Meta-analyses of chronic disease trials with competing causes of death may yield biased odds ratios

OBJECTIVE: To study the odds ratio (OR) as measure of treatment effect in the context of mutually exclusive causes of death. STUDY DESIGN AND SETTING: As example we consider meta-analyses of randomized trials of implantable cardioverter defibrillator implantation (ICD). We compare the pooled OR to the pooled cause-specific hazard ratio (HR) for each of the mutually exclusive outcomes "sudden cardiac death" (SCD) and "death other than SCD." RESULTS: The pooled OR and cause-specific HR for the reduction of SCD are similar (0.43 and 0.44, respectively) for nine included trials. However, the OR erroneously presumes a potential trend toward an adverse effect of the ICD on "death other than arrhythmia" (OR 1.11 [0.84-1.45]), whereas such an effect is small with the cause-specific HR (HR 1.03 [0.79-1.32]). In general, it is shown that a spurious association of treatment with "other death" may be seen when a substantial number of death from the cause of interest is postponed. CONCLUSION: The OR should be used with caution to study effects of treatment on mutually exclusive causes of death. Practically this concern applies primarily to meta-analysis where the use of the cause-specific HR, whenever available, is recommended.