Warfarin and Antiplatelet Therapy in Chronic Heart Failure

CSP #442 - Warfarin and Antiplatelet Therapy Study in Patients With Congestive Heart Failure (WATCH)

Whether patients with chronic heart failure (CHF) should be anticoagulated is one of the oldest unresolved questions in cardiovascular therapeutics. Some authorities do not recommend anticoagulation for CHF patients in sinus rhythm, others recommend anticoagulation in patients with primary cardiomyopathy, and still others consider it more appropriate in patients with coronary artery disease (CAD). This absence of consensus reflects the lack of evidence in this area and different outlooks on the objectives of such therapy (e.g., prevention of arterial emboli or reduction in vascular events).

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Warfarin titrated to an INR of 2.5-3.0; Drug: Aspirin; Drug: Clopidogrel 75

Detailed Description

Primary Hypothesis: The hypothesis to be tested is whether aspirin, warfarin, and clopidogrel are equally effective in the treatment of patients with symptomatic CHF and reduced ejection fraction.

Secondary Hypothesis: If one therapy proves to be superior with regard to outcomes, what is the cost of this benefit? Can subsets of patients be identified who benefit more from a specific approach to antithrombotic therapy?

Intervention: The three treatment regimens are:

1. Open-label Warfarin titrated to an INR of 2.5-3.0;
2. Double blind aspirin 162 mg once daily;
3. Double blind clopidogrel 75 mg once daily.

Primary Outcomes: Any death (all causes), non-fatal stroke, non-fatal MI.

Study Abstract: Whether patients with chronic heart failure (CHF) should be anticoagulated is one of the oldest unresolved questions in cardiovascular therapeutics. Some authorities do not recommend anticoagulation for CHF patients in sinus rhythm, others recommend anticoagulation in patients with primary cardiomyopathy, and still others consider it more appropriate in patients with coronary artery disease (CAD). This absence of consensus reflects the lack of evidence in this area and different outlooks on the objectives of such therapy (e.g., prevention of arterial emboli or reduction in vascular events).

The original target sample size was 4,500 over a 3 year enrollment period with a 2 year follow-up. This sample size yielded 90% power to detect a relative difference of 20% between treatment groups. The sample size was later amended to 1,500 over a 30 month enrollment period with a 12 month follow-up. The reduced sample size yielded 85% to detect a between treatment difference of 30%. This change became effective in March 2002.

This clinical trial enrolled 1,587 patients in 142 medical centers; VA and non-VA centers in the U.S., and medical centers in the United Kingdom and Canada. Patients were randomly and equally allocated to the 3 treatments: warfarin (administered open-label), aspirin and clopidogrel (the latter two administered double-blind). The study was conducted over a 3.5 year period, with a 2.5 year enrollment phase.

Patients with NYHA class II, III, or IV and left ventricular ejection fractions less than or equal to 35% on an ACE inhibitor (unless not tolerated) and a diuretic were entered. The primary end point is the composite of death from any cause, non-fatal MI, and non-fatal stroke. All-cause mortality is the secondary end point.

The WATCH design paper has been published in the Journal of Cardiac Failure. Preliminary results were presented at the meeting of the American College of Cardiology in New Orleans on March 9, 2004. There were no significant differences between the treatment groups for the primary endpoints. The paper with final results is being prepared.

