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Heart DiseasePhase 3WARCEFNCT00041938

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

A Phase 3 study testing aspirin and Warfarin in people with Heart Disease and Stroke, run by Columbia University at 64 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Heart Disease, Stroke, Ischemic Heart Disease
What is being tested?
aspirin and Warfarin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2,305 participants
Where
64 sitesin 2 countries
Study dates
Oct 2002to Jul 2014
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 12Show fewer
  • 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.

Trial locations and contacts

64 sites in 2 countries.

64 sites in 2 countries

United States54 sites

  • Albany Medical College

    Albany, New York

  • Lehigh Valley Hospital

    Allentown, Pennsylvania

  • Morehouse School of Medicine

    Atlanta, Georgia

  • Tri-State Medical Group Cardiology

    Beaver, Pennsylvania

  • Buffalo General Hospital

    Buffalo, New York

  • Kaleida Health Millard Fillmore Hospital

    Buffalo, New York

  • Lahey Clinic

    Burlington, Massachusetts

  • Five Towns Neuroscience Research

    Cedarhurst, New York

  • University of North Carolina at Chapel Hill

    Chapel Hill, North Carolina

  • University of Illinois at Chicago

    Chicago, Illinois

  • MetroHealth Medical Center

    Cleveland, Ohio

  • Concord Hospital

    Concord, New Hampshire

  • Denver Health Medical Center

    Denver, Colorado

  • Denver Veterans Affairs Medical Center

    Denver, Colorado

  • Veterans Affairs Medical Center

    Detroit, Michigan

  • Black Hills Health Care System

    Fort Meade, South Dakota

  • Brooke Army Medical Center MCHE - MDC Cardiology Service

    Fort Sam Houston, Texas

  • Northeast Georgia Heart Center

    Gainesville, Georgia

  • Michael E. DeBakey Veterans Affairs Medical Center-MEDVAMC

    Houston, Texas

  • Huntington Veterans Affairs Medical Center

    Huntington, West Virginia

  • Mayo Clinic Transplant Center

    Jacksonville, Florida

  • Sewickley Valley Medical Group, Cardiology

    Leetsdale, Pennsylvania

  • University of Kentucky

    Lexington, Kentucky

  • Louisville Veterans Affairs Medical Center

    Louisville, Kentucky

  • University of Louisville

    Louisville, Kentucky

  • William S. Middleton Memorial Veterans Hospital

    Madison, Wisconsin

  • Melbourne Internal Medicine Associates

    Melbourne, Florida

  • Gulf Regional Research, LLC

    Metairie, Louisiana

  • Jackson Memorial Hospital/U. of Miami

    Miami, Florida

  • Mercy Research Institute

    Miami, Florida

  • Mercy Health Partners

    Muskegon, Michigan

  • UMDNJ - New Brunswick

    New Brunswick, New Jersey

  • Long Island Jewish Medical Center

    New Hyde Park, New York

  • Columbia University, New York Presbyterian Hospital PH 3-342

    New York, New York, 10032

  • Columbia University Medical Center

    New York, New York

  • Mount Sinai Medical Center

    New York, New York

  • University of Medicine and Dentistry of New Jersey

    Newark, New Jersey

  • Northport Veterans Affairs Medical Center

    Northport, New York

  • Oklahoma City Veterans Affairs Medical Center

    Oklahoma City, Oklahoma

  • Methodist Heart, Lung and Vascular Institute

    Peoria, Illinois

  • Albert Einstein Medical Center

    Philadelphia, Pennsylvania

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania

  • Penn Presbyterian Medical Center

    Philadelphia, Pennsylvania

  • Temple University Hospital

    Philadelphia, Pennsylvania

  • Reno Veterans Affairs Medical Center

    Reno, Nevada

  • University of Rochester Medical Center

    Rochester, New York

  • Salem VAMC

    Salem, Virginia

  • Santa Clara Medical Center

    Santa Clara, California

  • LSU Health Sciences Center

    Shreveport, Louisiana

  • Cardiovascular Consultants of South Florida

    Tamarac, Florida

  • Southern Arizona Veterans Affairs Medical Center

    Tucson, Arizona

  • University of Arizona Health Sciences Center

    Tucson, Arizona

  • George Washington University

    Washington D.C., District of Columbia, 20037

  • West Los Angeles Veterans Affairs Medical Center

    West Los Angeles, California

Other trials in United States

Canada10 sites

  • QE II Health Sciences Centre

    Halifax, Nova Scotia

