Review from JAMA Internal Medicine — Antiarrhythmic Drugs for Maintaining Sinus Rhythm After Cardioversion of Atrial Fibrillation — A Systematic Review of Randomized Controlled Trials

Mixed treatment comparisons (MTC) were performed to assess the relative efficacy and tolerability of the main anti-arrhythmic drugs used for the treatment of atrial fibrillation (AF)/flutter. Electronic databases were systematically searched to identify randomized controlled trials (RCTs) examining amiodarone, dronedarone, flecainide, propafenone, sotalol, or placebo for the treatment of AF. Thirty-nine RCTs met inclusion criteria and were combined using MTC models to provide direct and indirect comparisons in a single analysis. Results are presented vs. placebo. Amiodarone had the largest effect in reducing AF recurrence (OR 0.22, 95% CI 0.16–0.29). Amiodarone was associated with the highest rate of patients experiencing at least one serious adverse event (OR 2.41, 95% CI 0.96–6.06) and treatment withdrawals due to adverse events (OR 2.91, 95% CI 1.66–5.11). Dronedarone was associated with the lowest rate of proarrhythmic events including bradycardia (OR 1.45, 95% CI 1.02–2.08). Dronedarone significantly reduced the risk of stroke (OR 0.69, 95% CI 0.57–0.84). Trends towards increased mortality for sotalol (OR 3.44, 95% CI 1.02–11.59) and amiodarone (OR 2.17, 95% CI 0.63–7.51) were found, which were stronger when small studies randomizing <100 subjects per group were excluded. Amiodarone has been demonstrated to be the most effective drug in maintaining sinus rhythm. Differences in outcomes between the anti-antiarrhythmic drugs were reported, with sotalol and possibly amiodarone increasing mortality and dronedarone possibly decreasing the incidence of serious adverse events and proarrhythmia.

Manual dexterity measures can be useful for early detection of age-related functional decline and for prediction of cognitive decline. However, what aspects of sensorimotor function to assess remains unclear. Manual dexterity markers should be able to separate impairments related to cognitive decline from those related to healthy aging. In this pilot study, we aimed to compare manual dexterity components in patients diagnosed with cognitive decline (mean age: 84 years, N = 11) and in age comparable cognitively intact elderly subjects (mean age: 78 years, N = 11). In order to separate impairments due to healthy aging from deficits due to cognitive decline we also included two groups of healthy young adults (mean age: 26 years, N = 10) and middle-aged adults (mean age: 41 years, N = 8). A comprehensive quantitative evaluation of manual dexterity was performed using three tasks: (i) visuomotor force tracking, (ii) isochronous single finger tapping with auditory cues, and (iii) visuomotor multi-finger tapping. Results showed a highly significant increase in force tracking error with increasing age. Subjects with cognitive decline had increased finger tapping variability and reduced ability to select the correct tapping fingers in the multi-finger tapping task compared to cognitively intact elderly subjects. Cognitively intact elderly subjects and those with cognitive decline had prolonged force release and reduced independence of finger movements compared to young adults and middle-aged adults. The findings suggest two different patterns of impaired manual dexterity: one related to cognitive decline and another related to healthy aging. Manual dexterity tasks requiring updating of performance, in accordance with (temporal or spatial) task rules maintained in short-term memory, are particularly affected in cognitive decline. Conversely, tasks requiring online matching of motor output to sensory cues were affected by age, not by cognitive status. Remarkably, no motor impairments were detected in patients with cognitive decline using clinical scales of hand function. The findings may have consequences for the development of manual dexterity markers of cognitive decline.

WHAT IT IS ALREADY KNOW ABOUT THIS SUBJECT • Amiodarone is a highly effective antiarrhythmic drug, but is limited in practice by its adverse effects, which are frequent on long‐term administration and can be severe.• Amiodarone is very lipophilic and attains high concentrations in many tissues.• Excessive accumulation in tissues is suspected as a possible cause of some of its adverse events, but sampling affected tissues (e.g. lung, thyroid, heart) in vivo is difficult.• Subcutaneous adipose tissue is more easily obtained, and studying concentrations of amiodarone and N‐desethyl‐amiodarone there could help to understand how amiodarone distributes and accumulates in tissues in general. WHAT THIS STUDY ADDS • No evidence of excessive or unexpected accumulation of amiodarone in fat tissue, with respect to dose, was found in patients treated for >3 months.• Concentrations in plasma and subcutaneous fat tissue were better related to maintenance daily dose than to cumulated dose or treatment duration.• Clinically relevant adverse effects of amiodarone, for the most part hypothyroidism, were significantly associated with longer duration of treatment and larger cumulated doses.• In contrast, adverse events were not correlated with higher amiodarone or N‐desethyl‐amiodarone concentrations, whether in plasma or in adipose subcutaneous tissue.• The measurement of these concentrations does not seem useful in predicting the risk of adverse effects.AIMS To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long‐term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects.METHODS Trough concentrations of amiodarone and N‐desethyl‐amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography–tandem mass spectrometry.RESULTS Plasma levels of amiodarone and N‐desethyl‐amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N‐desethyl‐amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for ≥2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue.CONCLUSIONS We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long‐term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.