title: Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: the case of rosiglitazone.
abstract: Rare cardiovascular events of commonly used drugs are important to document and investigate, but single trials are notoriously underpowered to provide conclusive evidence. Recently, meta-analyses have been used to improve on the power. A recent rosiglitazone meta-analysis heightened the debate about the usefulness and limitations of meta-analysis in this setting. In this review, we examined the methods used in previous published meta-analyses for harmful cardiovascular events, with special attention to the rosiglitazone meta-analyses, and give suggestions for the improvement of methods and interpretation of such meta-analyses. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on harms, and statistical expertise. There are important decisions that need to be made about selecting the appropriate analytical methods and performing sensitivity analyses to evaluate whether the results are robust to different analytical choices.
authors.affiliation: Department of Quantitative Health Sciences, Health Outcomes and Clinical Epidemiology Section, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. hernana1@ccf.org
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Hernandez
authors.forename: Esteban
authors.initials: E
authors.lastname: Walker
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kattan
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D035583:Rare Diseases; D015203:Reproducibility of Results; D018570:Risk Assessment; D000077154:Rosiglitazone; D012680:Sensitivity and Specificity; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone