Dronedarone: is it time to turn it down?

Keywords::

• antiarrhythmic drug
• atrial fibrillation
• Dronedarone
• efficacy
• safety

1. Introduction

Despite the widespread adoption of catheter ablation for the treatment of atrial fibrillation (AF) over the past decade, drug therapy remains a mainstay for the management of this common arrhythmia. Dronedarone is the latest drug to be developed for treating AF and is the first antiarrhythmic agent approved by the U.S. Food and Drug Administration (FDA) since 1999. Produced by the same manufacturer as Amiodarone, Dronedarone was designed to resemble Amiodarone, except the iodine moieties of Amiodarone were replaced by a hydrophilic methane-sulfonamyl group. The pharmaceutical company has had imagined their ‘holy grail': Dronedarone would be as effective as Amiodarone but with fewer side effects. Early clinical trials with Dronedarone showed that it was moderately effective in maintaining sinus rhythm in patients with paroxysmal or persistent AF. Additionally, the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter (ATHENA) study demonstrated a reduction in the risk of all-cause mortality or cardiovascular hospitalization and a reduction in stroke associated with Dronedarone use. Dronedarone is currently the only antiarrhythmic drug (AAD) that has been associated with a reduction in stroke risk in AF patients [1]. Based on these facts, the FDA approved Dronedarone in 2009 to reduce the risk of cardiovascular hospitalization in the treatment of AF and atrial flutter. This medication was then recommended by the Guideline [2] as the first-line therapy to maintain sinus rhythm in paroxysmal or persistent AF patients, except for those with NYHA Class III – IV heart failure. However, the post-market safety data raised multiple concerns about Dronedarone. Adverse events including renal failure, severe liver injury, worsened heart failure and drug-interaction with Warfarin and Digoxin have been reported with Dronedarone use. These adverse events ultimately led to a FDA Safety Communication [3] and a modification of the drug label [4]. Last year, the Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study was prematurely halted after the data monitoring committee found a twofold increase in death, as well as twofold increase in stroke and hospitalization for heart failure in permanent AF patients receiving Dronedarone, compared to patients taking a placebo [5]. Influenced by the disappointing results of the PALLAS study, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended restricting the use of Dronedarone [6]. The hope that Dronedarone could be an effective, safe, and ease-of-use drug in daily clinical practice for the management of AF has evaporated. It seems that many clinicians believe Dronedarone has become ‘tasteless but wasteful to discard'. What in the world has happened to Dronedarone after only 3 years since its approval?

2. We should not be discouraged by the PALLAS study

It is well known that the goals of using AADs in AF patients are ‘rate control' and ‘rhythm control'. The latter includes pharmacological cardioversion and maintenance of sinus rhythm after cardioversion. Bearing these in mind, we do not see any rationale for administrating Dronedarone in the PALLAS population. Patients enrolled in this study had permanent AF and at least one cardiovascular risk factor, but no plans to restore sinus rhythm. Of the patients in the PALLAS study, 70% had uninterrupted AF for over 2 years, making the pharmacological cardioversion less likely to be successful. At the 4-month visit, sinus rhythm was present in 3.7% of patients in the Dronedarone group and in 1.4% of the placebo group, which confirmed that the PALLAS population had true permanent AF [5]. To control the ventricular response to AF in this population, we can use beta-blockers, calcium antagonists and/or Digoxin. Alternatively, atrioventricular node ablation plus uni-/bi-ventricular pacing can be an option depending on patient's cardiac performance. Patients can also be referred to undergo catheter ablation. Catheter ablation, in conjugation with previously ineffective AADs, might restore normal sinus rhythm or even free patients completely from AADs. In the daily practice, most of the physicians will choose from the abovementioned options but not Dronedarone when they are dealing with permanent AF patients similar to those enrolled in the PALLAS study. Indeed, we have long known that patients with same characteristics as the PALLAS population have no indication for Dronedarone therapy and should not receive it. In this era of ‘evidence-based' medicine, any study conducted in the non-indicated population cannot be regarded as ‘evidence'. Thus, while appreciating the results of this clinical trial, we should not be discouraged and bothered by the PALLAS study.

