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 percent (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 Sanolfi, 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 quidelines 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 its 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.
-Wes
6 comments:
Excellent review. Shows how some guidelines are prematurely altered.
A drug should be well tested before it is marketed. Clinical trial systems should be changed for better so that post marketing surveillance requirements can be reduced.
Great - I just was started on this drug as an adjunct to an upcoming electrocardioversion. How long typically do patients stay on this drug after the cardioversion? It has destroyed my ability to exercise.
My father at the age of 76 died as a direct result of this drug! He started taking it in December, 2010. On April 21, 2011, he was admitted to the hospital because he had gained 17 pounds in ONE week. Needless to say, it caused acute liver failure. He died in June, 2011. This drug is NOT safe, and should be pulled from off the market.
Excellent review. I was taken off Multaq yesterday as it suddenly in the past month stopped helping me. On the contrary I got 3 shocks from the defibrilator as a nasty episode of afib led to VT, and my defib mistakingly thought it was VFib.
It worked for a while, no dofetilide is my next trial. Going to be admitted to the Northwestern Memorial for admission for dofetilide tomorrow.
Ablation is great but has lower success rates in patients with cardiomyopathy. So I hope the work you and your colleauges do, will make ablation success rates higher.
I had a recent exacerbation of my paroxysmal AF where episodes became increasingly more common and of longer duration. My cardiologist started me on Multaq, which caused intense intestinal cramping until I figured out that "some food" was not enough for me. Multaq taken with dinner solved that issue.
That said, in the ensuing 4-6 weeks of compliant therapy with Multaq my AF continued to ramp up to the point where I would be in afib for 12-24 hours, then in sinus for 12-24 hours. Afib episodes became a daily occurrence in a matter of a couple of months.
Not a very encouraging trend line. Finally, I decided to have a PVI via cryoablation and have only had one (31 hour!) afib in 12 days while no longer taking Multaq. I am hopeful this one episode of afib was an anomaly as my heart heals from the cryoablation.
So, in my very minuscule sample of one patient, the efficacy of Multaq in suppressing my AF was quite unimpressive, to say the least.
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