The risk of antiarrhythmic drugs in atrial fibrillation: 20 years of controversies

Abstract

For about 20 years, the safety of antiarrhythmic drugs used in the maintenance of sinus rhythm in atrial fibrillation patients remains questionable. Immediately after the publication of the CAST trial in 1989, Coplen, in a meta-analysis published in 1990, showed that quinidine treatment was more effective than no antiarrhythmic therapy in suppressing recurrences of atrial fibrillation but appeared to be associated with increased total mortality. 1 In the past 20 years, this major safety problem has been evoked for all other antiarrhythmic drugs, even if it was already clear at that time that the safety profile of quinidine itself could be unfavourable, when compared with other antiarrhythmic drugs, mainly due to the risk of QT prolongation and torsade de pointes induced by the drug. In a large, unselected population-based cohort of patients discharged with first time atrial fibrillation and subsequently treated with flecainide, propafenone, sotalol or amiodarone, Andersen et al. found no increased risk of death. 2 The results are based on the data obtained in 141 500 patients included in this nationwide registry conducted in Denmark. In this unselected population of patients discharged after a first hospitalization for atrial fibrillation, the main findings were that antiarrhythmic drug therapy was not associated with increased risk of death. Furthermore, deaths occurring in the treatment groups were fewer than observed in the population not receiving antiarrhythmic drugs. The authors concluded that this indicates adequate patient selection by the treating physicians from a safety perspective. This major concern shows that cardiologists, after 20 years, are very careful about the use of these drugs in these patients. So, the main questions that can be asked are the following: is the bad safety profile of these drugs a myth or a reality? Do we have to consider that these good results are due to safe drugs or to safe prescriptions or both? After the publication of AFFIRM trial results 3 showing no difference, in terms of survival, between the strategies of rhythm and rate control, several publications dealt with the problem of proarrhythmic events, survival, and mortality. 4–6 The overall risk of adverse arrhythmic events upon exposure to antiarrhythmic drugs in the AFFIRM study was reasonably low. 4 The authors concluded that strict criteria for the safe use of antiarrhythmic drugs were successful in minimizing proarrhythmic events. In another paper, which was an analysis of causespecific mortality in the AFFIRM study, Steinberg 5 concluded that management of atrial fibrillation with the rhythm-control strategy conferred no advantage over rate control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate. The results obtained by Andersen and the Danish group, in real life, clearly demonstrate that it is not the case. Annualized mortality rates were 2.54, 4.25, 4.29 and 7.42 per year per 100 person-years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariate Cox proportional hazard models did not show increased risk of death associated with any of the antiarrhythmic drugs. Sinus rhythm is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model of AFFIRM. In the paper dealing with relationship between sinus rhythm, treatment, and survival in the AFFIRM study, 6 the authors concluded that currently available antiarrhythmic drugs were not associated with improved survival, which could suggest that any beneficial antiarrhythmic effects of antiarrythmic drugs are offset by their adverse effects. From these data it is possible that if an effective method for maintaining sinus rhythm with fewer adverse effects would be available, it might be beneficial. Of course, the hope of all arrhythmologists is that ablation procedures could be this beneficial method with few adverse effects. It is necessary, to date, to have data concerning mortality of these patients by comparing antiarrhythmic drug therapy and ablative procedures as first line therapies. The safety of antiarrhythmic drugs in this indication is now very well established, mainly because of the 20 year experience of the cardiologists, but also by the pharmacovigilance processes.