Rise and fall of dronedarone: the need for new drugs

This editorial refers to ‘The evolving landscape of oral anti-arrhythmic prescriptions for atrial fibrillation in England: 1998–2014’, by C. Hayward et al., on page 90. While rhythm-control strategies have clearly been in the focus of atrial fibrillation (AF) therapy until the end of the last century, in more recent years there has been significant change to physicians' ways of thinking about this issue. While rhythm control is recommended in patients with AF-related symptoms despite rate control, this therapeutic concept has been less often applied since the publication of AFFIRM.1,2 If physicians decide for a rhythm-control strategy they will in most cases first apply anti-arrhythmic medication to maintain sinus rhythm simply because drugs are more readily available than ablation therapy. Given the large number of patients affected with AF and limited availability of ablation in respective centres, this is likely to stay. Perceived greater safety of drugs over catheter ablation may also contribute to this tendency. Nevertheless, several recently published rhythm-control trials of anti-arrhythmic drugs versus pulmonary vein isolation in patients with paroxysmal AF have demonstrated superiority of the interventional approach in terms of AF relapse and symptom suppression.3 These trials were relatively small by numbers but represented a randomized comparison of both strategies. If drugs were more effective in suppressing AF and had less side-effects there would probably be only minor interest in ablation therapy. In the current issue of European Heart Journal – Cardiovascular Pharmacotherapy, Hayward et al.4 describe a striking trend towards declining numbers in overall anti-arrhythmic drug prescription in England. It is a large-scale observational study overlooking a long period of time and providing interesting facts. Personal gut-feeling of many physicians in recent years might already have been that the overall use of anti-arrhythmic drugs was declining. The authors of the current report present data that precisely underpins this feeling. They illustrate less prescriptions of anti-arrhythmic drugs despite a continuous increase in numbers of patients affected by AF. This is consistent with reports that demonstrate a constant decrease in rhythm-control strategy in recent years.2 Only few new anti-arrhythmic substances have been introduced to the market in recent years. Dronedarone was the first relevant addition to the anti-arrhythmic armamentarium for over 20 years (Figure 1). In 2009, the ATHENA trial was published.5 Although it was already clear from dose-ranging studies that the effective rhythm-controlling potency of dronedarone was moderate,6 the drug at first glance represented a long-awaited addition to the group of substances available for rhythm-control. Subsequent trials shed a more critical light upon the substance and withdrew much of the optimism that had accompanied dronedarone upon its market launch. Dronedarone was strongly promoted by AF guidelines in 2010 and obtained a class I indication for rhythm-control therapy. Given the large number of patients in ATHENA compared with the numerically minor patient populations in previous trials, this was comprehensible. One interesting side-aspect of dronedarone was that a pre-specified secondary endpoint of ATHENA indicated a reduced rate of cardiovascular mortality for patients treated with the drug. This effect was largely attributable to a reduction in death from cardiac arrhythmia.5 It was the first time that such an observation was made for an anti-arrhythmic drug. There are data published in abstract form only indicating anti-arrhythmic potency of dronedarone in a canine model of sudden cardiac death.7 Accordingly, there was some additional evidence to support this interesting ATHENA finding. Nevertheless, in clinical practice, it was soon discovered that patients with symptomatic AF do not fancy the option of staying on a substance that might reduce cardiovascular mortality if it does not sufficiently help maintaining sinus rhythm. Unfavourable data in patients with permanent AF further discouraged the use of dronedarone.8 This figure illustrates the time-point of first scientific mention of anti-arrhythmic substances over time. Substances are grouped according to Vaughan–Williams classification. Some illustrative trials with impact on specific anti-arrhythmic drug use are included. It is of interest that almost all substances (except for moricizine, encainide, and d-sotalol) are still clinically available for use somewhere worldwide. There have been very little additions to this set of anti-arrhythmic drugs in the years after 2000. After dronedarone, the next drug to enter the market was vernakalant.9 This substance—representing a novel class of anti-arrhythmic drugs with an atrial-selective mode of action—had in fact good potential for wide-spread application given a favourable side-effect profile. However, it is available for intravenous cardioversion only. Moreover, due to data hinting towards overall limited efficacy and issues with re-imbursement it never made it to a blockbuster. In a historic perspective, it is interesting to see how much less effort has recently been put into the development of novel anti-arrhythmic drugs in comparison to the time before 2000 (Figure 1). It is the authors' credit that there is now scientific evidence rather than gut-feeling that anti-arrhythmic drug use is declining. With all the marketing effort for both new substances, with the many educational activities on the web, at conferences or at local physician practices the only apparently detectable effect is an increasing use of flecainide. This interesting observation may be related to the acceptable efficacy of flecainide in terms of cardioversion, relapse prevention together with a favourable side-effect profile. This increase in flecainide use also illustrates that there is indeed a continuing need for anti-arrhythmic therapy in patients with AF. There are several limitations to the study owing to its large-scale observational nature. For instance, while it is methodologically impossible for the authors to differentiate between the use of flecainide for AF and for ventricular arrhythmias, it is clear that the former will comprise the majority. After all—the present report represents a call to pharmaceutical industry to fill the gap and try to place novel substances. There is need, there is market and there is potential. All we need is new drugs to try out.