Comparison of Different Case-Crossover Variants in Handling Exposure-Time Trend or Persistent-User Bias: Using Dipeptidyl Peptidase-4 Inhibitors and the Risk of Heart Failure as an Example.

OBJECTIVES: Inappropriate use of the case-crossover design, which is efficient for examining associations between brief exposure and abrupt outcomes, in evaluating the effects of medications in the presence of exposure-time trends or persistent drug use may generate spurious associations. We compared different approaches to adjusting for these sources of bias by examining the risk of heart failure hospitalization (HFH) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors. Overall, existing evidence does not suggest a higher risk of HFH associated with DPP-4 inhibitors; however, case-crossover analyses of these medications may be susceptible to bias. METHODS: We conducted case-crossover; age, sex, risk-set (ASR) matched case-time-control; disease risk score (DRS)-matched case-time-control; and case-case-time-control analyses to assess the association between DPP-4 inhibitors and HFH among patients with diabetes mellitus (DM) in a population-based Taiwanese database. We also examined metformin and sulfonylureas, both with assumed null associations. RESULTS: Among 362 022 DM patients, 4105 (case-crossover), 4103 (ASR-matched case-time-control), 3957 (DRS-matched case-time-control), and 2812 (case-case-time-control) HFH cases were identified. The OR for DPP-4 inhibitors and HFH was elevated in the case-crossover analysis (1.52; 95% confidence interval [95% CI] 0.95-2.42). The ASR-matched case-time control, DRS-matched case-time-control, and case-case-time control analyses yielded near-null associations (0.90 [95% CI 0.45-1.83], 0.96 [95% CI 0.46-2.02], and 0.92 [95% CI 0.39-2.21], respectively). Null effects were observed for metformin across designs and for sulfonylureas in the case-case-time control analysis. CONCLUSIONS: Our case-crossover analysis suggested DPP-4 inhibitors may be associated with HFH; however, each method for adjusting for exposure-time and persistent user bias attenuated the findings. The case-case-time-control analysis had the least precision.