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Overestimation of the effects of adherence on outcomes: a case study in healthy user bias and hypertension
  1. Joanne LaFleur1,2,
  2. Richard E Nelson2,3,
  3. Brian C Sauer2,3,
  4. Jonathan R Nebeker4
  1. 1Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA
  2. 2Informatics, Decision Enhancement, and Surveillance (IDEAS) Center, VA Salt Lake City Health Care System, Salt Lake City, UT, USA
  3. 3Department of Medicine, University of Utah, Salt Lake City, UT, USA
  4. 4Geriatrics Research, Education, and Clinical Center, VA Salt Lake City Health Care System, Salt Lake City, UT, USA
  1. Correspondence to Joanne LaFleur, Assistant Professor, Department of Pharmacotherapy, University of Utah, 30 S. 2000 East, Room 258, Salt Lake City, Utah, 84112, USA; joanne.lafleur{at}


Background The healthy user bias is usually overlooked as an explanation in studies in which a strong association is found between poor patient medication adherence and worse disease outcomes. Such studies are increasing in frequency across disease states and influence clinical practice. Adherence to antihypertensive medications was studied to illustrate confounding in such studies.

Methods Using data from veterans with hypertension starting antihypertensive treatment, causal models were developed that predicted the risks of hospitalisation, myocardial infarction (MI) and death associated with poor adherence (<80%) while adjusting for patient demographics, baseline disease severity and disease comorbidity. In a second set of otherwise identical models, adjustment was made for time-varying blood pressure (BP), thus controlling for adherence effects that were mediated through the main pharmacological effects of the drugs. It was hypothesised that the second set of models would reveal a positive association between poor adherence and adverse disease outcomes that is largely explained by unmeasured confounders, including health-related behaviours.

Results The models that did not adjust for time-varying BP levels showed that patients with poor adherence had statistically significantly increased risks of 3.7% for hospitalisation, 28.1% for MI and 23.3% for death. These estimates exceed the benefits of these drugs demonstrated by clinical trials. When controlling for time-varying BP, the increased risks were similar (3.4% for hospitalisation, 27.7% for MI and 23.4% for death). The findings were consistent across a range of adherence thresholds (50–90%) and when allowing disease status variables to vary.

Conclusions The associations between poor adherence and outcomes are largely independent of the pharmacological effects of the drugs on BP control as well as commonly measured patient covariates. This finding suggests that even carefully designed observational adherence studies using rich clinical data are impossibly confounded and probably overestimate the true magnitude of the effect. Clinical practice guidelines based on reported adherence effects should be reconsidered.

  • ACE
  • angiotensin receptor blockers
  • β blockers
  • calcium channel blockers, epidemiology

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  • Funding This project was supported by the Veterans Affairs (VA) Geriatric Research, Education, and Clinical Center (GRECC), the University of Utah Primary Care Research Center Scholarship and Novartis Pharmaceuticals.

  • Competing interests JL has support from the United States (US) Veterans Affairs (VA) Geriatric Research, Education, and Clinical Center (GRECC), the University of Utah Primary Care Research Center Scholarship and Novartis Pharmaceuticals for the submitted work. JL, REN, BCS and JRN have no relationships with any other companies that might have an interest in the submitted work in the previous 3 years or any non-financial interests that may be relevant to the submitted work. Their spouses, partners, or children have no financial relationships that might be relevant to the submitted work.

  • Ethics approval This study was conducted with the approval of the University of Utah Institutional Review Board and Salt Lake City Veterans Affairs Office of Research and Development.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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