Clinical trial NCT00041938: Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial
Official title: Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Disease
Stroke
Ischemic Heart Disease
Myocardial Infarction
Keywords: heart disease
stroke
ischemic heart disease
myocardial infarction
atrial fibrillation
low ejection fraction
cardiac failure
aspirin
Warfarin
anticoagulant
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2002-07-22
Enrollment: 2305
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine which of two treatments, Warfarin or aspirin, is better for preventing death and stroke in patients with poor heart function.

We are now transitioning into the sub-analysis part of the WARCEF patient data.

The study has recently completed data analysis for its Primary Aim. All randomized patients have completed their follow up. All study related procedure as per the protocol has been completed. We are now in the extension phase of the study to obtain more patient data to address further aims of the study. No new procedures are performed and data already in place at the sites will be collected (EKG and echocardiograms).

The aims for this study extension are:

* To assess progression of cardiac dysfunction over time among heart failure patients
* To correlate prognosis with cardiac dysfunction

Detailed description: Warfarin has proven effective in patients with ischemic heart disease, especially in the reduction of stroke, death and re-infarction following myocardial infarction, and in the reduction of stroke in atrial fibrillation. Warfarin is the most promising unstudied intervention in patients with cardiac failure. This randomized, double-blind, multi-center study will define optimal antithrombotic therapy for patients with cardiac (heart) failure and patients with low ejection fraction (EF). EF is the proportion of left ventricular volume emptied during systole. It reliably measures left ventricular systolic function.

With the rapidly increasing numbers of elderly patients with heart failure, this study has important public health implications. The study will determine which of two commonly used treatments Warfarin, an anticoagulant, or aspirin, a drug which affects platelet function is better for preventing death and stroke in patients with low ejection fraction.

Eligibility criteria: Inclusion Criteria

* Cardiac EF \<=35% by radionuclide ventriculography, left ventriculography or quantitive echocardiographic measurement or an echocardiographic Wall Motion Index of \<=1.2, within three months of enrollment. The patient's clinical cardiac state at enrollment should be similar to their state at the time of the qualifying echocardiogram. The qualifying left ventricular function measurement must be obtained at least three months after an MI, coronary bypass grafting, PTCA, and at least one month after pacemaker insertion. Patients scheduled for mitral valve repair should have qualifying echo after surgery.
* Modified Rankin score \<=4.
* Patient must be taking ACE inhibitors. If intolerant of ACE inhibitor, patient must be on angiotensin II receptor blockers or hydralazine and nitrates.
* Patient is able to follow an outpatient protocol (requiring monthly blood tests and clinic visits every four months for the duration of the study) and is available by telephone.
* Patient understands the purpose and requirements of the study, can make him/herself understood, and has provided informed consent.
* Patients with recent stroke or TIA within twelve (12) months will be eligible to be included in the recent stroke (RS) subgroup.
* Chronic CHF patients (NYHA I \* IV) admitted to the hospital can be randomized prior to discharge if the patient is stable, taking oral medications for 24 hours and ambulatory at the time of discharge. Stable New York Heart Association Class IV patients will be eligible for randomization.

Exclusion Criteria

* The presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal AF, mechanical valve, endocarditis, intracardiac mobile or pedunculated thrombus, and valvular vegetation.
* Cyanotic congenital heart disease, Eisenmenger's syndrome.
* Decompensated heart failure.
* Cardiac surgery, angioplasty, or MI within the past 3 months prior to randomization.
* A contraindication to the use of either warfarin or aspirin, e.g. active peptic ulcer disease, active bleeding diathesis, platelets \<100,000\*, hematocrit \<30, INR \>1.3 (if not on warfarin), clotting factor abnormality that increases the risk of bleeding, alcohol or substance abuse, severe gait instability, cerebral hemorrhage, systemic hemorrhage within the past year, severe liver impairment (AST \>3x normal\*, cirrhosis), any condition requiring regular use of non-steroidal anti-inflammatory agents, allergy to aspirin or warfarin, uncontrolled severe hypertension (systolic pressure \>180 mm Hg or diastolic pressure \> 110 mm Hg), positive stool guaiac not attributable to hemorrhoids, creatinine \>3.0\*. \*on most recent test done within 30 days prior to randomization
* Patient needs continuing therapy with intravenous heparin or low molecular weight heparin or a specific antiplatelet agent.
* Dementia or psychiatric or physical problem that prevents the patient from following an outpatient program reliably.
* Comorbid conditions that may limit survival to less than five years.
* Pregnancy, or female of childbearing potential who is not sterilized or is not using a medically accepted form of contraception\* (see procedure manual). \*A pregnancy test is required for all women of childbearing age.
* Enrollment in another study that would conflict with WARCEF.
* Hospitalization for new diagnosis of onset CHF within the past one month or carotid endarterectomy or pacemaker insertion within the past one month prior to randomization .
* Person under 18 years of age.

