July 9th, 2011

Will You Still Use Multaq (Dronedarone)? A CardioExchange Panel

With the news that the PALLAS study of dronedarone (Multaq) for permanent AF has been stopped early, CardioExchange convened a panel to address a simple question:

What use—if any—do you see for dronedarone given both the cessation of this trial and the recent data on liver toxicity associated with this agent?

Sorry, there are no polls available at the moment.

Stuart Connolly, MD (PI for the PALLAS study)

There is a big difference between the ATHENA and PALLAS trials—with only intermittent AF in the former and only permanent AF in the latter. The results of PALLAS do not negate ATHENA. Because ATHENA had more patients and much longer follow up compared with PALLAS, it had much more statistical power as well. It is still unclear if there is a causal link between dronedarone and liver toxicity. So there still appears to be a good rationale to  use dronedarone in intermittent AF.

John Mandrola, MD

A basic tenet of treating AF is to avoid making the treatment worse than the disease. Multaq is not only ineffective in controlling AF episodes and often associated with side effects, but now, recent reports suggest it confers an increased risk of cardiovascular and hepatic toxicity. Therefore, I see no role for Multaq in the treatment of AF.

Eric N. Prystowsky, MD

I read the brief announcement on the trial that was stopped, but with no additional data yet available, I plan to continue using dronedarone as I have been for suppressing atrial fibrillation episodes in appropriate symptomatic AF patients.  I am routinely adding occasional liver-function tests as part of the follow-up of patients taking dronedarone.

Sanjay Kaul, MD

The premature stopping of the PALLAS trial due to unacceptable safety concerns strengthens our previous caveat against off-label, indiscriminate use of dronedarone and narrows the therapeutic window of dronedarone to “low-risk” patients with non-permanent atrial fibrillation/flutter who are unable to tolerate other antiarrhythmic agents including amiodarone. Given its modest antiarrhythmic efficacy, lack of well-established safety advantage over amiodarone, huge cost disadvantage, and potential hepatic toxicity, I see this agent as having a limited role that is far from making dronedarone a “game changer” or an “important milestone” in management of atrial fibrillation.

Finally, this should strike a cautionary note for the guidelines to refrain from making strong recommendations that are not driven by high-quality evidence.


For those of you on the front lines of AF treatment, who among these panelists do you agree withif anyone?

14 Responses to “Will You Still Use Multaq (Dronedarone)? A CardioExchange Panel”

  1. The only line of thought I would be unwilling to take on at this time is the one by Dr. Mandrola. As stated by Dr. Prystowsky, we need to see the data before making permanent changes to our practice. In the meanwhile, Dr. Kaul’s line of thought of restricting dronedarone to low risk PAF seems like a good idea. Once we see the data, “low risk” or “acceptable risk” can be better defined. I imagine Dr. Connolly has insight into that aspect. Clearly the catch line of dronedarone being the risk-free amiodarone is out of the door!

    Competing interests pertaining specifically to this post, comment, or both:

  2. Adeniyi Molajo, BSc(Hons), MB ChB(Hons), MD says:

    I have always considered Class III drugs mainly for use in patients with paroxysmal atrial fibrillation where there is a chance of pharmacologically maintaining sinus rhythm and preventing permanent atrial fibrillation or reducing atrial fibrillation burden. The success rate of achieving this in permanent atrial fibrillation is low and thus I would not have and will not consider dronedarone for this indication.

    Unfortunately permanent atrial fibrillation appears to be yet another contarindication for Dronedarone; the other being severe left ventricular dysfunction. Experience shows that clinical judgement of moderate/severe left ventricular dysfunction is difficult; remember Xamoterol.

    Competing interests pertaining specifically to this post, comment, or both:

  3. This new report is very concerning, although there has been remarkable lack of detail as to what specifically were the safety concerns and how frequently they occrurred. Previously I had been surprised about the decision to stop Andromeda prematurely given the very small number of events at that point, but the stopping of a second trial early must mean that where there is smoke, there is fire. Nor am I sure why they chose to study permanent AF, a condition that can usually be managed quite well with anticoagulation and and rate control.

    That being said, my bigger concern remains hepatotoxicity. The initial reports from Europe are so classical for fulminant drug-induced hepatotoxicity that it seems very likely that other reports will follow. At the least dronedarone use will plummet, and it is not unlikely that regulatory agencies will ask for its withdrawal.

    For all the concerns about amiodarone toxicity, its occurrence at currently used doses is very uncommon and its efficacy is clearly superior to that of dronedarone.

    Competing interests pertaining specifically to this post, comment, or both:
    As Co-PI of the I-Preserve study of irbesartan in heart failure with preseved EF, I received consulting fees from Bristol Myers Squibb, which had licensed this agent from Sanofi.

  4. Alain Efstratiou, MD says:

    The fact that they are not telling us what exactly went wrong makes one think of the worse. At present I would agree with Dr Mandrola.

  5. Guy De Gent, MD says:

    Dr Connolly’s point is irrelevant as far as the indication and side effects as well as risk. CV events are hard end points no matter the indication for the drug. I also agree with previous remarks. I find dronaderone far less effective then amiodarone and now clearly it’s side effect profile is significant, contrary to it’s marketing label. One of the EP doctors in our group uses it for rate control, clearly off label and unacceptable given it’s potential risks. The lack of transparancy of industry sponsored and performed trials is a real problem. DrPrystowsky, I strongly disagree with your viewpoint.

