Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone

Background A meta-analysis of randomized controlled trials suggested that rosiglitazone, a drug used for the treatment of diabetes, may be associated with an increased risk of cardiovascular adverse events. Three large randomized trials, designed specifically to address cardiovascular outcomes of rosiglitazone treatment, have published new or updated results. Purpose To provide a cumulative summary of the clinical trial evidence on rosiglitazone along with a sensitivity analysis of different methods to estimate the combined effect. Methods A previous meta-analysis (N Engl I Med 2007; 356: 2457-2471) was updated to include event rates of myocardial infarction and death due to cardiovascular causes from the recent reports of the RECORD, DREAM and ADOPT trials. Odds ratios (OR) with their confidence intervals were calculated for all outcomes using the Mantel-Haenszel method with Robins-Breslow-Greenland variance estimation and a fixed effects model. Sensitivity analysis was performed, using different methods for estimating the combined effect and using different continuity corrections for studies with zero events in one or both arms. Results Rosiglitazone was associated with an increased risk of myocardial infarction (OR, 1.29; Cl: 1.01-1.66; p = 0.05) but not death due to cardiovascular causes (OR, 1.12; Cl: 0.80-1.55; p=0.58). Pooled analysis of the ADOPT, RECORD, and DREAM trials did not reach statistical significance for either myocardial infarction (OR, 1.29; Cl: 0.95-1.74; p = 0.12) or death due to cardiovascular causes (OR, 0.90; Cl: 0.61-1.33; p=0.67). Based on these three trials, rosiglitazone was associated with a clear increase in the risk of heart failure (OR, 2.17; Cl: 1.49-3.17; p < 0.0001). Despite minor discrepancies, different calculation methods demonstrated an increased risk of myocardial infarction for rosiglitazone treated patients. There was no evidence of an association between rosiglitazone and death due to cardiovascular causes regardless of the calculation method used. The increased risk of heart failure conferred by rosiglitazone treatment was consistently demonstrated across different calculation methods. Limitations Trials with short-term follow-up and trials not specifically designed to evaluate cardiovascular outcomes were included in this meta-analysis and patient-level data where not available. Conclusions Rosiglitazone appears to be associated with an increased risk of myocardial infarction and heart failure, but not death due to cardiovascular causes. When a meta-analysis of rare events is contemplated, a thorough sensitivity analysis using different methods to combine studies and an evaluation of different continuity corrections should be undertaken. When possible, an individual patient data meta-analysis should be performed, allowing time-to-event analysis and the identification of patient subgroups at an increased risk of adverse outcomes.