Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial

Abstract

Observational research on postmenopausal hormone therapy suggests a 40-50% reduction in coronary heart disease incidence among women using these preparations. In contrast, the Women's Health Initiative clinical trial of estrogen plus progestin found an elevated incidence over a 5.6-year intervention period through July 7, 2002. Toward explaining this discrepancy, the authors analyzed data from this trial, which included 16,608 postmenopausal women aged 50-79 years, and corresponding data from 53,054 women in the Women's Health Initiative observational study, 33% of whom were estrogen-plus-progestin users at baseline. Estrogen-plus-progestin hazard ratio estimates for coronary heart disease, stroke, and venous thromboembolism in the observational study were 39-48% lower than those in the clinical trial following age adjustment. However, hazard ratios tended to decrease with increasing time from initiation of estrogen-plus-progestin use, and observational study hazard ratio estimates are heavily weighted by longer-term use while clinical trial hazard ratio estimates reflect shorter-term use. Following control for time from estrogen-plus-progestin initiation and confounding, hazard ratio estimates were rather similar for the two cohorts, although there was evidence of some remaining difference for stroke. These analyses have implications for both the design and the analysis of observational studies.

Interpretation of the evidence for the efficacy and safety of statin therapy

“…121,122 Likewise, randomized trials have not confirmed the 30% increased risk of breast cancer found in observational studies of estrogen-alone preparations, although the results for combined estrogen-progestin preparations appear similar. [123][124][125] Despite these discrepancies, the similarity of the direction -but not the size 126,127 -of the differences in the rates of stroke and pulmonary embolism in observational studies and in randomized trials of hormone replacement therapy has been used to justify continued reliance on observational evidence, 2 rather than as an illustration of the difficulty of determining which -if any -associations with treatment in observational studies provide a reliable basis for safe and effective care of patients and the public.…”

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

“…However, the proportion of women at high risk for VTE was similar across all the estrogen and progestogen subgroups. In addition, adjustment for these potential confounders and other relevant covariates 38 made few changes to the results. On the other hand, stratified analyses by characteristics of hormone therapy, including estrogen dose and duration of treatment, 38 showed consistent results.…”

“…In addition, adjustment for these potential confounders and other relevant covariates 38 made few changes to the results. On the other hand, stratified analyses by characteristics of hormone therapy, including estrogen dose and duration of treatment, 38 showed consistent results. Another selection bias could be related to the differential prescription of progestogens according to the estrogen status of women using hormone therapy.…”

Promises and pitfalls of electronic health record analysis

“…Including prevalent users in a study of drug effects can lead to serious bias if treatment effects or risks vary over time, as is often (although not always) the case in diabetes. This is because prevalent users will have already 'survived' the early period of therapy [31]. For this reason, so-called new-user designs are generally encouraged, wherein new drug users are typically identified by requiring a certain period (e.g.…”