    Competing interests pertaining specifically to this post, comment, or both:

  6. Dr. Madrola and Dr.Kaul pay attention to the safety and efficacy issues – that is what every doctor should do when treating patiens. I agree with them. As for Dr. Connoly and Dr.Prystowsky, I just register their viewpoints as those with conflicts of interest, their stance cannot be but suppotive, and it really is. I feel sorry for the clinical trial investigators if they are often denied information about the character i.e the spectrum of CV events. Are they familiar with this? Has the company released this kind of information?

  7. Jeff Dickey, MD says:

    Unfortunately, one of the biggest harms here is to the credibility of the “guidelines” fad which has gripped medicine in the last decade or so. How could our leaders have gotten it so wrong? How does this experience inform our faith in guidelines? What other pillars of knowledge upon which we build our practices are similarly tainted? How does this effect the faith which our patients place in us? Is advancement our profession dependent on whether a treatment can be patented? How does our process need to change to improve our faith in the system? The ACCF/AHA standard(http://circ.ahajournals.org/content/123/1/104.full) that fewer than half the members of the guideline writing committee be precluded from having a “relationship with industry” might be reviewed. Why would anyone with a conflict of interest be allowed on a guideline writing committee? Aren’t there enough smart cardiologists without industry relationships available to review the literature?

    Competing interests pertaining specifically to this post, comment, or both:

  8. David Powell , MD, FACC says:

    Dronedarone was always a shaky drug, starting with the ATHENA trial itself, the main stimulus for its class 2a indication. But the indication is to reduce cardiovascular events and hospitalization….strange and unexplained benefit for atherosclerosis? I guess not in light of the diametrically opposed preliminary announcements above. Most people using the drug want to reduce recurrent afib, but the indication is not for that. As mentioned, the drug is not that effective and has never been shown to compare favorably with an alternative agent. There is a torsades risk, interactions with simvastatin and dabigatran, now hepatotoxicity, and contrary to the real indication…a purported increase in CV events. Embedded in the “updated” afib guidelines is that oversimplified flow diagram for antiarrhythmic therapy…with dronedarone making multiple appearances, as supported by at least one of the above commentators with well know COIs. This diagram ha no AHA/ACC level of evidence support or Class designation. It is rediculously robotic, useless for astute practitioners and probably should not have been included in the document.

  9. VAZHA AGLADZE, MD., PhD says:

    I’m AF managment ESC guideline’s official reviewer. As most part of reviewers’ team, I also was against Dronedarone, as IA class drug. It is much less potent, than Amiodarone and it’s less toxicity isn’t adequately verified, as it was discussed during EHRA congress recently in Madrid.

    Competing interests pertaining specifically to this post, comment, or both:

  10. Prudencio Monasterio, M.D says:

    We have to wait and see

  11. I am very unhappy to read that most of the ESC guidelines reviewers´ objections (see Dr.Agladze above) had not been taken into account. Conflicts of interest prevail in the guidelines, ucurbed by reviewers. What is the credibility of theses guidelines, then? Till when are the doctors to be fooled??

  12. Juergen Schiefermueller, MD says:

    On the day PALLAS was stopped I admitted a patient who suddenly -without any preceding symptoms- passed out in his garden (which he had never before), lost consciousness for 3 minutes, was very pale and his wife actually thought he was dead. He has a history of paroxysmal AF for which he was taking Amiodarone for the last 8 years, but a fortnight ago was swapped to Dronedarone (by an consultant in another hospital). On arrival of the paramedics he had somehow regained consciousness, ECG then showed prolonged QT at ~500ms (which normalized a few days after stopping Dronedarone). I’d be interested what exactly the patients in PALLAS died of, was this SCD/PVT?

  13. Three points are my views to incite other opinions. Send your opinions or disproving arguments, please.
    1/ The limited use of dronedarone just for paroxysmal atrial fibrillation is challenged by the fact that after some time, in most of the cases, the paroxysmal AFib is followed by permanent AFib where the adverse effects from PALLAS trial may change the patient´s outcome. Can one guard this transition?
    2/ There is a difference between amiodarone and dronedarone (see: Charles Antzelevitch: Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes, Europace, 2007, doi:10.1093/europace/eum166). Chronic administration of amiodarone reduces transmural dispersion of repolarization (TDR) whereas amiodarone treatment was shown to produce a major QT prolongation without producing torsades (TdP). In contrast, after 6 weeks of dronedarone treatment, TdP occurred in four of eight dogs displaying the highest spatial dispersion of repolarization.
    Besides reverse use dependency this might be one of the reasons for greater mortality – there are certainly some patients with increased TDR and thus prone to TdP.
    3/ Dr.Schiefermueller´s patient might be the candidate to be examined for the possiblity of being a carrier with LQTS mutation lacking diagnostic QT interval prolongation when not exposed to any drug or challenge. (His QT intervals later shortened, but what is his TDR?)

  14. David Powell , MD, FACC says:

    I have seen VT shocked by an ICD after starting dronedarone, compounded by mild hypokalemia. The dissociation between QT prolongation and propensity for torsades is likely mediated not only by the aforementioned variability in transmural dispersion of repolarization but also the differing potential for EADs, the likely triggers. Amiodarone’s calcium chanel blockade may help account for the lower torsades tate as compared with sotalol, for example.

    In any event, the risk with dronedarone in ANDROMEDA was reported as mostly CHF. This new unpublished study suggests ischemia. QT intervals, CHF, ischemia: all intertwined: look at ranolazine: prolongs QT, but antiarrhthmic and trials on the way for HFpEF.
    I know…off topic a bit…but a agree very interesting.

    Competing interests pertaining specifically to this post, comment, or both: