Pharmaceutical Research

Confounding factors may be the reason that randomized controlled trials of HRT conflict with observational studies

Recent clinical trials demonstrating that hormone replacement therapy (HRT) does not prevent coronary heart disease in women have raised doubts concerning observational studies that had shown a cardioprotective effect of HRT. Much of the explanation likely lies in what has been called the "healthy user" effect. Most women who decided to use HRT probably had a more favorable cardiovascular risk factor profile than nonusers, and these differences were due to factors not measured in many of the observational studies, explains Wayne A. Ray, Ph.D., of Vanderbilt University Medical Center, in a recent article.

Dr. Ray points out that another contributing factor may be that most of the observational studies included women who had been taking HRT for some time before study followup began (prevalent users). This practice can cause two types of bias, both of which plausibly may have contributed to the discrepancy in findings between the observational and randomized studies of HRT.

First, prevalent users are "survivors" of the early period of medication, which can introduce substantial bias if risk varies with time, just as in studies of operative procedures that enroll patients after they have survived surgery. Second, covariates for drug users at study entry often are plausibly affected by the drug itself. Investigators often do not adjust for these factors on the causal pathway, which may introduce confounding. A new-user design, which eliminates these biases by restricting the analysis to people under observation at the start of the current course of treatment, should be used more frequently in pharmacoepidemiology research, concludes Dr. Ray. Dr. Ray's work was supported in part by the Agency for Healthcare Research and Quality through a cooperative agreement (HS10384) as part of the Agency's Centers for Education and Research on Therapeutics (CERTs) initiative.

See "Evaluating medication effects outside of clinical trials: New-user designs," by Dr. Ray, in the American Journal of Epidemiology 158(9), pp. 915-920, 2003.

Editor's Note: In a related study, Dr. Ray discusses the limitations of post-marketing studies of drug safety, which are usually observational studies of patients who receive drugs in the course of clinical practice. For details, see Ray, W.A. (2003, October). "Population-based studies of adverse drug effects." (AHRQ grant HS10384). New England Journal of Medicine 349(17), pp. 1592-1594.

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