The billion dollar question is this: when to use Multaq (dronedarone)? A new viewpoint and commentary in JACC from Sanjay Kaul’s group (Singh et al) offers a highly conservative answer to the question. An accompanying editorial by Christian Torp-Pedersen, Ole Dyg Pedersen, and Lars Køber provides a much more liberal view of the drug.
It all comes down to different ways of interpreting the safety and efficacy data. Surprisingly, both groups agree that dronedarone is less effective than amiodarone as an antiarrhythmic drug, and both agree that dronedarone is safer than amiodarone in the indicated population of low and intermediate risk patients. And both agree that dronedarone should not be used in high risk patients (unstable NYHA class 3 and class 4 HF patients).
Singh et al get with the guidelines and write that “it is difficult to support an approach to rhythm control in most patients with AF without first trying a rate-control strategy.” Once a rhythm-control strategy is adopted, however, they argue that dronedarone should generally be used as either a second- or third-line agent. (They then offer a detailed flow chart for treatment choices based on the clinical characteristics of the patient.)
Although we recognize that reconciling efficacy versus safety is ultimately a matter of clinical judgment and patient preference, we nevertheless caution against the indiscriminate use of dronedarone. To further understand how dronedarone will fare against amiodarone in the wider population with heart disease, more studies with longer follow-up are needed. At the very least, these studies need to demonstrate superior tolerability of dronedarone without unacceptable loss of efficacy in the maintenance of sinus rhythm and quality of life, or without an increase in morbidity or mortality compared with amiodarone. Until then, dronedarone may be best viewed only as half a step forward in our efforts to expand the antiarrhythmic armamentarium.
Torp-Pedersen and colleagues agree with Singh et al that dronedarone, like other antiarrhythmic drugs, has only moderate efficacy, but “whether it is more or less efficacious than flecainide, sotalol, and propafenone when rhythm control is pursued needs to be tested in randomized trials.” They further point out that the safety profile of other antiarrhythmics is even less well studied than dronedarone, suggesting the possibility that it is impossible to rule out very high risks with these drugs.
Sanjay Kaul sent the following comment to CardioBrief in response to the editorial:
Editorial Comment: There’s another issue here that bothers me, relating to the partial paradox of deploying a low-efficacy drug for safety purposes in a low-risk population. AF patients are not static. Many of them will go on to progress to more advanced heart failure. And there is no good evidence to guide behavior in a patient with worsening heart failure who is already on dronedarone.
The larger problem here concerns drugs that are designed to be used only in low risk patients. Having failed in high risk heart failure patients in its earlier trials, Sanofi was able to cherry pick a lower-risk subgroup and gather the low-hanging fruit. In general, with the most successful drugs the risk-benefit equation means that higher risk patients are the ones most likely to benefit. There’s something very suspicious about a drug intended only for low risk patients.