Placebo Adherence, Clinical Outcomes, and Mortality in the Women's Health Initiative Randomized Hormone Therapy Trials

Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1530 3rd Ave South, FOT 805D, Birmingham, AL 35294, USA.
Medical care (Impact Factor: 3.23). 03/2011; 49(5):427-35. DOI: 10.1097/MLR.0b013e318207ed9e
Source: PubMed


Medication adherence may be a proxy for healthy behaviors and other factors that affect outcomes. Prior studies of the association between placebo adherence and health outcomes have been limited primarily to men enrolled in clinical trials and cardiovascular disease outcomes. We examined associations between adherence to placebo and the risk of fracture, coronary heart disease, cancer, and all-cause mortality in the 2 Women's Health Initiative hormone therapy randomized trials.
Postmenopausal women randomized to placebo with adherence measured at least once were eligible for analysis. Time-varying adherence was assessed by dispensing history and pill counts. Outcome adjudication was based on physician review of medical records. Cox proportional hazards models evaluated the relation between high adherence (≥80%) to placebo and various outcomes, referent to low adherence (<80%).
A total of 13,444 postmenopausal women were under observation for 106,066 person-years. High placebo adherence was inversely associated with most outcomes including hip fracture [hazard ratio (HR), 0.50; 95% confidence interval (CI), 0.33-0.78], myocardial infarction (HR, 0.69; 95% CI, 0.50-0.95), cancer death (HR, 0.60; 95% CI, 0.43-0.82), and all-cause mortality (HR, 0.64; 95% CI, 0.51-0.80) after adjustment for potential confounders. Women with low adherence to placebo were 20% more likely to have low adherence to statins and osteoporosis medications.
In the Women's Health Initiative clinical trials, high adherence to placebo was associated with favorable clinical outcomes and mortality. Until the healthy behaviors and/or other factors for which high adherence is a proxy can be better elucidated, caution is warranted when interpreting the magnitude of benefit of medication adherence.

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    • "One study analyzed the same placebo subjects as in the present study [19]. This study found that women with adherence to placebo less than 80% had significantly worse outcomes than women with greater adherence. "
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    ABSTRACT: Background Previous studies found an association of greater adherence to placebo medication with better outcomes. The present study tested whether this association was explained by any of the following factors: 1) adherence to other medications, 2) healthcare behaviors, 3) disease risk, or 4) predicted degree of adherence. Data included information on more than 800 risk factors from 27,347 subjects in two randomized controlled trials of hormone therapy in the Women's Health Initiative. Results Greater adherence to placebo was not associated with colon cancer but was substantially and significantly associated with several diverse outcomes: death, myocardial infarction, stroke, and breast cancer. Adherence to hormone therapy was only weakly associated with outcomes. The WHI risk factors only poorly predicted degree of adherence, R2 < 4%. No underlying factors accounted for the association between placebo adherence and outcome. Conclusion The results suggest that adherence to placebo is a marker for important risk factors that were not measured by WHI. Once identified these risk factors may be used to increase the validity of observational studies of medical treatment by reducing unmeasured confounding.
    Emerging Themes in Epidemiology 02/2013; 10(1):1. DOI:10.1186/1742-7622-10-1 · 2.59 Impact Factor
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    • "Finally, we note that whenever adherence was measured, we were obtaining information on more than the ingestion of medication. Research shows that adherence to a placebo is consistently associated with mortality risk in various patient populations (34,35). The relationship between measures of medication adherence and clinical outcomes likely reflects other behaviors and respondent characteristics that directly influence health; this is often referred to as the “healthy adherer effect.” "
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