Updating Insights into Rosiglitazone and Cardiovascular Risk through Shared Data: Individual Patient- and Summary-Level Meta-Analyses

Objective To conduct a systematic review and meta-analysis of the effects of rosiglitazone therapy on cardiovascular risk and mortality using multiple data sources and varying analytical approaches. Design Systematic review and meta-analysis of randomized controlled trials. Data sources GlaxoSmithKline’s (GSK) Clinical Study Data Request (CSDR) and Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019. Study selection criteria Randomized, controlled, phase II-IV clinical trials comparing rosiglitazone with any control for at least 24 weeks in adults. Data extraction and synthesis For analyses of trials for which individual patient-level data (IPD) were available, we examined a composite of the following events as our primary outcome: acute myocardial infarction, heart failure, cardiovascular-related deaths, and non-cardiovascular-related deaths. As secondary analyses, these four events were examined independently. When also including trials for which IPD were not available, we examined myocardial infarction and cardiovascular-related deaths, ascertained from summary-level data. Multiple meta-analyses were conducted, accounting for trials with zero events in one or all arms with two different continuity corrections (i.e., 0.5 constant and treatment arm comparator continuity correction), to calculate odds ratios and risk ratios with 95% confidence intervals. Results There were 33 eligible trials for which IPD were available (21156 participants) through GSK’s CSDR. We also identified 103 additional trials for which IPD were not available from which we ascertained myocardial infarctions (23683 patients) and 103 trials for cardiovascular-related deaths (22772 patients). Among trials for which IPD were available, we identified a greater number of myocardial infarctions and fewer cardiovascular-related deaths reported in the IPD as compared to the summary-level data. When limited to trials for which IPD were available and accounting for trials with zero-events in only one arm using a constant continuity correction of 0.5, patients treated with rosiglitazone had a 39% increased risk of a composite event compared with controls (Mantel-Haenszel odds ratio 1.39, 95% CI 1.15 to 1.68). When examined separately, the odds ratios for myocardial infarction, heart failure, cardiovascular-related death, and non-cardiovascular-related death were 1.25 (0.99 to 1.60), 1.60 (1.20 to 2.14), 1.18 (0.64 to 2.17), and 1.13 (0.58 to 2.20), respectively. When all trials for which IPD were and were not available were combined for myocardial infarction and cardiovascular-related deaths, the odds ratios were attenuated (1.13 (0.92 to 1.38) and 1.10 (0.73 to 1.65), respectively). Effect estimates and 95% confidence intervals were broadly consistent when analyses were repeated including trials with zero events across all arms using constant continuity corrections of 0.5 or treatment arm continuity corrections. Conclusions Results of this comprehensive meta-analysis aggregating a multitude of trials and analyzed using a variety of statistical techniques suggest that rosiglitazone is consistently associated with an increased cardiovascular risk, likely driven by heart failure events, whose interpretation is complicated by varying magnitudes of myocardial infarction risk that were attenuated through aggregation of summary-level data in addition to IPD. Systematic review registration https://osf.io/4yvp2/ What is already known on this topic - Since 2007, there have been multiple meta-analyses, using various analytic approaches, that have reported conflicting findings related to rosiglitazone’s cardiovascular risk. - Previous meta-analyses have relied primarily on summary-level data, and did not have access to individual patient-level data (IPD) from clinical trials. - Currently, there is little consensus on which method should be used to account for sparse adverse event data in meta-analyses. What this study adds - Among trials for which IPD were available, rosiglitazone use was consistently associated with an increased cardiovascular risk, likely driven by heart failure events. - Interpretation of rosiglitazone’s cardiovascular risk is complicated by varying magnitudes of myocardial infarction risk that were attenuated through aggregation of summary-level data in addition to IPD. - Among trials for which IPD were available, we identified a greater number of myocardial infarctions and fewer cardiovascular deaths reported in the IPD as compared to the summary-level data, which suggests that IPD may be necessary to accurately classify all adverse events when performing meta-analyses focused on safety.