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    • br Discussion The present meta analysis of randomized trials

    2019-05-16


    Discussion The present meta-analysis of randomized trials demonstrated that treatment with AAMs is associated with an increase in non-cardiac and all-cause mortality as compared to non-arrhythmic therapy or control group. There was no significant reduction in cardiac or arrhythmic mortality between the two groups. The finding was independent of the ICD or AV nodal blocking agents use in the control group. Amiodarone was the most commonly used drug in these trials. Current evidences show that amiodarone is the most effective form of treatment for life threatening arrhythmias [18,19]. Singh et al. reported that prolonged use of amiodarone increases the left ventricular ejection fraction possibly by prolonging repolarization hygromycin [20]. Amiodarone primarily acts by blocking potassium channels, leading to a prolonged repolarization phase; however, it also has inhibitory effects on sodium and calcium channels, as well as beta and alpha adrenergic receptors. Heart Rhythm Society (HRS) has provided class 1C evidence for amiodarone use in atrial fibrillation after considering its potential toxicities and when other agents have failed or are contraindicated [21]. Amiodarone has number of side effects and can affect the lungs, liver, and thyroid [19]. Multiple larger population-based trials have shown that AAMs are proarrhythmic and are capable of increasing cardiac mortality due to their proarrhythmic effects [4,13,14]. To our knowledge, there are no reports where primary endpoint was increase in non-cardiac mortality caused by AAMs (Figs. 5–9). The first study to show an increase in non-cardiac mortality was the mode-of-death analysis of the AFFIRM study that showed a significant increase in fatal non-cardiovascular events in the rhythm-control arm [9]. The most commonly used drug in the AFFIRM trial was amiodarone, prescribed in approximately 60% of patients. In the study, after adjusting for other significant covariates, the risk of non-cardiovascular death was increased 1.5 fold (p=0.0007) if the assignment in AFFIRM was to the rhythm-control arm. It is evident from Fig. 1, that six studies showed an increased trend in non-cardiac mortality with AAMs; however, none of them were statistically significant. Similar findings were also observed by Gronefeld et al., showing that significant quality of life at 1 year follow up was better with rate control strategy as compared to rhythm control strategy [22]. The reasons for increase in non-cardiac mortality with AAMs are unclear at this time. In our meta-analysis, the increase in AAMs has been seen in patients with and without LV dysfunction. Waldo et al. showed increased mortality with anti-arrhythmic medications in patients with low ejection fraction [13]; however, subsequent studies did not report any confirming evidence [13,15,16]. In our meta-analysis AFFIRM is the only study, which had included patients with normal ejection fraction, all other studies had patients with low ejection fraction and seven studies did not specify LV function (Table 2). Despite its clinical efficacy, amiodarone was found to be associated with increased non-cardiac mortality. Its long turn accumulation leads to serious end organ toxicities, mainly manifested in the lung, liver, and thyroid. A recent retrospective cohort analysis studying the mortality risk of amiodarone therapy in atrial fibrillation revealed a higher risk of non-cardiac death in patients treated with amiodarone compared to other AAMs [23]. Lung toxicity is considered the most serious adverse event, as it can lead to non-reversible damage and fatal outcomes [24]. Lung toxicity correlates with the dose and the duration of amiodarone use, and it can present as early as few days to years after the treatment is started. Fatal outcomes range from 10% in patients who develop pneumonitis, up to 50% in patient presenting with acute respiratory distress syndrome (ARDS) [25]. Amiodarone exposure was associated with an increased likelihood of interstitial pneumonitis, which can be explained by its immunologic mechanism of hypersensitivity [26]. Liver toxicity is a well-known adverse effect of amiodarone and is related to its cumulative doses. Symptomatic events are seen in less than 3% of the cases. Most patients have reversible liver damage; however, death secondary to cirrhosis and liver failure had been reported in several cases [27]. Several mechanisms had been attributed to thyroid dysfunction after amiodarone use, leading to hypo and hyperthyroidism. However, fatal outcomes had been reported in the literature in few cases and meta-analysis [28–31]. Optic neuropathy and corneal deposits had been reported with prolonged use of amiodarone due to its effect on endothelial and vascular smooth muscles [32]; few cases of leucocytoclastic vasculitis following treatment with amiodarone had also been reported explaining its cutaneous side effects [33].