There’s more bad news about the heavily marketed atrial fibrillation drug, Multaq (aka dronedarone). Fast on the heels of reports that the drug can cause liver failure, we learned yesterday that the PALLAS trial was stopped prematurely due to increased cardiovascular events in the group on Multaq. Incredibly the PALLAS trial was designed to test the somewhat ridiculous hypothesis that Multaq would reduce cardiovascular mortality in patients with permanent (i.e. chronic) atrial fibrillation. Why anyone thought this was a good idea is beyond me. Apparently Sanofi, the makers of this very expensive drug, was going for a grand slam here. A retrospective, ad hoc, subgroup analysis of the ATHENA trial (yes someone in the company has a fetish for Greek gods) apparently showed a trend toward mortality benefit in patients with permanent atrial fibrillation. Rather than chalking this up to be the statistical fluke it clearly was, the company decided to launch into a major prospective study that they hoped would show the drug reduces mortality in a group of patients who were unlikely to have any anti-arrhythmic benefit from the drug. Huh? Expose patients to all the pro-arrhythmic and potential heart failure inducing multiple ionic channel blocking effects without any hope of converting to sinus rhythm and then expect a mortality benefit?? Were no lessons learned from the CAST study, d-sotalol studies and many other studies of the 1980s that showed mortality increases with different anti-arrhythmic drugs, even despite suppression of arrhythmias by these drugs? Anti-arrhythmic drug trials have gotten so far away from examining simple arrhythmia suppression that the trials on the basis of which Multaq was approved didn’t even look at whether it works in preventing atrial fibrillation. Most electrophysiologists including me would say based on practical experience with the drug that it doesn’t prevent atrial fibrillation very well. Certainly collecting mortality data on anti-arrhythmic drugs is vital for their approval by the FDA. We need to know these drugs are reasonably safe to use. But it is naive to think that these drugs would have any mortality benefit apart from their anti-arrhythmic effect. Some hypotheses are worthy of study; some don’t make any sense because there is no theoretical basis for them. In the early thrombolytic trials of patients with acute myocardial infarction, retropective subgroup analysis showed that patients with certain horoscope signs had better outcome. No prospective trials were generated to test the hypothesis that your response to thrombolytic therapy is related to what stars were overhead on the day you were born. The hypothesis behind the PALLAS trial seems equally goofy to me, and Sanofi would certainly had been better off leaving it untested.
I am a retired cardiac electrophysiologist who has worked both in private practice in Louisville, Kentucky and as a Professor of Medicine at the University of Colorado in Denver. I am interested not only in medicine, but also in computer programming, music, science fiction, fantasy, 30s pulp literature, and a whole lot more.View all of mannd's posts.