Advisory panel recommends approval of vernakalant for AF

Shelley Wood

December 12, 2007

Beltsville, MD - In a vote of six to two, the FDA Cardiovascular and Renal Drugs Advisory Committee has recommended approval of vernakalant hydrochloride injection (Cardiome Pharma/Astelleas) for converting atrial fibrillation (AF) to sinus rhythm. While most of the panel agreed that information on important subgroups was lacking and that the total number of patients studied was small, they also, for the most part, agreed that electrical cardioversion—the accepted alternative—also carried certain risks and discomfort to patients.

Dr Frederick J Kaskel (Children's Hospital at Monterfiore, Bronx, NY), who voted yes, emphasized the need for a safer drug that could be used as an alternative to electrical cardioversion in symptomatic AF patients and in patients who develop AF postoperatively. "I think we've discussed the safety issues, and I think they're reasonable."

Similarly, Dr A Michael Lincoff (Cleveland Clinic, OH), who also voted to recommend approval, said he believed vernakalant would be "a worthwhile addition to the armamentarium for the conversion of AF."

But Dr Robert Harrington (Duke University, Durham, NC), who along with panel chair Dr William Haitt (University of Colorado, Denver), voted against recommending approval, said that although he felt the drug "could be useful" for physicians, he had outstanding concerns about safety issues in specific subgroups that will not be adequately addressed in postmarketing studies. "I don't think a drug that potentially could be used in a very large population of patients should count a couple hundred patients exposed as adequate to define the benefits and the risks," he said.

ACT study program

Vernakalant (previously RSD1235) is an antiarrhythmic that blocks early-activating K+ channels and frequency-dependent Na+ channels. In the ACT I and III trials, vernakalant was significantly better than placebo in converting recent-onset acute atrial fibrillation to sinus rhythm for at least one minute within 90 minutes of infusion in nonsurgical patients. In ACT II, which looked specifically at patients who developed AF or atrial flutter following CABG or valvular surgery, almost half of all patients with AF postsurgery who were treated with vernakalant converted to sinus rhythm within 90 minutes, as opposed to 15% of patients who received placebo.

Panel members spent some of the day deliberating the fact that the trials of the drug, while positive, did not point to reductions in clinically meaningful events, such as reduced thromboembolic or hemorrhagic events. An attractive feature of an IV drug to restore sinus rhythm would be that it might reduce the amount of time patients spent in AF, since electrical cardioversion is usually employed only after an interval deemed sufficient to see whether the patient would revert spontaneously. Reducing this time spent in AF might translate into a reduced risk of stroke or possibly reduced need for anticoagulation, which in itself increases the risk of the adverse events. Ultimately the panel concluded that any benefits of this kind were hypothetical; avoidance of electrical cardioversion alone, however, was in and of itself a desirable result, they concluded.

They also struggled throughout the day to identify any safety signals that might become more of a problem when the drug is used outside the confines of a clinical trial. In the combined study population, there were no significant differences in the risk of arrhythmias, embolic events, or bleeding, but the studies were powered to look at efficacy, not safety. But as several presenters and panel members noted, dofetilide and ibutilide are the only other drugs approved in the US and still in use today for the conversion of atrial fibrillation: the increased risk of ventricular arrhythmias associated with these drugs and the fact that they work better for the treatment of atrial flutter than for AF have limited their use.

A worthwhile addition

In an interview with heart wire after the day's proceedings, Lincoff pointed out that roughly 80% of patients with AF in the US today are treated with electrical cardioversion, rather than dofetilide and ibutilide. "Cardioversion works well, but it's not a trivial procedure. If half the patients who would otherwise require electrical cardioversion can be fixed by a relatively brief infusion of a drug, under careful monitoring, but not with a risk of large complications, that's a worthwhile addition to what we have available," he said.

Lincoff and others also raised concerns about vernakalant's use in the setting of hypotension, a point he emphasized to heart wire : "If you're worried about someone who might be hypotensive, then you've got to say that the likelihood of success is outweighed by the risk of the complication, and to me, hypotension was the biggest concern."

Others also expressed misgivings about the use of the drug in patients with heart failure or acute coronary syndromes: in Lincoff's opinion, these are two groups in whom further studies of the drug should be conducted. The FDA had proposed that the labeling list recent MI, advanced CHF, and obstructive heart disease as contraindications, pending further studies in these groups. Panel members pointed out that the patients enrolled in the vernakalant trials were mostly white and that this should also be noted in the label.

Lincoff, on the whole, said he was reasonably persuaded that vernakalant was as safe as the other options for converting AF to sinus rhythm. "You can never know for sure, but I think the alternative of waiting for several years to do another study is just not warranted. The safety data are reassuring enough, at least in the low-risk population that was studied, to have confidence that this drug is at least as good as other drugs approved for this indication."

Drug developer Cardiome Pharma, which signed a codevelopment and commercialization agreement in North America with Astellas Pharma, plans to market the drug under the brand name Kynapid.


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