Jill Miller, MD; Benjamin K.S. Chan, MS; Heidi D. Nelson, MD, MPH
Postmenopausal estrogen replacement is widely used in the United States but poses important health risks.
To assess the risk for venous thromboembolism with postmenopausal estrogen replacement by using literature review and meta-analysis.
All relevant English-language studies identified in searches of the MEDLINE (1966 to December 2000), HealthSTAR (1975 to December 2000), and Cochrane Library databases, and references lists of key articles.
All published studies of postmenopausal estrogen replacement reporting venous thromboembolism as an outcome or adverse event.
12 studies of estrogen were identified (3 randomized, controlled trials; 8 caseâ€“control studies; and 1 cohort study). Data were extracted on participants, interventions, event rates, and confounders. Two reviewers independently rated study quality on the basis of established criteria.
A Bayesian meta-analysis was conducted. When data from all studies were pooled, current estrogen use was associated with an increased risk for venous thromboembolism (relative risk, 2.14 [95% credible interval, 1.64 to 2.81]). Estimates did not significantly change when studies were pooled according to study design, quality score, or whether participants had preexisting coronary artery disease. The absolute rate increase was 1.5 venous thromboembolic events per 10 000 women in 1 year. Six caseâ€“control studies that reported risk according to duration of use found that risk was highest in the first year of use (relative risk, 3.49 [credible interval, 2.33 to 5.59]).
Postmenopausal estrogen replacement is associated with an increased risk for venous thromboembolism, and this risk may be highest in the first year of use.
Odds ratios for thromboembolic events were higher in the first or second year than in subsequent years in all six studies reporting results by year of use.
The pooled estimate of venous thromboembolism risk for all 12 studies meeting eligibility criteria was 2.14 (95% credible interval, 1.64 to 2.81). Numbers above the lines ending in arrows indicate the outer limits of the confidence intervals. PEPI = Postmenopausal Estrogen/Progestin Interventions trial.
Adequate randomization, including concealment and information on whether potential confounders were distributed equally among groups
Maintenance of comparable groups (includes attrition, cross-overs, adherence, contamination)
Important differential loss to follow-up or overall high loss to follow-up
Measurements: equal, reliable, and valid (includes masking of outcome assessment)
Clear definition of interventions
Important outcomes considered
Accurate ascertainment of cases
Nonbiased selection of case-patients and controls, with exclusion criteria applied equally to both
High response rate
Diagnostic testing procedures applied equally to each group
Measurement of exposure accurate and applied equally to each group
Appropriate attention to potential confounding variables
Consideration of potential confounders with either restriction or measurement for adjustment in the analysis; consideration of inception cohorts
Consideration of important outcomes
Adjustment for potential confounders in analysis
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Miller J, Chan BK, Nelson HD. Postmenopausal Estrogen Replacement and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:680-690. doi: 10.7326/0003-4819-136-9-200205070-00011
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Published: Ann Intern Med. 2002;136(9):680-690.
Prevention/Screening, Venous Thromboembolism.
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