title: The effect of adherence to statin therapy on cardiovascular mortality: quantification of unmeasured bias using falsification end-points.
abstract: BACKGROUND
  To determine the clinical effectiveness of statins on cardiovascular mortality in practice, observational studies are needed. Control for confounding is essential in any observational study. Falsification end-points may be useful to determine if bias is present after adjustment has taken place.
  
  
  METHODS
  We followed starters on statin therapy in the Netherlands aged 46 to 100 years over the period 1996 to 2012, from initiation of statin therapy until cardiovascular mortality or censoring. Within this group (n = 49,688, up to 16 years of follow-up), we estimated the effect of adherence to statin therapy (0 = completely non-adherent, 1 = fully adherent) on ischemic heart diseases and cerebrovascular disease (ICD10-codes I20-I25 and I60-I69) as well as respiratory and endocrine disease mortality (ICD10-codes J00-J99 and E00-E90) as falsification end points, controlling for demographic factors, socio-economic factors, birth cohort, adherence to other cardiovascular medications, and diabetes using time-varying Cox regression models.
  
  
  RESULTS
  Falsification end-points indicated that a simpler model was less biased than a model with more controls. Adherence to statins appeared to be protective against cardiovascular mortality (HR: 0.70, 95 % CI 0.61 to 0.81).
  
  
  CONCLUSIONS
  Falsification end-points helped detect overadjustment bias or bias due to competing risks, and thereby proved to be a useful technique in such a complex setting.
authors.affiliation: Unit PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, A. Deusinglaan 1, PO BOX 9713 AV, Groningen, The Netherlands. Maarten.bijlsma@rug.nl.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Bijlsma
authors.affiliation: Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Krijgslaan 281, S9, 9000, Ghent, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Vansteelandt
authors.affiliation: Population Research Centre (PRC), Faculty of Spatial Sciences, University of Groningen, Landleven 1, 9747 AD, Groningen, The Netherlands.
authors.forename: Fanny
authors.initials: F
authors.lastname: Janssen
authors.affiliation: Unit PharmacoEpidemiology & PharmacoEconomics (PE2), Department of Pharmacy, University of Groningen, A. Deusinglaan 1, PO BOX 9713 AV, Groningen, The Netherlands.
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015982:Bias; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D012306:Risk; D016903:Drug Monitoring
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: Bias; Cardiovascular; Falsification end-points; Mortality; Overadjustment; Statin therapy