How safe is the antiarrhythmic drug therapy in atrial fibrillation?

Abstract

While the predominant symptom(s) related to atrial fibrillation (AF) are due to either a poorly controlled—or irregular— ventricular rate, still there is some debate with regard to the optimal strategy (that is, rate or rhythm control) to treat individual patients. Indeed, recent large, randomized, controlled trials have shown that neither rate nor rhythm control was superior in reducing mortality in AF patients, although achieving rhythm control appears to improve functional class, 1 at least in the short term. Interestingly, a post hoc analysis from the AFFIRM trial found that sinus rhythm (and warfarin use) was related to improved survival but this was offset by a greater mortality from antiarrhythmic drugs (AADs). 2 Anderson et al., 3 from a large retrospective (n ¼ 40 823) Swedish nationwide study (conducted between 1995 and 2004), reported that AAD therapy was not associated with an increased mortality in AF patients. As expected, various AADs (mainly flecainide, propafenone, sotalol, and amiodarone) were used in the treatment of AF, but in this unselected, non-randomized cohort, considerably more patients were on sotalol (16%) when compared with the rest of the AADs (flecainide 2.4%, propafenone 2.6%, or amiodarone 7.3%). However, in patients with previous myocardial infarction (MI) or ischaemic heart disease, the preferred choice of AAD was amiodarone (24.3%) compared with sotalol (15%) or class-Ic drugs (8.6%). Similarly, more patients with heart failure were on amiodarone (21.5%) when compared with other AADs (sotalol 9.5%, class-Ic drugs 6.1%). The authors quoted annual mortality rates (per year/100 patient-years) of 7.4 vs. 5.3% vs. 4.3% vs. 2.5% with amiodarone, sotalol, propafenone and flecainide, respectively. Approximately a third of these unselected patients were noted to be on digoxin, whilst a fifth were on betablockers or calcium blockers—on top of prescribed AAD therapy for AF. In a Cox-regression analysis, treatment with AAD was generally associated with a lower mortality (flecainide HR 0.38, 95% CI 0.32‐0.44; propafenone HR 0.65, 95% CI 0.58‐0.71; sotalol HR 0.65, 95% CI 0.63‐0.67) but the effect of amiodarone was borderline (HR 0.94, 95% CI 0.89‐1.00). Perhaps AADs may be safe in AF after all? The quoted mortality in the paper by Anderson et l. 3 with individual AADs may well be related to disease progression rather than effect of antiarrhythmic therapy per se, and cause(s) of death in these patients is not that clear. But also, the choice of AADs were carefully selected in individual patients which also might account for the observed low mortality. These observations are contrary to the post hoc analysis of AFFIRM trial data 2,4 that there was a non-significant trend towards a higher mortality in patients assigned to rhythm when compared with rate control, predominantly due to noncardiovascular causes. The significant predictors of higher noncardiovascular mortality on multivariate analysis were rhythm control, male gender, heart failure, age, and coronary artery disease. Nevertheless, this increased mortality seen in rhythm control group may well be related to adverse effects of the various AADs used (amiodarone, sotalol, disopyramide, flecainide, moricizine, procainamide, propafenone, and quinidine) in these AF patients without heart failure, although the precise mechanism(s) was not well elucidated. In a subsequent analysis using time-dependent variables towards in these patients, there was a 1.5-fold increased risk of death noted with AAD therapy after adjusting to co-variables in the presence of sinus rhythm (HR 1.49, 99% CI 1.11‐2.01). 4 The use of digoxin for rate control also appears to increase the risk of death (HR 1.42, 99% CI 1.18‐1.89) in these patients with persistent AF. 2,4 Notably, neither beta-blockers nor calcium-channel blockers had any effect on improving survival of these AF patients. Broadly similar results were noted in the Stroke Prevention in Atrial Fibrillation (SPAF) 5 trial, where there was a 2.5-fold increase in cardiac mortality (HR 2.5, 95%CI 1.3‐4.9) and a 2.6-fold increase in arrhythmic deaths (HR 2.6, 95% CI 1.2‐5.6) in AF patients on AAD therapy, even after adjusting for cardiovascular risk factors. However, AF patients with history of congestive heart failure