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
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.
Available from: Arthur J Hartz
- "One study analyzed the same placebo subjects as in the present study . 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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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.
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.
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.
Available from: Enrico Cagliero
- "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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To assess the validity of self-report measures of diabetes medication adherence and evaluate the effect of depression on the validity of these reports.RESEARCH DESIGN AND METHODS
Adults with type 2 diabetes, treated with oral medications, completed a set of medication adherence self-reports that varied response scales and time frames, were administered structured clinical interviews for depression, and provided blood samples for HbA(1c) as part of a screening for an intervention study. A subsample of participants with HbA(1c) ≥7.0% and clinically significant depression received Medication Event Monitoring System (MEMS) bottle caps to record adherence. Analyses examined relationships between adherence measures and HbA(1c) and, in the subsample, MEMS. Moderated linear regression evaluated whether depression severity modified relationships with HbA(1c).RESULTSParticipants' (n = 170, 57% men, 81% white, mean HbA(1c) = 8.3% [SD, 1.7]) adherence self-reports were significantly (r = -0.18 to -0.28; P < 0.03) associated with lower HbA(1c). In the subsample (n = 88), all self-reports were significantly (r = 0.35 to 0.55; P ≤ 0.001) associated with MEMS-measured adherence. Depression significantly moderated the relationship between three of six self-reports and HbA(1c); at high levels of depression, associations with HbA(1c) became nonsignificant.CONCLUSIONS
Results support the validity of easily administered self-reports for diabetes medication adherence. One-month, percentage-based ratings of adherence had the strongest associations with MEMS and HbA(1c); those requiring the report of missed doses had weaker associations. One-week self-ratings and measures that require respondents to record the number of missed doses appear to be vulnerable to bias from depression severity.
Available from: Francesco Cappuccio
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ABSTRACT: Overwhelming evidence shows that reducing salt intake from 9-12 to 5-6 g/d lowers blood pressure, thereby preventing cardiovascular disease. A recent paper claims that lower salt intake is associated with higher cardiovascular mortality despite lower blood pressure. The study is flawed and cannot refute the evidence for the benefits of salt reduction. The WHO recommends salt reduction as crucial in tackling the global non-communicable-disease crisis. A reduction in population salt intake remains a public-health priority.
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