Curriculum in CardiologyChallenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: The case of rosiglitazone
Section snippets
Methods
We retrieved and examined English-language meta-analyses of RCTs exploring adverse cardiovascular events of drugs. Keywords used were “meta-analysis” or “meta-analy⁎”; “randomized clinical trials” or “randomized controlled trials” or “randomized trials”; “adverse cardiovascular event” or “cardiovascular event” or “cardiovascular risk” or “cardiovascular safety” or “cardiovascular harm”; “rare event⁎”; and “method⁎.” If 2 or more similar meta-analyses were performed by the same research group,
Meta-analyses of rare cardiovascular events: interventions other than rosiglitazone
We retrieved 8 major meta-analyses of RCTs for rare harmful cardiovascular events due to drugs other than rosiglitazone. Each meta-analysis included data on >3,000 patients (range 3,089-145,373) and summarized between 4 and 121 RCTs (Table I). A total of 7 meta-analyses15, 17, 18, 19, 20, 21, 22 were based on published results, and 1 was based on individual-patient data16; 6 meta-analyses16, 17, 19, 20, 21, 22 focused on cyclooxygenase-2 inhibitors (coxibs), and 5 of them15, 16, 18, 19, 21
Rosiglitazone meta-analyses
Seven rosiglitazone meta-analyses6, 9, 10, 11, 12, 13, 14 were conducted in a short span of time after the publication of the original meta-analysis.1 Nissen and Wolski1 reported that in >27,000 patients with type 2 diabetes, rosiglitazone was associated with a statistically significant increase in the odds of MI (OR 1.43, 95% CI 1.03-1.98, P = .03) with a trend for increase in the odds of cardiovascular death (OR 1.64, 95% CI 0.98-2.74, P = .06) when compared with a control group (active
Inherent problems in meta-analyses of rare cardiovascular events
Most of the problems of meta-analyses of rare events, as highlighted in the rosiglitazone situation, are intrinsic of the original trials. Short-term scope, small sample size, or the definition of cardiovascular events as secondary outcomes are examples of shortcomings of individual trials. Meta-analysis allows a systematic examination and discussion of these shortcomings, and this is a clear advantage over the fragmented examination of single trials. Some of these shortcomings can be improved
What is desirable in a meta-analysis for cardiovascular harms?
A clearer description of the absolute risks per treatment arm is advised. For example, it would be desirable, given its direct clinical usefulness,26 to express the results using NNH (calculated from the summary OR or RR) with the caveats of heterogeneity of absolute risks. For instance, Singh et al13 incorporated NNHs in their meta-analysis of cardiovascular effects of long-term use of rosiglitazone. They used baseline risks from several RCTs or cohorts and incorporated the RR found in their
Conclusions
Rare harmful cardiovascular events associated to commonly used drugs are very important from clinical and public health perspectives because they can have a heavy toll on morbidity and mortality. However, the evaluation of these rare events present several challenges. Because of the sparcity of harms, meta-analyses are powerful tools in this endeavor. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on
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