title: Validation of methods to control for immortal time bias in a pharmacoepidemiologic analysis of renin-angiotensin system inhibitors in type 2 diabetes.
abstract: BACKGROUND
  Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin-angiotensin system (RAS) inhibitors as the reference cardioprotective drug.
  
  
  METHODS
  We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs.
  
  
  RESULTS
  During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68-1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs.
  
  
  CONCLUSIONS
  In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital.
authors.forename: Xilin
authors.initials: X
authors.lastname: Yang
authors.forename: Alice Ps
authors.initials: AP
authors.lastname: Kong
authors.forename: Andrea Oy
authors.initials: AO
authors.lastname: Luk
authors.forename: Risa
authors.initials: R
authors.lastname: Ozaki
authors.forename: Gary Tc
authors.initials: GT
authors.lastname: Ko
authors.forename: Ronald Cw
authors.initials: RC
authors.lastname: Ma
authors.forename: Juliana Cn
authors.initials: JC
authors.lastname: Chan
authors.forename: Wing Yee
authors.initials: WY
authors.lastname: So
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015982:Bias; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D017891:Pharmacoepidemiology; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents
references.citation: Am J Epidemiol. 2008 Feb 15;167(4):492-9
references.pmid: 18056625
references.citation: Am J Epidemiol. 1999 Jun 1;149(11):981-3
references.pmid: 10355372
references.citation: Nephrol Dial Transplant. 2008 Sep;23(9):2834-40
references.pmid: 18372388
references.citation: J Epidemiol. 2013 Sep 5;23(5):344-50
references.pmid: 23912052
references.citation: Pharmacoepidemiol Drug Saf. 2007 Mar;16(3):241-9
references.pmid: 17252614
references.citation: Cardiovasc Diabetol. 2010 Nov 22;9:77
references.pmid: 21092182
references.citation: Diabet Med. 1993 May;10(4):371-7
references.pmid: 8508624
references.citation: Diabetes. 2010 May;59(5):1129-31
references.pmid: 20427699
references.citation: Diabetes Res Clin Pract. 2012 Apr;96(1):68-75
references.pmid: 22197527
references.citation: J Diabetes. 2014 Jan;6(1):30-2
references.pmid: 23944992
references.citation: Arch Intern Med. 2008 Mar 10;168(5):451-7
references.pmid: 18332288
references.citation: Am J Epidemiol. 2005 Nov 15;162(10):1016-23
references.pmid: 16192344
references.citation: BMJ. 2010 Mar 12;340:b5087
references.pmid: 20228141
references.citation: J Am Geriatr Soc. 1999 Jun;47(6):749-54
references.pmid: 10366179
references.citation: Diabetes Care. 2007 Apr;30(4):953-9
references.pmid: 17259475
references.citation: Diabetes Care. 2011 Feb;34(2):375-80
references.pmid: 20980414
references.citation: J Am Soc Nephrol. 2006 Oct;17(10):2937-44
references.pmid: 16988059