Objective:

Cardiovascular disease (CVD) is the leading cause of death among women in the United States (US), and hormone replacement therapy (HRT) is commonly used, often for the prevention of CVD. The goal of this systematic evidence review and meta-analysis is to evaluate the association between HRT and the primary prevention of CVD, including total CVD, coronary artery disease (CAD), and stroke, when they were evaluated as separate subsets.

Data Sources:

The MEDLINE (1966-2000) and Cochrane databases were searched for all published studies reporting CVD, CAD, and stroke incidence and/or mortality in association with HRT among the general population of women; reference lists, letters, editorials, and reviews were also reviewed.

Methods:

All studies were reviewed, abstracted and rated in quality; only studies of good or fair quality according to U.S. Preventive Services Task Force (USPSTF) criteria were included in the detailed review and meta-analysis. Meta-analysis was conducted using a random effects model.

Results:

The summary relative risk for CVD mortality with any HRT use was 0.75 (95% CI, 0.42–1.23) and for current users was 0.64 (95% CI, 0.44–0.93). CAD mortality was associated with a relative risk of 0.74 (95% CI, 0.36–1.45) for any use and 0.62 (95% CI, 0.40–0.91) for current use. No significant association between HRT and risk of stroke death was identified. In contrast to the mortality findings, the summary relative risk for CVD incidence is 1.28 (95% CI, 0.86–2.00) for any use and 1.27 (95% CI, 0.80–2.00) for current use. Stroke incidence was significantly increased among women using HRT, with a summary relative risk of 1.12 (95% CI 1.01–1.23), largely due to a significant increase in atherothrombotic stroke among women using HRT.

In our meta-analysis, the pooled relative risk of CAD associated with any use of HRT was 0.87 (95% CI, 0.62–1.21) and for current use was 0.80 (95% CI, 0.68–0.95). When studies adjust for socioeconomic status (SES) as well as other major CAD risk factors, the summary relative risk of CAD is 0.97 (95% CI, 0.82–1.16) among current users and 1.04 (95% CI, 0.79–1.44) among ever users. Similar results were found when the analysis stratified by studies adjusting for alcohol consumption and/or exercise, in addition to other major risk factors.

Conclusion:

The association between HRT and CVD incidence and mortality, as well as CAD and stroke incidence and mortality, is uncertain, based on conflicting findings, and limited by lack of randomization and consequent selection biases among women using HRT in the observational studies. Our meta-analysis differs from prior meta-analyses by evaluating potential explanatory variables of the HRT-CVD/CAD relationship, as well as different measures of HRT exposure. It shows a small decrease in CVD and CAD deaths only among current HRT users and no effect on stroke, and suggests that SES, alcohol use, and exercise are important confounders of the HRT/CVD/CAD relationship. A valid answer to the potential role of HRT in the primary prevention of CVD will best come from randomized controlled trials.