Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin–Angiotensin System Inhibitors in Type 2 Diabetes

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  • Yang Xilin
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University
  • Kong Alice PS
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital
  • Luk Andrea OY
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital
  • Ozaki Risa
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital
  • Ko Gary TC
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital
  • Ma Ronald CW
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital
  • Chan Juliana CN
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital
  • So Wing Yee
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital

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  • Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin^|^ndash;Angiotensin System Inhibitors in Type 2 Diabetes

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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.<BR>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.<BR>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.<BR>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.

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