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CHICAGO -- Botulinum toxin type A (AGN-151607) did not lead to significant suppression of atrial fibrillation (Afib) after heart surgery, though some patient groups appeared to respond better than others, a small randomized study showed.

In the first 30 days after surgery, the proportion of patients with at least one continuous Afib episode lasting over 30 seconds was no different between groups receiving placebo and botulinum toxin 250U (relative risk [RR] 1.04, 95% CI 0.79-1.37) or 125U (RR 0.80, 95% CI 0.58-1.10), reported Jonathan Piccini, MD, MHS, an electrophysiologist at Duke University Medical Center in Durham, North Carolina, who presented the NOVA trial at the American Heart Association (AHA) annual meeting.

However, the study was not powered to show superiority for all clinically relevant differences in Afib occurrence, and was not powered to discern differences in cardiovascular outcomes, he said.

There was a nonsignificant trend toward reduced postoperative Afib with the 125U dose of botulinum toxin in the subgroup of patients undergoing isolated coronary artery bypass grafting (CABG) surgery, with this lower dose having an effect reaching significance in people 65 and older. Yet, subgroup analyses should be interpreted with caution due to a limited sample size in this proof-of-concept study, Piccini noted.

Postoperative Afib is associated with increased risks of stroke, morbidity, and mortality, as well as higher healthcare utilization costs. Piccini emphasized the unmet need for therapies to reduce the occurrence of postoperative Afib, which occurs in 30% to 60% of patients and has not budged in decades. Available guideline-recommended perioperative beta-blockers are often withdrawn due to side effects.

The NOVA trial was initiated with the idea that epicardial botulinum toxin might reduce postoperative Afib because it works on the autonomic nervous system and impairs cholinergic signaling.

With a finding of decreased interleukin-6 and high-sensitivity C-reactive protein among botulinum toxin recipients in the study, Piccini said the mechanism of Afib suppression may be related to both direct autonomic influences and decreased inflammation.

"Postoperative Afib after cardiac surgery is an extremely important problem for our patients that undergo open-chest cardiac surgery," agreed AHA session discussant Usha Tedrow, MD, MSc, of Brigham and Women's Hospital and Harvard Medical School in Boston.

However, she questioned the idea that inflammation is a responsible mechanism due to similar reductions in inflammatory markers observed for both the 125U and 250U doses in NOVA.

Analysis of heart rate variability or other autonomic assessments might better elucidate the mechanism of action of botulinum toxin in these patients, Tedrow noted.

The phase II NOVA study included 323 patients ages 55 to 90 who were undergoing open-chest cardiac surgery and had been in sinus rhythm over the 48 hours before surgery. Mean age was 67, over 80% were men, and nearly all were white. Participants were instructed to wear an ECG patch for 30 days post-surgery and for 7 days after each study visit.

They were randomized to 250U or 125U of botulinum toxin or placebo during surgery. Over 60% underwent CABG; others underwent isolated valve and concomitant CABG and valve operations.

As for the exploratory endpoints of the trial, hospital length of stay was unchanged with both doses of botulinum toxin, while rehospitalizations fell from 16% with placebo to around 9% for both doses.

Rates of adverse events were also similar across study arms.

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