3. Do not be confused about the clinical studies on Dronedarone

Published in the latest issue of Expert Opinion on Drug Safety, a review article by Dr Ferrari and Dr Dusi [7] summarized 7 major clinical studies on Dronedarone in AF. Out of these seven trials, four included persistent/permanent AF patients, while the ATHENA study included both paroxysmal and persistent AF patients. However, the endpoint of these clinical studies was defined differently: efficacy of Dronedarone, safety of Dronedarone or a composite endpoint. It is important to emphasize that results of clinical trials conducted in paroxysmal, persistent or permanent AF patients cannot be generalized, as these patients have different atrial substrates, remodeling statuses, neurohumoral regulations, etc. Action and side effects of the same drug, for example, Dronedarone, may vary in different types of AF. For instance, the potency of a potassium channel blocker required to maintain sinus rhythm in persistent AF may be different from that required in paroxysmal AF [8]. In the PALLAS study, enrolled patients had permanent AF and at least one of the predefined cardiovascular risk factors. However, the hazard ratio of these risk factors might be different when they are associated with paroxysmal or persistent AF due to differing patients' characteristics. Even though each of the studies included in Dr Ferrari and Dusi's review [7] was statistically significant, they had different primary study endpoints. Methodology of systematic review or meta-analysis [9] by simply pooling data of all these clinical trials on Dronedarone, without categorizing by AF type, is questionable. Consequently, the results and conclusion of this kind of review or meta-analysis are controversial.

4. The position of Dronedarone in the management of AF

A recent Atrial Fibrillation International Registry reported that the distribution of paroxysmal, persistent and permanent AF in routine clinical practice is 26.5, 23.8 and 49.6% respectively. Among those with paroxysmal AF, 72.7% had no heart failure or NYHA Class I cardiac function. Similarly, in patients with persistent AF, 62% had no heart failure or NYHA Class I cardiac function [10]. Accordingly, 34% of the entire AF population were patients with paroxysmal or persistent AF but had no heart failure. Treatment with Dronedarone may potentially be beneficial and indicated for these patients. Whether or not Dronedarone can be used in paroxysmal or persistent AF patients with NYHA Class II cardiac function or with pre-existing cardiovascular risk factor(s) remains unclear. Some permanent AF patients may also require Dronedarone to maintain sinus rhythm after they undergo catheter ablation. Dr Ferrari and Dr Dusi listed in the review other contraindications, warnings and precautions for Dronedarone use, but most of them are not specific to Dronedarone. Putting all of these considerations together, we should conclude that the potential beneficiary of Dronedarone is a large cohort and not a ‘minority' of AF patients as indicated by Dr Ferrari and Dr Dusi [7].

It was speculated in Dr Ferrari and Dr Dusi's review [7] that the antiarrhythmic potency of Dronedarone is grossly weaker than Flecainide and similar to that of Propafenone or Sotalol. This speculation may apply to the condition of pharmacological cardioversion but may not be true if these medications are used to maintain sinus rhythm. Further studies are needed to directly compare Dronedarone's effectiveness with that of other AADs in the management of AF. Additionally, the comparison should be based on a specific endpoint, that is, success rates of pharmacological cardioversion, efficacy in maintaining sinus rhythm or both. Considering that we have effective alternatives to perform AF cardioversion (electrical, I.V. AADs and oral AADs), it is expected that Dronedarone will be more frequently used for sinus rhythm maintenance in paroxysmal or persistent AF patients.

5. Two major components are involved in pharmacological action and drug side effect

We should always keep in mind that both the drug and the individual taking the drug contribute to the pharmacological action and side effects of a certain medication. Little attention was given to drug-takers until the establishment of pharmacogenetics. Pharmacogenetics is the science that emphasizes the role that an individual's genetic makeup plays in drug efficacy and side effects. It has become a mainstream research discipline and has expanded to study a broad range of cardiovascular drugs, including Warfarin, statins, antiplatelet agents and AADs. Lately, Parvez et al. [11] investigated a cohort of AF patients and screened common AF-predicting single nucleotide polymorphisms on chromosome 4q25. The results revealed that a patient's response to Class I and Class III AAD therapy is associated with different types of AF-predicting single nucleotide polymorphisms. Despite the fact that the authors did not specify which Class III AADs were included, this evidence strongly supports the concept of individual AAD therapy that may also apply to Dronedarone.