• Study Type: Interventional
• Enrollment (Anticipated): 1587
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2E 7C5
      • Cardiology Consultants
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
    • Edmonton, Alberta, Canada, T6L 5X8
      • Grey Nuns Com. Hospital and Health Centre
  • British Columbia
    • Campbell River, British Columbia, Canada, V9W 6X8
      • Alder Medical Centre
    • North Vancouver, British Columbia, Canada, V7L 2P7
      • North Shore Cardiology Laboratory
    • Surrey, British Columbia, Canada, V3V 1Z2
      • Surrey Memorial Hospital - Cardiology
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface General Hospital
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Health Sciences Centre - Cardiology Research
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II HSC
  • Ontario
    • Ajax, Ontario, Canada, L1S 7K8
      • Ajax and Pickering General Hospital
    • Brampton, Ontario, Canada, L6V 1B4
      • Bramptom, Research Associates
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences Corp. - General Div
    • Hamilton, Ontario, Canada, L8P 3B6
      • St. Joseph's Hospital
    • London, Ontario, Canada, N6A 5A5
      • London HSC - University Campus
    • Mississauga, Ontario, Canada, L5M 2N1
      • Credit Valley Hospital Research Associates
    • Niagara Falls, Ontario, Canada, L2E 7H1
      • Niagara Falls Medical Center
    • Ottawa, Ontario, Canada, K1Y 4W7
      • Ottawa Heart Institute
    • Rexdale, Ontario, Canada, M9V 4B8
      • Etobicoke General Hospital
    • Scarborough, Ontario, Canada, M1S 4V5
      • Cardiology Research Associates
    • Sudbury, Ontario, Canada, P3E 6B4
      • Neureka Research Inc. Willett Green Millr Cntr
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
  • Quebec
    • Longeuil, Quebec, Canada, J4N 1E1
      • Invascor Clinical Research Inc.
    • Montreal, Quebec, Canada, H1T 2M4
      • Cardiology Clinic - Maisonneuve-Rosemont
    • Victoriaville, Quebec, Canada, G6P 6N2
      • Hotel-Dieu D'Artabaska
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4P 0W5
      • Regina General Hospital
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Royal University Hospital
    • Saskatoon, Saskatchewan, Canada, S7K 0Z9
      • St. Paul's Hospital
• United Kingdom
  • Bridlington, United Kingdom, YO16 4QP
    • Bridlington and District Hospital
  • Derby, United Kingdom, DE1 2QY
    • Derbyshire Royal Infirmary
  • Devon, United Kingdom, PL6 8DH
    • Derriford Hospital
  • Glasgow, United Kingdom, G12 8QQ
    • Glasgow Western Infirmary
  • London, United Kingdom, SE1 7EH
    • St. Thomas' Hospital
  • Wakefield, United Kingdom, WF1 4DG
    • Pinderfields General Hospital
  • Antrim
    • Belfast, Antrim, United Kingdom, BT12 6BA
      • Royal Victoria Hospital
  • Beds
    • Luton, Beds, United Kingdom, LU4 0DZ
      • Luton and Dunstable Hospital
  • Birmingham
    • Selly Oak, Birmingham, United Kingdom, B29 6JD
      • Selly Oak Hospital
  • Cheshire
    • Stockport, Cheshire, United Kingdom, SK2 7JE
      • Stepping Hills Hospital
  • Cleveland
    • Middlesborough, Cleveland, United Kingdom, TS4 3BW
      • South Cleveland Hospital
  • Devon
    • Torbay, Devon, United Kingdom, TQ2 7AA
      • Torbay District General
  • Essex
    • Ilford, Essex, United Kingdom, IG3 8YB
      • King Geroge Hospital
  • Hull
    • Cottingham, Hull, United Kingdom, HU16 5JG
      • Castle Hill Hospital
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY3 8NR
      • Blackpool Victoria Hospital
  • London
    • Plaistow, London, United Kingdom, E13 8SL
      • Newham General Hospital
  • Manchester
    • Wythenshawe, Manchester, United Kingdom, M23 9LT
      • Wythenshawe Hospital
  • Middlesex
    • Harrow, Middlesex, United Kingdom, HA1 3UJ
      • Northwick Park Hospital and Institue for Medical R
  • North Lincolnshire
    • Scunthorpe, North Lincolnshire, United Kingdom, DN15 7BH
      • Scunthorpe General Hospital
  • North Yorkshire
    • York, North Yorkshire, United Kingdom, YO3 7HE
      • York District Hospital
  • Renfrewshire
    • Paisley, Renfrewshire, United Kingdom, PA2 9PN
      • Royal Alexandra Hospital
  • South Humberside
    • Grimsby, South Humberside, United Kingdom, DN33 2BA
      • Princess of Wales Hospital (Grimsby)
  • South Yorkshire
    • Barnsley, South Yorkshire, United Kingdom, S75 2EP
      • Barnsley District General
  • Sussex
    • Brighton, Sussex, United Kingdom, BN2 1ES
      • Cardiology Research Unit Sussex House
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • St. James' University Hospital
  • West Yorshire
    • Pontefract, West Yorshire, United Kingdom, WF8 1PL
      • Pontefract General Infirmary
  • Yorkshire
    • Sheffield, Yorkshire, United Kingdom, S5 7AU
      • Northern General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • VA Medical Center, Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Carl T. Hayden VA Medical Center
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System, Tucson
  • Arkansas
    • No. Little Rock, Arkansas, United States, 72114-1706
      • Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock
  • California
    • Downey, California, United States, 90242
      • Rancho Los Amigos National Rehabilitation Center
    • Fresno, California, United States, 93703
      • VA Central California Health Care System, Fresno
    • Loma Linda, California, United States, 92357
      • VA Medical Center, Loma Linda
    • Palo Alto, California, United States, 94304-1290
      • VA Palo Alto Health Care System
    • San Francisco, California, United States, 94121
      • VA Medical Center, San Francisco
    • Sepulveda, California, United States, 91343
      • VA Greater Los Angeles HCS, Sepulveda
    • Walnut Creek, California, United States, 94598
      • Cardiovascular Consultants, Walnut Creek
    • West Los Angeles, California, United States, 90073
