title: Overestimation of the effects of adherence on outcomes: a case study in healthy user bias and hypertension.
abstract: 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.
authors.affiliation: Department of Pharmacotherapy, University of Utah, Salt Lake City, 84112, USA. joanne.lafleur@pharm.utah.edu
authors.forename: Joanne
authors.initials: J
authors.lastname: LaFleur
authors.forename: Richard E
authors.initials: RE
authors.lastname: Nelson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Sauer
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Nebeker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D015982:Bias; D001794:Blood Pressure / Q000187:drug effects*; D016022:Case-Control Studies; D019317:Evidence-Based Medicine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D007297:Inpatients / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D018570:Risk Assessment; D012307:Risk Factors; D012494:Sampling Studies; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014728:Veterans / Q000706:statistics & numerical data; D016903:Drug Monitoring
chemical_list: D000959:Antihypertensive Agents