Primary outcomes:
measure: Event Rate Per 100 Patient Years for Composite Endpoint of Ischemic Stroke, Intracerebral Hemorrhage, or Death
timeFrame: From date of randomization until the date of the first to occur of ischemic stroke, intracerebral hemorrhage, or death, up to 6 years
Secondary outcomes:
measure: Event Rate Per 100 Patient-years for Composite Endpoint of Hospitalization for Heart Failure, Myocardial Infarction, Ischemic Stroke, Intracerebral Hemorrhage, or Death.
timeFrame: 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.
Other outcomes:
measure: Event Rate Per 100 Patient-years for Ischemic Stroke
timeFrame: From date of randomization to date of ischemic stroke component of primary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient-years for Intracerebral Hemorrhage
timeFrame: From date of randomization to date of intracerebral hemorrhage component of primary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient-years for Death
timeFrame: From date of randomization to date of death component of primary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient Years of Myocardial Infarction Component of Secondary Composite Outcome
timeFrame: From date of randomization to date of myocardial infarction component of secondary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient Years of Heart Failure Hospitalization Component of Secondary Composite Outcome.
timeFrame: From date of randomization to date of heart failure hospitalization component of secondary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient Years of Ischemic Stroke Component of Secondary Composite Outcome
timeFrame: From date of randomization to date of ischemic stroke component of secondary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient Years of Intracerebral Hemorrhage Component of Secondary Composite Outcome
timeFrame: From date of randomization to date of intracerebral hemorrhage component of secondary composite outcome, up to 6 years
measure: Event Rate Per 100 Patient Years of Death Component of Secondary Composite Outcome
timeFrame: From date of randomization to date of death component of secondary composite outcome, up to 6 years
measure: Rate Per 100 Patient Years of Major Hemorrhage
timeFrame: From date of randomization until end of scheduled follow-up, up to 6 years
measure: Rate Per 100 Patient-years of Minor Hemorrhage.
timeFrame: From date of randomization until the end of scheduled follow-up, up to 6 years
Locations:
city: Tucson
country: United States
facility: Southern Arizona Veterans Affairs Medical Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Santa Clara
country: United States
facility: Santa Clara Medical Center
state: California
city: West Los Angeles
country: United States
facility: West Los Angeles Veterans Affairs Medical Center
state: California
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Denver
country: United States
facility: Denver Veterans Affairs Medical Center
state: Colorado
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Transplant Center
state: Florida
city: Melbourne
country: United States
facility: Melbourne Internal Medicine Associates
state: Florida
city: Miami
country: United States
facility: Jackson Memorial Hospital/U. of Miami
state: Florida
city: Miami
country: United States
facility: Mercy Research Institute
state: Florida
city: Tamarac
country: United States
facility: Cardiovascular Consultants of South Florida
state: Florida
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Heart Center
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Peoria
country: United States
facility: Methodist Heart, Lung and Vascular Institute
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Louisville Veterans Affairs Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Metairie
country: United States
facility: Gulf Regional Research, LLC
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Sciences Center
state: Louisiana
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Detroit
country: United States
facility: Veterans Affairs Medical Center
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Partners
state: Michigan
city: Reno
country: United States
facility: Reno Veterans Affairs Medical Center
state: Nevada
city: Concord
country: United States
facility: Concord Hospital
state: New Hampshire
city: New Brunswick
country: United States
facility: UMDNJ - New Brunswick
state: New Jersey
city: Newark
country: United States
facility: University of Medicine and Dentistry of New Jersey
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Buffalo
country: United States
facility: Buffalo General Hospital
state: New York
city: Buffalo
country: United States
facility: Kaleida Health Millard Fillmore Hospital
state: New York
city: Cedarhurst
country: United States
facility: Five Towns Neuroscience Research
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Columbia University, New York Presbyterian Hospital PH 3-342
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Northport
country: United States
facility: Northport Veterans Affairs Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City Veterans Affairs Medical Center
state: Oklahoma
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: Beaver
country: United States
facility: Tri-State Medical Group Cardiology
state: Pennsylvania
city: Leetsdale
country: United States
facility: Sewickley Valley Medical Group, Cardiology
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Fort Meade
country: United States
facility: Black Hills Health Care System
state: South Dakota
city: Ft. Sam Houston
country: United States
facility: Brooke Army Medical Center MCHE - MDC Cardiology Service
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey Veterans Affairs Medical Center-MEDVAMC
state: Texas
city: Salem
country: United States
facility: Salem VAMC
state: Virginia
city: Huntington
country: United States
facility: Huntington Veterans Affairs Medical Center
state: West Virginia
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital
state: Wisconsin
city: Lethbridge
country: Canada
facility: Center for Neurologic Research
state: Alberta
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: QE II Health Sciences Centre
state: Nova Scotia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Heart Institute
state: Ontario
city: Rexdale
country: Canada
facility: Etobicoke Cardiac Research Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
Study officials:
affiliation: Principal Cardiologist, Associate Chief, Division of Cardiology, and Director, Echocardiography Laboratories Professor of Medicine
name: Shunichi Homma, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Statistical PI: Clinical Professor of Biostatistics and Neurology
name: Seamus Thompson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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. doi: 10.1016/j.ijcard.2014.10.012. No abstract available.
citation: 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.
citation: 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.