Flecainide 22 years after CAST: safe at last? (For atrial fib, that is)

In 1989 CAST reported increased non-fatal cardiac arrest, arrhythmic mortality, and all cause mortality attributable to the use of flecainide for suppression of ventricular ectopic beats following myocardial infarction. Although that was in the pre-Internet era we had real time cable news coverage available to hype the results. I remember well when the announcement came. It was the middle of a busy afternoon at my clinic and the switchboards lit up like a Christmas tree. We had to pull a couple of employees away from their usual duties to handle the patient calls.


Although the CAST investigators recommended that flecainide be removed from clinical use as a treatment for ventricular arrhythmias post MI they acknowledged that the results did not necessarily apply to other uses of the drug:

We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown.

But it didn't matter. Flecainide was suddenly cyanide and the trial lawyers got busy. There was no reason, though, to think it wouldn't be safe for other indications.


A little background. Even though the pilot to CAST, CAPS, showed no adverse safety signal, ventricular proarrhythmic effects of flecainide were already known, and it was no secret. This came from EP lab data, back when EP catheter guided antiarrhythmic drug therapy was the order of the day. But these studies suggested that the proarrhythmic effect was confined largely to patients in whom the drug was being used to suppress bad (symptomatic) ventricular arrhythmias, and who had bad structural heart disease. There was no reason to think it was bad for people with healthier hearts taking it to stay out of a fib.


In the ensuing years, accumulated experience suggested that indeed it is safe for this indication in patients with good LV function and no significant CAD. That was the topic of the new paper that prompted this post, but first a digression.


In the aftermath of CAST sotolol became a popular alternative to help keep patients out of a fib. While sotolol was in development, long before it was launched, it held the promise of being a “non-toxic amiodarone.” That promise didn't hold up because sotolol proved to have proarrhythmic effects of its own. But, unlike the case with flecainide, the adverse experience with sotolol did not come in the form of a breaking news type clinical trial for the media to grab hold of. Also unlike flecainide sotolol's proarrhythmia, torsades de pointes, was less predictable. It was not restricted to patients with diseased hearts and occurred in treatment of supraventricular as well as ventricular arrhythmias. In addition to idiosyncratic patient susceptibility, risk factors included dosage, renal function, electrolyte disturbances and interacting drugs. These factors made safe use of the drug pretty tricky. Proper patient selection and safety monitoring were elaborate. So much so that when it came time to consider approval of sotolol, already in use for life threatening ventricular arrhythmias, for the more benign condition of atrial fibrillation, the FDA would only approve a special branded version (Betapace-AF). Betapace-AF came with its own patient information materials and special product labeling for professionals. You can view the black box warning against substituting any other form of sotolol for Betapace-AF here. It was the elaborate and complex nature of the product labeling, which if meticulously followed would minimize proarrhythmia, that justified separate branding.


In real world practice, and this is only a subjective observation, generic sotolol (after all, it's the same medication) is often substituted off label for the branded Betapace-AF, increasing the risk of unsafe use. I suspect this practice is widespread, driven in part by the thinking that Betapace-AF is little more than a pharmaceutical industry gimmick. I've often wondered how many adverse events, including deaths, are attributable to such thinking and how sotolol's safety record in a fib compares with flecainide. Although there's been no single large trial to catch the attention of the news media and trial lawyers I imagine the info's out there somewhere. (Note to self: good question for a future literature search).




That brings me back to flecainide and this paper which reviews its use in a fib and concludes that when used in patients without significant structural heart disease it's quite safe. The paper also provides a nice general review of atrial fibrillation management and general aspects of the pharmacology of flecainide.