Jill Miller

Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.

Although postmenopausal estrogen replacement is widely used (1), it poses important health risks. One risk is an increase in venous thromboembolic events. This relationship was initially established on the basis of studies of oral contraceptives (2) and was not supported by studies of postmenopausal estrogen replacement (3-5). Findings from more recent studies (6-13) indicate an increased risk. To precisely estimate the venous thromboembolic risk with postmenopausal estrogen replacement therapy, we reviewed the literature and conducted a meta-analysis of eligible studies. The most recent review of this topic did not include a meta-analysis (14). We conducted our review in conjunction with the U.S. Preventive Services Task Force to update the Task Forces recommendations on hormone replacement therapy. This paper is part of a larger project on hormone replacement therapy; other risks and benefits are reported separately (15). Methods With assistance from a medical librarian, we searched the following databases: MEDLINE (1966 to December 2000), HealthSTAR (1975 to December 2000), and the Cochrane Controlled Trials Register. Because venous thromboembolism is usually reported as a secondary or adverse outcome in studies with unrelated primary outcomes, we used multiple search terms: hormone replacement therapy, estrogen replacement, thromboembolism, thrombophlebitis, pulmonary embolism, blood clot, thrombosis, blood coagulation disorders, hemostasis, hypercoagulation, fibrinogen, fibrinolysis, anticoagulants, thrombolytic therapy, and randomized, controlled trials. Additional articles were obtained by reviewing reference lists of pertinent reports and reviews. We used only published data. Seven content experts reviewed this report. The studies included in this review enrolled postmenopausal women and included deep venous thrombosis, pulmonary embolism, or venous thromboembolism as a primary or secondary outcome or as a reportable adverse event related to estrogen use. When data were available, we report effects of dosage, duration, and progestin use. Only articles with English-language abstracts were considered. We excluded studies with participants selected on the basis of previous thrombotic events or presence of conditions that are associated with higher risk for thrombosis. From each included study, we abstracted the number of participants, treatment (for randomized, controlled trial) or definition and method of determining exposure (for casecontrol and cohort studies), event rates, confounders controlled for, methods of outcome measurement, and study duration. Two reviewers independently rated each studys quality using criteria developed by the U.S. Preventive Services Task Force (Appendix); ratings between reviewers had 76% agreement. Reviewer disagreements were resolved by consensus. We performed a meta-analysis of the 12 studies of estrogen use meeting the inclusion criteria. Two studies (11, 12) reported hazard ratios derived from Cox proportional-hazards models. A hazard ratio is the ratio of the instantaneous probability of venous thromboembolism in the treatment group compared with that in the control group and can be considered the relative risk. Two studies provided the raw data with which to calculate unadjusted relative risks (16, 17). One study provided data with which to calculate an age-adjusted relative risk (3). The remaining studies reported odds ratios from logistic regression models; for these studies, we used the most adjusted value provided (6-10, 13, 18). Because venous thromboembolism is a rare event, the odds ratio is a good estimate for the relative risk. Thus, for uniformity, we report pooled estimates as relative risk. Under the modeling assumptions made by each study, the logarithm of the relative risk (log relative risk) had a normal distribution. Standard errors for log relative risk were calculated from the reported 95% confidence intervals or from the raw data. The log relative risk and SEs provided the data points for the meta-analysis. We fit fixed-effects and random-effects models on the data using the Bayesian data analytic framework (19). We report only the random-effects model because the results of the two models were sufficiently similar. To analyze the data, we used WinBUGS software (20), which uses Gibbs sampling to simulate posterior probability distributions. Noninformative (proper) prior probability distributions were used (N[0, 106] for log relative risks). Point estimates and 95% credible intervals were calculated from 5000 simulated draws (1000 draws from 5 chains) from the posterior distribution after adequate convergence. Because the study designs among the 12 studies differed, a meta-analysis was performed for each study type, excluding the single cohort study. We constructed a regression model with study design as a variable and found no differences in results. Thus, we combined all 12 studies for a pooled analysis. In