Dr Ferrari and Dr Dusi's review summarized [7] the post-marketing safety data of Dronedarone with an emphasis on hepatic injury. There is a trend that the total number of serious adverse events has declined, since Dronedarone was first launched to market in July 2009. Most importantly, none of these side effects have demonstrated dose- or time-dependence. This leaves us to question if an individual's characteristics play a more important role in the development of these adverse events. The panel of CHMP has suggested that most of the cases of post-marketing hepatocellular injury may be due to ischemic hepatitis and heart failure. This finding also explains the pattern of alanine aminotransferase elevations in the PALLAS study [12]. It is possible that during the early phase of the PALLAS study, Dronedarone was inappropriately given to a certain amount of patients with preexisting heart failure. The majority of severe hepatic injury cases may have come from this subgroup of patients. According to Dr Ferrari and Dr Dusi [7] and the EMA recommendation on closer monitoring of liver enzymes in Dronedarone users, since December 2011, no other cases of acute hepatic failure requiring transplantation have been reported. In fact, only after the results of the PALLAS study were officially published, on December 15, 2011 in the New England Journal of Medicine, was Dronedarone use avoided in non-indicated patients. This allows us to see the real safety profile of Dronedarone.

6. Miscellaneous

When compared to Amiodarone, Dofetilide and Ibutilide, the feature of ease-of-use remains an advantage of Dronedarone. It can easily be initiated without in-hospital monitoring or a loading dose. This drug is also more cost effective than Amiodarone, Flecainide and Sotalol, which can be attributed to the increased survival rate of paroxysmal and persistent AF patients on Dronedarone [13]. Given these facts, if we can demonstrate that Dronedarone is non-inferior, if not superior, to other available antiarrhythmic agents, this drug will remain the first-line therapy to treat paroxysmal and persistent AF in indicated patients. Dronedarone is a cardiac multiple ion-channel blocker but exhibits its main effects at potassium channels. In ‘A Study to Evaluate the Effect of Ranolazine and Dronedarone when Given Alone and in Combination in Patients with Paroxysmal Atrial Fibrillation' (HARMONY, ClinicalTrials.gov Identifier: NCT01522651), an ongoing randomized clinical trial, the investigators aim to reveal the efficacy and safety of a combination of Dronedarone and Ranolazine to decrease AF burden in paroxysmal AF patients. Ranolazine is currently approved for the treatment of angina, but it also shows the unique feature of atrial-selective sodium channel blockage [14]. Based on previous experience, any AAD that predominantly acts on only one cardiac ion-channel may not be enough to control AF. The combination in HARMONY may pave the way to achieve a simple, safe and effective therapeutic option for AF patients [15].

7. Expert opinion

Most of the current concerns about Dronedarone are generated by the PALLAS study, in which Dronedarone was unnecessarily used in non-indicated patients. It is likely true that Dronedarone may not fulfill the high expectations for which it was designed. However, in the indicated AF patient cohort, Dronedarone is still a promising drug. Similarly, side effects of Dronedarone might be diminished if it is not used in patients just like the PALLAS population. Actions to be taken at this time include: i) conducting head-to-head randomized clinical trials to compare the efficacy of Dronedarone with that of other AADs in paroxysmal and persistent AF patients with a specific primary study endpoint, such as termination of AF or maintenance of sinus rhythm; ii) clarifying the ‘true' safety profile of Dronedarone from these new studies; and iii) performing further pharmacogenetic research with an aim to achieve personalized Dronedarone therapy in the near future. It is expected that Dronedarone will remain as one of the first-line treatments in a large cohort of AF patients.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript. L Lin is supported by the National Natural Science Foundation of China (NSFC-81001005). R Bai is supported from China by the Program for New Century Excellent Talents in University (NCET-09-0376); the National Natural Science Foundation (NSFC-30973601) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars (SFR ROCS 2008-101).