154; CRC
• First Submitted: July 19, 2002
• First Posted: July 22, 2002
• Results First Submitted: January 3, 2013
• Results First Posted: May 14, 2013
• Last Update Posted: September 5, 2014