Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study

Abstract

Objectives: Electronic health records (EHR) provide a valuable resource for assessing drug side-effects, but treatments are not randomly allocated in routine care creating the potential for bias. We conduct a case study using the Prior Event Rate Ratio (PERR) Pairwise method to reduce unmeasured confounding bias in side-effect estimates for two second-line therapies for type 2 diabetes, thiazolidinediones, and sulfonylureas.

Study design and settings: Primary care data were extracted from the Clinical Practice Research Datalink (n = 41,871). We utilized outcomes from the period when patients took first-line metformin to adjust for unmeasured confounding. Estimates for known side-effects and a negative control outcome were compared with the A Diabetes Outcome Progression Trial (ADOPT) trial (n = 2,545).

Results: When on metformin, patients later prescribed thiazolidinediones had greater risks of edema, HR 95% CI 1.38 (1.13, 1.68) and gastrointestinal side-effects (GI) 1.47 (1.28, 1.68), suggesting the presence of unmeasured confounding. Conventional Cox regression overestimated the risk of edema on thiazolidinediones and identified a false association with GI. The PERR Pairwise estimates were consistent with ADOPT: 1.43 (1.10, 1.83) vs. 1.39 (1.04, 1.86), respectively, for edema, and 0.91 (0.79, 1.05) vs. 0.94 (0.80, 1.10) for GI.

Conclusion: The PERR Pairwise approach offers potential for enhancing postmarketing surveillance of side-effects from EHRs but requires careful consideration of assumptions.

Keywords: Electronic health record; Observational data; PERR Pairwise; Pharmacovigilance; Side-effects; Unmeasured confounding.

Fig. 1

How to compute the PERR, PERR-ALT, and Pairwise estimates. Abbreviations: PERR, Prior Event Rate Ratio.

Fig. 2

Schematic of Prior Event Rate Ratio method for our case study. SU group are equivalent to the “Unexposed” group and TZD to the “exposed” group in the standard definitions of the PERR methodology. Time between start MFN and start SU/TZD is a maximum of 5 y. Pre-exposure and follow-up periods are up to 2 y. Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione; MFN, metformin; PERR, Prior Event Rate Ratio.

Fig. 3

Case study results: adjusted models, PERR Pairwise N = 32,242 SU N = 9,629 TZD in edema and gastrointestinal analyses, N = 10,807 SU N = 4,468 weight gain analysis. Column 4 shows percentage of patients who experience the side-effect in each period. An HR greater than 1 indicates a greater risk of side-effect in the TZD group relative to SU. An HR less than 1 indicates greater risk of a side-effect in the SU group. HR from the prior and study are used to calculate PERR; PERR Pairwise is calculated by minimizing the negative log-likelihood of the paired Cox model. Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione; MFN, metformin; HR, hazard ratio; PERR, Prior Event Rate Ratio.