      • VA Greater Los Angeles Healthcare System, West LA
  • Colorado
    • Denver, Colorado, United States, 80220
      • VA Eastern Colorado Health Care System, Denver
  • Connecticut
    • Derby, Connecticut, United States, 06418
      • Cardiology Associates of Derby, P.C.
    • Hartford, Connecticut, United States, 06120
      • St. Francis Hospital and Medical Center
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Health Care System (West Haven)
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • VA Medical Center, DC
  • Florida
    • Atlantis, Florida, United States, 33462
      • Florida Cardiovascular Research
    • Bay Pines, Florida, United States, 33708
      • VA Medical Center, Bay Pines
    • Gainesville, Florida, United States, 32608
      • North Florida/South Georgia Veterans Health System
    • Lakeland, Florida, United States, 33805
      • Watson Clinic LLP
    • Merritt Island, Florida, United States, 32952
      • Brevard Cardiology
    • Miami, Florida, United States, 33125
      • VA Medical Center, Miami
    • Pensacola, Florida, United States, 32501
      • Cardiology Consultants - Pensacola
    • Tamarac, Florida, United States, 33321
      • University Cardiology Consultants
    • Tampa, Florida, United States, 33612
      • James A. Haley Veterans Hospital, Tampa
  • Georgia
    • Augusta, Georgia, United States, 30904
      • VA Medical Center, Augusta
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Medical and Rehab Center, Decatur
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Jesse Brown VAMC (WestSide Division)
    • Hines, Illinois, United States, 60141-5000
      • Edward Hines, Jr. VA Hospital
    • Peoria, Illinois, United States, 61603
      • Heart Care Midwest
  • Indiana
    • Jeffersonville, Indiana, United States, 47130
      • River Cities Cardiology
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • Overton Brooks VA Medical Center, Shreveport
  • Massachusetts
    • Bedford, Massachusetts, United States, 01730
      • Edith Nourse Rogers Memorial Veterans Hospital, Bedford
    • Brockton, Massachusetts, United States, 02301
      • VA Boston Healthcare System, Brockton Campus
    • Springfield, Massachusetts, United States, 01104
      • Bay State Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48113
      • VA Ann Arbor Healthcare System
    • Detroit, Michigan, United States, 48201
      • John D. Dingell VA Medical Center, Detroit
    • Trey, Michigan, United States, 48095
      • William Beaumont Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • VA Medical Center, Minneapolis
  • Mississippi
    • Biloxi, Mississippi, United States, 39531
      • VA Gulf Coast Veterans Health Care System, Biloxi
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • VA Medical Center, Kansas City MO
    • St Louis, Missouri, United States, 63106
      • VA Medical Center, St Louis
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Lincoln Division VA Nebraska Western IA HCS
  • Nevada
    • Reno, Nevada, United States, 89502
      • VA Sierra Nevada Health Care System
  • New York
    • Albany, New York, United States, 12208
      • VA Stratton Medical Center, Albany
    • Buffalo, New York, United States, 14215
      • VA Western New York Healthcare System at Buffalo
    • Flushing, New York, United States, 11355
      • New York Hospital Medical Center of Queens
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10010
      • New York Harbor HCS
    • Northport, New York, United States, 11768
      • VA Medical Center, Northport
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • VA Medical Center, Syracuse
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7075
      • Univ of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • VA Medical Center, Durham
    • Hendersonville, North Carolina, United States, 28739
      • Margaret Pardee Memorial Hospital
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • VA Medical Center, Fargo
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • VA Medical Center, Cincinnati
    • Cleveland, Ohio, United States, 44106
      • VA Medical Center, Cleveland
    • Columbus, Ohio, United States, 43203-1278
      • Chalmers P. Wylie VAOPC
    • Dayton, Ohio, United States, 45428
      • VA Medical Center, Dayton
  • Oklahoma
    • Muskogee, Oklahoma, United States, 74401
      • VA Medical Center, Muskogee
    • Oklahoma City, Oklahoma, United States, 73104
      • VA Medical Center, Oklahoma City
  • Oregon
    • Portland, Oregon, United States, 97201
      • VA Medical Center, Portland
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • VA Medical Center, Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Health Care System
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • VA Medical Center, Providence
  • South Dakota
    • Fort Meade, South Dakota, United States, 57741
      • VA Black Hills Health Care System, Fort Meade
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • VA Medical Center, Memphis
    • Nashville, Tennessee, United States, 37212-2637
      • Va Medical Center
  • Texas
    • Galveston, Texas, United States, 77555-0553
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center (152)
    • San Antonio, Texas, United States, 78229
      • VA South Texas Health Care System, San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84148
      • VA Salt Lake City Health Care System, Salt Lake City
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes McGuire VA Medical Center
    • South Boston, Virginia, United States, 24592
      • DUCCS Research of South Boston
  • West Virginia
    • Huntington, West Virginia, United States, 25704
      • VA Medical Center, Huntington
    • Martinsburg, West Virginia, United States, 25041
      • VA Medical Center, Martinsburg
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Wlliam S. Middleton Memorial Veterans Hospital, Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Inclusion Criteria:

