Vernakalant Seems Safe, Effective for AF Cardioversion in Lead-up to FDA Advisory Panel

December 03, 2019

PHILADELPHIA — A quick-acting, fast-clearing antiarrhythmic agent appeared both safe and effective for conversion of atrial fibrillation (AF) in the emergency department (ED) in a registry analysis that is part of the drug's case before regulators in the United States.

One or two short infusions of the drug, vernakalant (Brinavess, Correvio Pharma in Europe; Cipher Pharma in Canada), successfully cardioverted about 70% of episodes of recent-onset, symptomatic AF in more than 1000 patients tracked in the SPECTRUM registry.

Most successfully cardioverted patients needed only a single 10-minute infusion, which achieved sinus rhythm within an average of 12 minutes with a rate of hypotension or bradycardia below 1%. None developed serious ventricular arrhythmias.

The patients' median length of stay was about 7.5 hours, with more than 85% staying no longer than 24 hours.

The findings, presented here at the American Heart Association Scientific Sessions 2019, in general support a number of randomized and observational studies of the drug's IV formulation that led to its approval in Canada, much of Europe, and some countries in Asia. Its US regulatory history is more complicated.

Vernakalant IV is slated to go before the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee on December 10, with an agency decision expected before the end of the year, for the indication of cardioversion of recent-onset AF in surgical or nonsurgical patients.

It will be the drug's second time before an FDA advisory panel. The agency declined to approve vernakalant in 2008, citing concerns in part about potential hemodynamic effects, pending more safety data. The decision went against a decidedly positive advisory-panel recommendation.

For the FDA resubmission, its advisors have additional data to go on, which include the current findings from SPECTRUM, said Beate Ritz, PhD, medical information manager at Correvio, who presented the study at the AHA sessions. The registry study launched in 2010 as a postmarket safety assessment at 53 European centers.

Although labeled a class III antiarrhythmic because of its potassium-channel blocking action, vernakalant doesn't fit easily into the Vaughan-Williams classification system, Ritz told | Medscape Cardiology. It appears to be atrial-selective, in that it prolongs the atrial but not ventricular refractory period, she observed.

"It has a very steep plasma-level curve, unlike amiodarone and other antiarrhythmics, so it's not very typical," Ritz said. It can convert AF to sinus rhythm within about 12 minutes after starting the infusion, and its elimination half life is 3 to 5 hours, depending on how rapidly the patient metabolizes the drug. "So it's very quick."

The current analysis "is encouraging, in that patients can be converted quickly in the emergency room and discharged, minimizing admission to the hospital," Gerald V. Naccarelli, MD, Penn State University Heart and Vascular Institute, Hershey, Pennsylvania, told | Medscape Cardiology.

Vernakalant in this setting has been effective in about half of patients, he said. The rate is even better in real-world studies conducted after its international approval, "and I feel it's very safe if the patient is under telemetry conditions."

The FDA's "concerns about sinus pauses and hemodynamic issues" that kept it from approving the drug in 2008 were to some extent addressed by European regulators in their positive decision in 2010, "and this seems to have been a good idea," said Naccarelli, who is not involved in SPECTRUM.

The European labeling contraindicates vernakalant in patients with hypotension, severe aortic stenosis, advanced heart failure, recent acute coronary syndrome, or a prolonged QT interval (which elevates proarrhythmic risk).

"I still think the FDA will be very critical of the resubmission, although the real-world data are somewhat reassuring," Naccarelli said.

"The United States has one of the bigger needs for such a medication. The only approved option is IV ibutilide, which is rarely used."

Amiodarone is also used for AF cardioversion; but not only does it have slower action than vernakalant, it has been less effective in trials.

In the current analysis of 1289 episodes of recent-onset symptomatic AF in 1120 patients treated in the ED, the median duration of AF prior to the cardioversion attempt was about 9 hours, and 78.7% of episodes were treated within 24 hours of onset. The AF was a new diagnosis in 24% of cases.

Conversion to sinus rhythm was achieved after one vernakalant infusion of 3 mg/kg in 61% of cases; the remainder went on to receive a second dose at 2 mg/kg. The overall conversion rate was 70.2%

There were 12 noteworthy adverse events in 11 patients (0.9%), most of which were seen during a second infusion and included atrial flutter and significant bradycardia and hypotension, without important clinical consequences, Ritz reported.

Of note, there were no cases of ventricular fibrillation or torsade de pointes, an especially malignant ventricular tachycardia that has been an issue with ibutilide.

Ritz is an employee of Correvio, which funded SPECTRUM.

American Heart Association Scientific Sessions 2019: Abstract Mo2028. Presented November 18, 2019.

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