The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety

Abstract

Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01).

Use of Disproportionality Analysis to Identify Previously Unknown Drug-Associated Causes of Cardiac Arrhythmias Using the Food and Drug Administration Adverse Event Reporting System (FAERS) Database

“…33 Their findings indicated no difference in association between the 2 thiazolidinediones of sudden cardiac death or ventricular arrythmias. 33 Despite these findings, the FAERS database may yield key safety information for rosiglitazone and other potential medication associations found in our study.…”

“…32 Nonetheless, Leonard et al examined outcomes of rosiglitazone versus pioglitazone in sudden cardiac death, which included ventricular arrhythmias. 33 Their findings indicated no difference in association between the 2 thiazolidinediones of sudden cardiac death or ventricular arrythmias. 33 Despite these findings, the FAERS database may yield key safety information for rosiglitazone and other potential medication associations found in our study.…”

Predictors of Sudden Cardiac Arrest Among Patients With Post‐Myocardial Infarction Ejection Fraction Greater Than 35%

“…Third, although SCA was not validated in the Optum database per se, prior studies have validated SCA in large administrative data sets like Optum. 44 , 45 Finally, the mechanism of SCA cannot be determined from this study. Although arrhythmic SCA can be prevented by ICD therapy, events due to nonarrhythmic causes would not be affected.…”

Current and recommended practices for evaluating adverse drug events using electronic health records: A systematic review

“…The remaining were a prospective cohort study 36 and a genome-wide association study. 37 All studies utilized EHR data, of which 18 (69.2%) [14][15][16]18,19,22,23,[25][26][27][28][29][30][31][32][34][35][36] analyzed claims databases as well. The sample sizes ranged from 100 to 1000 (n = 4, 15.4%), 1001 to 10 000 (n = 7, 26.9%), and > 10 000 (n = 15, 57.7%).…”