a sensitivity analysis, we combined only studies with a good or fair quality rating, studies enrolling participants with coronary artery disease, and studies excluding women with coronary artery disease. We evaluated studies for selection bias using funnel plots (21), and we investigated the sensitivity of the analysis to possible missing studies due to publication bias by using the trim and fill method (22, 23). The results were unaffected. The U.S. Agency for Healthcare Research and Quality funded this research. Agency for Healthcare Research and Quality staff and U.S. Preventive Services Task Force members helped design the study initially and reviewed interim analyses and the final manuscript. Results Search Results We identified 3363 abstracts from our search of postmenopausal estrogen and venous thromboembolism; most abstracts did not specifically address this topic and were excluded from full-text review. Twelve abstracts met the inclusion criteria and contained primary data (3 randomized, controlled trials [12, 16, 17]; 8 casecontrol studies [3, 6-10, 13, 18]; and 1 cohort study [11]). Three other studies (4, 5, 24) identified from a review article (14) did not meet the inclusion criteria (Appendix Figure). Randomized, Controlled Trials None of the 3 randomized, controlled trials had venous thromboembolism as a primary outcome (Table 1). The Heart and Estrogen/progestin Replacement Study (HERS) (12) was a 4-year secondary prevention trial of estrogen and progestin therapy in postmenopausal women with heart disease. Although the primary outcomes were nonfatal myocardial infarction or death from coronary heart disease, deep venous thrombosis and pulmonary embolism were reported as secondary outcomes. Deep venous thrombosis was diagnosed by using venography, impedance plethysmography, or ultrasonography; pulmonary embolism was diagnosed by nuclear lung scanning or pulmonary angiography. The treatment group had 34 venous thromboembolic events (2.5% of the 1380 participants), and the placebo group had 13 (0.9% of the 1383 participants) (Table 2). The hazard ratio for venous thromboembolism was 2.89 (95% confidence interval, 1.50 to 5.58). A second HERS report (25) presented idiopathic events (hazard ratio, 3.1 [confidence interval, 0.8 to 11.3]) and nonidiopathic events (hazard ratio, 2.5 [confidence interval, 1.2 to 5.3]) separately. Risk was highest in the first 2 years of estrogen use (Figure 1). Table 1. Characteristics of Estrogen Studies Table 2. Studies of Estrogen Included in the Meta-Analysis Figure 1. Risk for venous thromboembolism by year of estrogen use. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (16) studied healthy postmenopausal women receiving estrogen replacement, alone or with a progestin, in various forms and dosages compared with placebo. Four measures of cardiovascular risk were the primary end points. Thromboembolic events were reported as adverse experiences during the follow-up phase; the study did not report the method for measuring events. The definition of venous thromboembolism included deep venous thrombosis, pulmonary embolism, and superficial phlebitis. Ten venous thromboembolic events occurred among the four estrogen treatment groups, and none occurred in the placebo group (P > 0.2). The Estrogen Replacement and Atherosclerosis (ERA) trial (17) randomly assigned 309 women with angiographically proven coronary heart disease to estrogen, estrogen and progesterone, or placebo and performed follow-up coronary angiography after approximately 3 years to assess disease progression. A total of 8 venous thromboembolic events were reported5 in the estrogen group, 2 in the estrogenprogesterone group, and 1 in the placebo groupwith no significant difference among the groups (P = 0.16). The quality ratings, which used U.S. Preventive Services Task Force criteria, were good for HERS and fair for the PEPI and ERA trials (Table 2). Although HERS reported venous thromboembolism as a secondary outcome and described how the diagnosis was made, both the PEPI and ERA trials reported these events as an adverse experience and did not describe the method of diagnosis. The studies also differed in ways unrelated to quality ratings. The HERS and ERA trials enrolled older, postmenopausal women with documented coronary artery disease (mean age, 66.7 years), while the PEPI trial enrolled younger, healthy postmenopausal women (mean age, 56.1 years). The HERS trial (n = 2763) randomly assigned more than three times as many participants as the PEPI trial (n = 875) and nearly nine times as many as the ERA trial (n = 309), allowing for greater power to detect events. The PEPI trial included superficial phlebitis in its definition of venous thromboembolism and had only four cases of deep venous thrombosis or pulmonary embolism. CaseControl Studies Six (6-10, 13) of the 8 casecontrol studies reported an increased risk for venous thromboembolism with estrogen use; in 3 of the 6 studies, the results were statistically sig