The first study to show an increase

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 Calcitriol 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]. Amongst other anti-arrhythmic medications, disopyramide (class 1A AAM) has anticholinergic side effects such as dry mouth, urinary hesitancy, constipation and exacerbation of conditions like glaucoma and myasthenia gravis. Disopyramide acts by targeting the fast sodium channels in the cardiac tissue. However, it also blocks potassium channels in pancreatic cells, which increases insulin secretion, leading to episodes of hypoglycemia, resulting in coma and neurological damage. This side effect is seen at normal therapeutic levels [34], therefore it should be avoided in patients taking potassium (ATP) channel inhibitor such as glimepiride [35]. Procainamide was widely used in the past; however, its use has been limited as its chronic administration leads to frequent side effects manifested mainly by lupus like syndrome in around 30% of patients [36]. On the other hand, bone marrow toxicity is a serious but less frequent side effect, manifested in less than 0.22% of the patients. It should be considered in any patient who develops pancytopenia once procainamide treatment is stopped [37]. Mexelitine is a well-tolerated class 1B antiarrhythmic drug. Its side effects are limited to gastrointestinal (GI) and neurological manifestation such as dizziness and numbness [38]. However more serious effects like thrombocytopenia are rare, and are based on case reports [39]. Propafenone is a Class 1C antiarrhythmic drug. It has been reported to be associated with suppressive sympathetic effects such as dizziness, nausea, visual disturbances [40]. A negative inotropic effect of propafenone significantly increases pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance, and cardiac output especially in patients with low ejection fraction, leading to increase in non-cardiac mortality and morbidity [41]. Although GI side effects such as nausea and metallic taste are frequent and mild, propafenone has been implicated in acute cholestatic hepatitis as described in a case report [42].