• Patients with NYHA class II, III, or IV and left ventricular ejection fractions less than or equal to 35%, on an ACE inhibitor (unless not tolerated) and on a diuretic.

Exclusion Criteria:

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Warfarin Titrated to an INR of 2.5-3.0	Drug: Warfarin titrated to an INR of 2.5-3.0; anticoagulation (administered without blinding) titrated to a target INR of 2.5 to 3.0, monitored by measurements at 6 week intervals after initial titration and stabilization.
Active Comparator: 2; Aspirin 182 mg	Drug: Aspirin; an antiplatelet agent whose mechanism is inhibition of thromboxane, a platelet activator) administered in a double blind manner.
Active Comparator: 3; Clopidogrel 75 mg	Drug: Clopidogrel 75; (an antiplatelet agent whose mechanism is ADP inhibition) administered in a double blind manner)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
acomposite of mortality, nonfatal myocardial infarction and nonfatal stroke	The primary safety end point was major bleeding episodes, defined as bleeding episodes leading to death or disability (including loss of neurological or special senses function), requiring surgical intervention, or associated with an acute decline of hemoglobin 2gm/dl or transfusion of >1 U packed red cells or whole blood.	30 months intake; 12-42 months follow-up

Collaborators and Investigators

• Sponsor: US Department of Veterans Affairs
• Collaborators: Bristol-Myers Squibb; Sanofi-Synthelabo
• Investigators: Study Chair: Barry M. Massie, MD, VA Medical Center, San Francisco

Publications and helpful links

General Publications

• Massie BM, Krol WF, Ammon SE, Armstrong PW, Cleland JG, Collins JF, Ezekowitz M, Jafri SM, O'Connor CM, Packer M, Schulman KA, Teo K, Warren S. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. J Card Fail. 2004 Apr;10(2):101-12. doi: 10.1016/j.cardfail.2004.02.006.
• Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M, Jafri SM, Krol WF, O'Connor CM, Schulman KA, Teo K, Warren SR; WATCH Trial Investigators. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation. 2009 Mar 31;119(12):1616-24. doi: 10.1161/CIRCULATIONAHA.108.801753. Epub 2009 Mar 16.
• Patterson ME, Grant WC, Glickman SW, Massie BM, Ammon SE, Armstrong PW, Cleland JG, Collins JF, Teo KK, Schulman KA, Reed SD. Resource use and costs of treatment with anticoagulation and antiplatelet agents: results of the WATCH trial economic evaluation. J Card Fail. 2009 Dec;15(10):819-27. doi: 10.1016/j.cardfail.2009.07.004. Epub 2009 Aug 21.

Study record dates

Study Major Dates

• Study Start: October 1, 1998
• Primary Completion (Actual): July 1, 2003
• Study Completion (Actual): December 1, 2004

Study Registration Dates

• First Submitted: December 29, 2000
• First Submitted That Met QC Criteria: December 30, 2000
• First Posted (Estimate): January 1, 2001

Study Record Updates

• Last Update Posted (Estimate): June 16, 2011
• Last Update Submitted That Met QC Criteria: June 14, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: clopidogrel; warfarin; aspirin; embolic events; Left ventricular ejection fraction less than or eq; NYHA Class II, III or IV CHF; symptomatic CHF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Aspirin; Clopidogrel; Warfarin
• Other Study ID Numbers: 442