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A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

Background: The use of aspirin in primary prevention of cardiovascular disease in women has been based on limited direct data from women.

Objective: The purpose of the study was to evaluate the balance of risks and benefits of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in women.

Methods: This was a large, placebo-controlled, randomized primary prevention trial. Letters of invitation were mailed to more than 1.7 million female health professionals. Eligibility criteria included: female; aged 45 years or older; no history of coronary heart disease, cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other major chronic illnesses; no history of side effects to any of the study medications; not taking any aspirin or NSAIDs more than once a week (or were willing to forego their use during the trial); not taking anticoagulants or corticosteriods; and not taking individual supplements of vitamin A, E or beta carotene more than once a week. A total of 39,876 women underwent randomization: 19,934 were assigned to receive aspirin and 19,942 to receive placebo. The women were sent a year’s supply of monthly calendar packs containing active agents or placebo as well as questionnaires on compliance, side effects, the occurrence of relevant clinical end-points, and risk factors. Subjects received 100mg aspirin on alternate days or placebo by mouth and were monitored for an average of 10.1 (range, 8.2 to 10.9) years for a first major cardiovascular event. Originally the study included vitamin E 600IU every other day and beta-carotene 50mg every other day. These were components of the trial for a median of 2.1 years. The primary outcome measure was a combination of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and death from cardiovascular causes. Secondary end-points included the individual end-points of fatal or nonfatal MI, fatal or nonfatal stroke, ischemic stroke, hemorrhagic stroke, and death from cardiovascular causes. Cardiovascular outcomes were confirmed or refuted by an endpoints committee that reviewed medical records in a blinded fashion. To examine the effects among women who were compliant, a sensitivity analysis was performed on women who were greater than two-thirds compliant. Subgroup analyses were performed according to the presence or absence of major cardiovascular risk factors. A power of 86% was reported for the primary endpoint but was not reported for the secondary endpoints or subgroup analyses. All primary analyses were performed on an intention-to-treat basis. Cox proportional-hazards models were used to calculate relative risks and 95 percent confidence intervals were reported for the comparison of events in the aspirin and placebo groups after adjustment for age and other randomized treatment assignments (vitamin E and beta-carotene).

Results: At the completion of the trial, 999 women had a first major cardiovascular event: 477 in the aspirin group and 522 in the placebo group. There was a reduction in risk of 9% (RR, 0.91; 95% CI, 0.80 to 1.03; p=0.13) for the primary end-point. Women in the aspirin group had a 17% reduction in the risk of stroke (RR, 0.83; 95% CI, 0.69 to 0.99; p=0.04) as compared to women in the placebo group; a 24 % reduction in the risk of ischemic stroke (RR, 0.76; 95% CI, 0.63 to 0.93; p=0.009); and a increase in the risk of hemorrhagic stroke (RR, 1.24; 95% CI, 0.82 to 1.87; p=0.31). As compared with placebo, there was no evidence that aspirin reduced the risk of fatal or nonfatal MI (RR, 1.02; 95% CI, 0.84 to 1.25; p=0.83), or death from cardiovascular causes (RR 0.95; 95% CI, 0.74 to 1.22; p=0.68). Subgroup analyses showed no evidence that any of the cardiovascular risk factors considered, except smoking status and age, modified the effect of aspirin on the primary endpoint of major cardiovascular events. In the subgroup of women aged 65 or greater at study entry, the risk of major cardiovascular events was reduced by 26 percent among those who took aspirin compared to placebo (RR, 0.74, 95% CI, 0.59 to 0.92; p=0.008), and the risk of ischemic stroke was reduced by 30 percent (RR, 0.70; 95% CI, 0.49 to 1.00; p=0.05). This was also the only subgroup in which aspirin significantly reduced the risk of MI (RR, 0.66; 95% CI, 0.44 to 0.7; p=0.04). Reports of GI bleed and peptic ulcer were confirmed by means of follow-up questionnaires. GI bleed requiring transfusion in the aspirin group was more frequent as compared with the placebo group (RR 1.40, 95%CI 1.07 to 1.83 p=0.02). The authors concluded that aspirin lowered the risk of stroke without affecting the risk of MI or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point.

Strengths: This was a prospective, randomized, placebo-controlled study in a peer-reviewed journal. There were a large number of study subjects. The subjects were blinded to treatment. Outcomes were confirmed or refuted by an endpoints committee in a blinded fashion.

Weaknesses: This study was 10 years in duration, but this may not have been long enough considering that the subgroup with consistent benefits were aged 65 and older at study entry. Approximately 90% of women were aged 45 to 64 years and were at lower risk throughout the study. Subgroup analyses contained a smaller number of people and may not have provided enough power. The dose of 100mg of aspirin every other day may not have been sufficient to prevent cardiovascular complications and the regimen may have been difficult to be compliant with. Also, compliance was assessed on the basis of questionnaires, which could have led to inaccurate reporting of compliance. Diet was not standardized or accounted for in the study, which could have affected cardiovascular risk.

Conclusions:

Low-dose aspirin may be beneficial in women 65 years of age and older in preventing major cardiovascular events, ischemic stroke and MI. Aspirin lowered the risk of stroke in women less than 65 years old, but not myocardial infarction or death from cardiovascular causes. Although, this study did not find low-dose aspirin to be beneficial in the primary prevention of cardiovascular events in women less than 65 years of age, power and study length may have been insufficient in this subgroup. More research in women is needed to further validate this finding; ideally, a large-scale trial of longer duration. The decision to use low-dose aspirin in women needs to be made on an individual basis after weighing individual risks and benefits.

Ridker PM, Cook NR, Lee I, Gordon D, Gaziano JM, Manson JE, Hennekens CH, and Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New Eng J Med. 2005:352.

Kolleen Koast, Pharm D. Candidate