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Women's Health Study (WHS): A Randomized Trial of Low-dose Aspirin and Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer (WHS)

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ClinicalTrials.gov Identifier: NCT00000479
Recruitment Status : Completed
First Posted : October 28, 1999
Results First Posted : June 13, 2012
Last Update Posted : June 15, 2012
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Julie E. Buring, Brigham and Women's Hospital

Brief Summary:
The purpose of this study is to evaluate the effects of low-dose aspirin and vitamin E in primary prevention of cardiovascular disease and cancer in apparently healthy women.

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Cerebrovascular Disorders Coronary Disease Heart Diseases Myocardial Infarction Myocardial Ischemia Vascular Diseases Drug: Aspirin Drug: Vitamin E Behavioral: Placebo Phase 3

Detailed Description:


Various doses of aspirin have been shown to be effective in preventing thrombosis or vascular occlusion in several clinical conditions. Short-term studies have documented the efficacy of aspirin in preventing occlusion of saphenous vein bypass grants, preventing myocardial infarction in patients with unstable angina, preventing transient ischemic attacks and stroke in men with cerebral vascular disease, preventing occlusion of injured coronary arteries following transluminal angioplasty and aiding in reducing myocardial infarction and total mortality in patients receiving fibrinolytic therapy. Additionally, aspirin has been effective in the secondary prevention of myocardial infarction in subjects with known coronary artery disease. The results of the Physicians' Health Study, a large-scale primary prevention trial of aspirin in male physicians, have shown a decrease in myocardial infarction, a non-significant increase in cerebral vascular events, and no difference in overall mortality. However, few studies have addressed the efficacy of aspirin in vascular diseases in women, and it is possible that the risk to benefit ratio may be different in women. Specifically, there have been no large primary prevention trials in women, who are at risk of coronary heart disease, especially after menopause.


The Women's Health Study (WHS) is a randomized, double-blind, placebo-controlled trial using a 2x2 factorial design. The WHS is sponsored by both NHBLI (HL080467) and NCI (CA047988). Approximately 1.75 million female health professionals were contacted by mail to determine if they were suitable for inclusion in the study. A three-month run-in phase was performed to screen out those with poor compliance. Randomization, which began in February 1993 and ended in January 1996, was stratified on five-year age groups. A total of 39,876 participants were randomly assigned to either Vitamin E (600 IU every other day) or placebo; and to aspirin (100 mg every other day) or placebo. IN the 2x2 factorial design, women were randomly assigned to active aspirin and placebo vitamin E (n=9,968), placebo aspirin and active vitamin E (n=9,971), active aspirin and active vitamin E (n=9,966), or placebo aspirin and placebo vitamin E (n=9,971). A description of the characteristics of women in these 4 groups is provided in J Women's Health Gend Based Med 2000;9:19-27. In the main analyses, all women on active aspirin (n=19,934) were compared to women on placebo aspirin (n=19,942); and all women on active vitamin E (n=19,937) were compared to women on placebo aspirin (n=19,939).

As part of the initial trial, pre-randomization blood samples from 28,345 participants were frozen and stored for genetic analysis which has been supported by non-federal sources.

The primary endpoint is the reduction of the risk of all important vascular events (a combined endpoint of nonfatal myocardial infarction, nonfatal stroke, and total cardiovascular death) and a decrease in the incidence of total malignant neoplasms of epithelial cell origin. Secondary endpoints are the individual components of the combined endpoints. Compliance is measured by replies to a questionnaire sent out every year. The trial was completed in 2004 and results were published in 2005 (N Engl J Med 2005;352:1293-304; JAMA 2005;294:47-55; JAMA 2005;294:56-65).

Currently, women are being followed on an observational basis.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39876 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Women's Health Study of Low-dose Aspirin and Vitamin E in Apparently Healthy Women
Study Start Date : September 1992
Actual Primary Completion Date : March 2004
Actual Study Completion Date : February 2005

Arm Intervention/treatment
Experimental: 1
Vitamin E (600 IU every other day) and aspirin (100 mg every other day)
Drug: Aspirin
Participants will receive 100 mg of aspirin every other day.

Drug: Vitamin E
Participants will receive 600 IU of vitamin E every other day.

Experimental: 2
Vitamin E (600 IU every other day) and placebo
Drug: Vitamin E
Participants will receive 600 IU of vitamin E every other day.

Behavioral: Placebo
Participants will receive placebo.

Experimental: 3
Aspirin (100 mg every other day) and placebo
Drug: Aspirin
Participants will receive 100 mg of aspirin every other day.

Behavioral: Placebo
Participants will receive placebo.

Placebo Comparator: 4
Placebo and placebo
Behavioral: Placebo
Participants will receive placebo.

Primary Outcome Measures :
  1. Number of Participants With Major Cardiovascular Events (a Combined Endpoint of Nonfatal Myocardial Infarction, Nonfatal Stroke, and Total Cardiovascular Death) [ Time Frame: Average follow-up 10.1 years ]
  2. Number of Participants With Cancer, Excluding Nonmelanoma Skin Cancer [ Time Frame: Average follow-up 10.1 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Healthy women
  • No previous history of cardiovascular disease or cancer
  • No contraindications to aspirin or vitamin E

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00000479

Sponsors and Collaborators
Brigham and Women's Hospital
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Julie Buring Brigham and Women's Hospital
Buring JE, Hennekens CH for the Women's Health Study Research Group. The Women's Health Study: rationale and background. J Myocardial Ischemia, 4:30-40, 1992.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Haslam DE, Peloso GM, Guirette M, Imamura F, Bartz TM, Pitsillides AN, Wang CA, Li-Gao R, Westra JM, Pitkanen N, Young KL, Graff M, Wood AC, Braun KVE, Luan J, Kahonen M, Kiefte-de Jong JC, Ghanbari M, Tintle N, Lemaitre RN, Mook-Kanamori DO, North K, Helminen M, Mossavar-Rahmani Y, Snetselaar L, Martin LW, Viikari JS, Oddy WH, Pennell CE, Rosendall FR, Ikram MA, Uitterlinden AG, Psaty BM, Mozaffarian D, Rotter JI, Taylor KD, Lehtimaki T, Raitakari OT, Livingston KA, Voortman T, Forouhi NG, Wareham NJ, de Mutsert R, Rich SS, Manson JE, Mora S, Ridker PM, Merino J, Meigs JB, Dashti HS, Chasman DI, Lichtenstein AH, Smith CE, Dupuis J, Herman MA, McKeown NM. Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants in the CHREBP (Carbohydrate Responsive Element Binding Protein) Locus and HDL-C (High-Density Lipoprotein Cholesterol) and Triglyceride Concentrations. Circ Genom Precis Med. 2021 Aug;14(4):e003288. doi: 10.1161/CIRCGEN.120.003288. Epub 2021 Jul 16.

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Responsible Party: Julie E. Buring, Professor of Medicine, Harvard Medical School, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00000479    
Other Study ID Numbers: 69
R01HL043851 ( U.S. NIH Grant/Contract )
First Posted: October 28, 1999    Key Record Dates
Results First Posted: June 13, 2012
Last Update Posted: June 15, 2012
Last Verified: June 2012
Additional relevant MeSH terms:
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Cerebrovascular Disorders
Cardiovascular Diseases
Myocardial Infarction
Heart Diseases
Vascular Diseases
Coronary Disease
Myocardial Ischemia
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vitamin E
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors