July 7th, 2011

Multaq’s Off Again, On Again, Then Off Again Ride

CardioExchange welcomes this guest post, reprinted with permission, from Dr. Westby Fisher, an electrophysiologist practicing at NorthShore University HealthSystem in Evanston, Illinois, and a Clinical Associate Professor of Medicine at University of Chicago’s Pritzker School of Medicine. This piece originally appeared on his blog, Dr. Wes.

Today was another tough day for Sanofi’s dronedarone antiarrhythmic medication (marketed as Multaq®) after the prospective randomized PALLAS Trial was stopped early. The PALLAS Trial was a trial that studied the safety and efficacy of patients with chronic atrial fibrillation (as opposed to the already-approved patient population with intermittent [or paroxysmal] atrial fibrillation). It seems there was an increased number of “cardiovascular events” in the drug-treatment arm of the trial and was NOT related to problems with hepatic toxicity as previously reported earlier this year.

Patients with intermittent atrial fibrillation already on the drug are encouraged NOT to stop their drug, but rather “consult your treating physician if you have any questions.”

But Multaq’s path through the drug approval process has been a rocky one. First came the ANDROMEDA Study, a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms. In this study, patients given Multaq had a greater than two-fold increase in mortality. Needless to say the FDA was not too pleased, so the drug failed to gain approval for that indication.

So the drug company decided to try a less sick population and began the ATHENA Trial. The ATHENA trial was the largest anti-arrhythmic drug trial conducted in patients with non-permanent AF/AFL, involving 4,628 patients with a follow-up of 30 months. In this trial, Multaq, on top of standard cardiovascular therapy, significantly reduced cardiovascular hospitalization or death by 24% (p<0.001) when compared to placebo, meeting the study’s primary endpoint. So the FDA granted the drug approval for this indication, provided the patients were carefully screened for heart failure (a contraindication to begin therapy).

All seemed right with the world for Sanofi, at least for a while. Doctors began using the drug but were generally disappointed in its efficacy despite its hype, being an amiodarone cogener and all. Still, plenty of pressure was applied to the writers of our guidelines to make sure this “highly studied” drug was first and foremost of recommended therapies in the latest atrial fibrillation treatment guidelines. In fact, Multaq® is currently available in 32 countries and is recommended as a first line treatment option in the majority of AF patients by BOTH the ESC and ACC/AHA.

Pretty impressive, given its earlier challenges getting approved.

But now we get the news about the PALLAS trial and we have to wonder: if it’s unsafe for older, sicker patients, why should it be okay for our younger ones?

We really don’t know.

But our antennae certainly are at attention now regarding Multaq. I suspect many doctors will now think long and hard before leaping to dronedarone as their “first line” therapy despite the current recommendations of our “guidelines.” More likely, this drug will be used when there are no other options (and there are those cases). Truth be told, most of our pharmachologic therapies to manage atrial fibrillation are problematic for many of our patients for one reason or another: either they have significant side effects or else they just don’t work. This is largely why the more invasive atrial fibrillation ablation procedure has gained favor.

But ablation is not a cake-walk either.

That is why the current NIH-co-sponsored CABANA trial comparing catheter ablation to drug therapy as first line therapy remains so important to continue.

Then maybe, just maybe, we can learn which therapy really does benefit our patients best long-term.

3 Responses to “Multaq’s Off Again, On Again, Then Off Again Ride”

  1. Robert L. Blum, MD, MD says:

    What should we tell patients who are on this drug to prevent high rate atrial flutter and who have already had one or 2 ablations?
    I have 2 such patients and am concerned in that they fall into the “older” category of patients and who were resistant to taking amiodarone when they were told of this drug. They both have EF’s of less than 40%.
    My own experience with amiodarone, in over 100 patients is one patient that developed pulmonary toxicity and none with liver issues. With the exception of the latter patient, they rest are still alive after 20+ years!

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

  2. Leon Hyman, Ms M.D. says:

    The ancient remedy or curse “Tincture of Time” shows up again. A wise older Pharmacology professor once told our class in the late 50’s(19 not 18) that it takes an absolute minimum of 5 years to really have any idea how safe/effective a drug is once it reaches the prescribing market. Also, he would wait at least 2 years before writing his first Rx on it unless there was absolutely no other choice and the drug was desperately needed.

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

  3. I read above that “plenty of pressure was applied to the writers of our guidelines”. The problem lies in the conflict of interests. It would be interesting to read the guidelines written by persons without conflicts of interest. This May, at Czech Cardiology Society Congress there were two lectures where expert electrophysiologists criticised the guidelines as biassed concerning dronedarone. A number of people is not willing to accept the guidelines. It is very bad.
    As for me, the safety concern is PALLAS and heart fialure contraindication. The efficacy is written in the ESC guidelines – “Combining data from the two trials, the median time to the first episode of AF was 53 days in the placebo group, compared with 116 days in the dronedarone group (HR 0.75; CI 0.65–0.87; P less than 0.0001).”
    I see very little support of using some drug if it will keep the patient for about 60 days in sinus rhythm – what next ? – atrial fibrilation again. To put the patient to inappropriate hazard with dronadarone just to keep him in sinus rhythm for two months? I would prefer not to.