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

Study Overview
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Brief Summary
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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.

Detailed Description
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BACKGROUND: 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. DESIGN NARRATIVE: 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.

Official Title
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Women's Health Study of Low-dose Aspirin and Vitamin E in Apparently Healthy Women

Conditions
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Cardiovascular Diseases, Cerebrovascular Disorders, Coronary Disease, Heart Diseases, Myocardial Infarction, Myocardial Ischemia, Vascular Diseases

Intervention / Treatment
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* Drug: Aspirin
* Drug: Vitamin E
* Behavioral: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy women No previous history of cardiovascular disease or cancer No contraindications to aspirin or vitamin E

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Vitamin E (600 IU every other day) and aspirin (100 mg every other day) | Drug: Aspirin<br>* Participants will receive 100 mg of aspirin every other day.<br>Drug: Vitamin E<br>* Participants will receive 600 IU of vitamin E every other day.<br>|
| Experimental: 2<br>Vitamin E (600 IU every other day) and placebo | Drug: Vitamin E<br>* Participants will receive 600 IU of vitamin E every other day.<br>Behavioral: Placebo<br>* Participants will receive placebo.<br>|
| Experimental: 3<br>Aspirin (100 mg every other day) and placebo | Drug: Aspirin<br>* Participants will receive 100 mg of aspirin every other day.<br>Behavioral: Placebo<br>* Participants will receive placebo.<br>|
| Placebo Comparator: 4<br>Placebo and placebo | Behavioral: Placebo<br>* Participants will receive placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Major Cardiovascular Events (a Combined Endpoint of Nonfatal Myocardial Infarction, Nonfatal Stroke, and Total Cardiovascular Death) |  | Average follow-up 10.1 years | 
| Number of Participants With Cancer, Excluding Nonmelanoma Skin Cancer |  | Average follow-up 10.1 years |