Jill Miller, MD; Benjamin K.S. Chan, MS; Heidi D. Nelson, MD, MPH
Acknowledgments: The authors thank Steven Teutsch, MD, MPH, and Janet Allan, PhD, RN, from the U.S. Preventive Services Task Force and Mark Helfand, MD, MS, from the Evidence-Based Practice Center for their helpful comments on earlier versions of this review. They also thank Peggy Nygren, MA, for assistance with manuscript preparation.
Grant Support: By the Oregon Health & Science University Evidence-Based Practice Center, under contract (no. 290-97-0018, task order no. 2) to the Agency for Healthcare Research and Quality. Additional support came from the Portland Veterans Affairs Medical Center Women's Health Fellowship.
Requests for Single Reprints: Jill Miller, MD, Oregon Health & Science University, Mail Code BICC 504, 3181 SW Sam Jackson Park Road, Portland, OR 97201.
Current Author Addresses: Drs. Miller and Nelson and Mr. Chan: Oregon Health & Science University, Mail code BICC 504, 3181 Southwest Sam Jackson Park Road, Portland, OR 97201.
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 case–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 case–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.
Table 1. Characteristics of Estrogen Studies
Table 2. Studies of Estrogen Included in the Meta-Analysis
Risk for venous thromboembolism by year of estrogen use.
Meta-analysis of estrogen studies.
Flowchart diagram of search and selection of articles.
Appendix Table. Summary of Meta-Analysis Results of Estrogen Replacement and Venous Thromboembolism
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. ;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.
Endocrine and Metabolism, Venous Thromboembolism.
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