Anti-arrhythmic medications increase non-cardiac mortality – A meta-analysis of randomized control trials

INTRODUCTION: Anti-arrhythmic medications (AAMs) are known to increase cardiac mortality significantly due to their pro-arrhythmic effects. However, the effect of AAMs on non-cardiac mortality has not been evaluated. METHODS: Trials published in English language journals from 1990 to 2015 were thoroughly retrieved by searching websites such as PubMed, Medline, Cochrane Library, and Google Scholar. Randomized controlled trials reporting non-cardiac deaths as primary or secondary outcomes were used to compare AAMs to non-arrhythmic therapy (AV nodal blocking agents, implantable cardiovascular defibrillation (ICD), or placebo). Information regarding the sample size, treatment type, baseline characteristics, and outcomes was obtained by using a standardized protocol. The fixed effect model was used to perform meta-analysis, and results were expressed in terms of odds ratio (OR) with confidence interval (CI) of 95%, inter study heterogeneity was assessed using I(2). Intention to treat principle was applied to extract data. RESULTS: Total of 18,728 patients were enrolled in 15 trials; 9359 patients received AAMs and 9369 received non-arrhythmic therapy. AAMs were associated with an increased risk of non-cardiac mortality (OR=1.30, [95% CI: 1.12, 1.50], p=0.0005, I(2) index=24%) and all-cause mortality (OR=1.09, [95% CI: 1.01, 1.18], p=0.04, I(2)=54%) as compared to non-arrhythmic therapy. There was no difference in the cardiac mortality (OR=1.01, [95% CI: 0.92, 1.11], p=0.82, I(2)=53%) or arrhythmic mortality (OR=1.00, [95% CI: 0.89, 1.13], p=0.94, I(2)=64%) between the two groups. CONCLUSION: AAMs are associated with an increased risk of non-cardiac and all-cause mortality. The effect of AAMs, especially amiodarone, on non-cardiac mortality requires further evaluation.