  • Center for Neurologic Research

    Lethbridge, Alberta

  • London Health Sciences Centre

    London, Ontario

  • Montreal General Hospital

    Montreal, Quebec

  • Montreal Heart Institute

    Montreal, Quebec

  • Ottawa Heart Institute

    Ottawa, Ontario

  • Etobicoke Cardiac Research Centre

    Rexdale, Ontario

  • Saint John Regional Hospital

    Saint John, New Brunswick

  • St. Michael's Hospital

    Toronto, Ontario

  • St. Boniface General Hospital

    Winnipeg, Manitoba

Other trials in Canada

About this study

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.

Read more

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
Read the 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.

Being tested
aspirin, Warfarin
Keywords
heart disease, stroke, ischemic heart disease, myocardial infarction, atrial fibrillation, low ejection fraction, cardiac failure, aspirin, Warfarin, anticoagulant
Medical subject headings
Heart Diseases, Stroke, Myocardial Ischemia, Myocardial Infarction, Atrial Fibrillation, Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00041938
Study groupRoleWhat they receive
aspirinActive comparatorAspirin: 325 mg per day
Receives: Drug: aspirin
warfarinActive comparatorWarfarin: International Normalized Ratio (INR) 2.5-3.0; target INR 2.75
Receives: Drug: Warfarin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Event Rate Per 100 Patient Years for Composite Endpoint of Ischemic Stroke, Intracerebral Hemorrhage, or Death

    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.

    Measured: 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 (1)

  1. Event Rate Per 100 Patient-years for Composite Endpoint of Hospitalization for Heart Failure, Myocardial Infarction, Ischemic Stroke, Intracerebral Hemorrhage, or Death.

    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.

    Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2002 (estimated)
  2. Study startOct 2002
  3. Primary completionAug 2011
  4. Study completionJul 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
2,305 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00041938
Sponsor's protocol ID
AAAC1093
Other IDs
U01NS039143-01, R01NS39154, CRC
Acronym
WARCEF
Status last verified
Aug 2014
First submitted
19 Jul 2002
Last updated
5 Sep 2014
Data monitoring committee
Yes

Publications

  • Romiti GF, Nabrdalik K, Corica B, Bucci T, Proietti M, Qian M, Chen Y, Thompson JLP, Homma S, Lip GYH; WARCEF Investigators. Diabetes mellitus in patients with heart failure and reduced ejection fraction: a post hoc analysis from the WARCEF trial. Intern Emerg Med. 2024 Jun;19(4):931-939. doi: 10.1007/s11739-024-03544-4. Epub 2024 Feb 23.

    PubMed 38393500

  • Corica B, Romiti GF, Simoni AH, Mei DA, Bucci T, Thompson JLP, Qian M, Homma S, Proietti M, Lip GYH; WARCEF Investigators. Educational status affects prognosis of patients with heart failure with reduced ejection fraction: A post-hoc analysis from the WARCEF trial. Eur J Clin Invest. 2024 May;54(5):e14152. doi: 10.1111/eci.14152. Epub 2024 Jan 11.

    PubMed 38205865

  • 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.

    PubMed 31779926

  • 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.

    PubMed 28774396

  • 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.

    PubMed 27354224

  • 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.

    PubMed 26549533

  • 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.

    PubMed 25850425

  • 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.

    PubMed 25456692

  • 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.

    PubMed 23881846

  • 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.

    PubMed 22551105

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing aspirin and Warfarin in people with Heart Disease and Stroke, run by Columbia University at 64 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 64 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 May 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event Rate Per 100 Patient Years for Composite Endpoint of Ischemic Stroke, Intracerebral Hemorrhage, or Death (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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00041938, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2014.

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