Researchers saw evidence of benefit in some subgroups in this phase II trial, and experts say further evaluation is needed.
CHICAGO, IL—The use of botulinum toxin type A in patients undergoing cardiac surgery does not appear to reduce the overall rate of postoperative atrial fibrillation (AF), according to the phase II NOVA study. But the trial showed it could offer benefits in certain subgroups. Postoperative AF affects one to two thirds of patients after cardiac surgery and may portend the same risk of AF as in other settings. “There is an unmet need for treatments that can effectively and safely reduce the occurrence of postoperative AF,” said Jonathan Piccini, MD (Duke Clinical Research Institute, Durham, NC), who presented the findings today in a late-stage clinical trial . session at the American Heart Association (AHA) Scientific Sessions 2022. “Suppression of atrial fibrillation by botulism toxin is likely mediated by both direct autonomic effects and reductions in inflammation,” he explained. Commenting on the TCTMD findings, Constantinos X. Siontis, MD (Mayo Clinic, Rochester, MN), said NOVA is “a long-awaited study that provides dose-specific safety and efficacy data.” However, he said in an email, “due to the sample size and event rates, it is still difficult to draw conclusions about clinically important outcomes, such as AF episodes that last longer than a few seconds or minutes.” Phase II results For the study, Piccini and colleagues randomized 323 patients (mean age 67 years, 83% male) undergoing cardiac surgery to receive epicardial injections of botulinum toxin type A in doses of either 125 units (n = 106) or 250 units (n = 109 ) or placebo (n = 108). About two-thirds of patients underwent CABG, one-quarter had valve repair/replacement, and the remaining 12% had both. All patients were in sinus rhythm for at least 48 hours before surgery and were willing to wear an ECG patch for 30 days after surgery and for 7 days after each study visit. Within the first 30 days, there were no differences in the rate of atrial fibrillation lasting at least 30 seconds (primary endpoint) for patients treated with either the 125-unit dose (RR 0.80; 95% CI 0.58-1.10) either with a dose of 250 units (RR 1.04; 95% CI 0.79-1.37) of botulinum toxin type A compared with placebo. A trend for benefit was observed with the 125-unit dose compared with placebo in those undergoing isolated CABG (RR 0.71, 95% CI 0.44-1.15) and a significant benefit in the subgroup of patients aged at least 65 years receiving the 125-unit dose in relation to AF episodes lasting at least 30 seconds (RR 0.64; 95% CI 0.43-0.94), 2 minutes (RR 0.63; 95% CI 0.42- 0.94) and 5 minutes (RR 0.64; 95 % CI 0.43-0.97). The mean length of hospital stay was similar for all patient groups, ranging between 6.4 and 6.6 days. However, there were numerical reductions in all-cause readmissions for those who received 125 and 250 units of the study drug—8.7% and 9.4%, respectively—compared to patients who received placebo (15.7% ). All patients in the CABG subgroup saw reductions in interleukin-6 regardless of study arm, and those who received any dose of botulinum toxin type A saw reductions in high-sensitivity C-reactive protein compared with placebo. Finally, the rates of adverse events were similar for the three groups (ranging from 88.6% to 95.4%), as were the rates of treatment-emergent adverse events (49.5% to 61.9%). The majority of events were supraventricular arrhythmias. Piccini emphasized that because the study was a “phase II dose-ranging exploratory clinical trial, it was not powered to detect all clinically relevant differences in postoperative AF, nor to detect some differences in cardiovascular outcomes.” Also, he continued, “subgroup analyzes were limited due to sample size.” More mechanistic insight desired Siontis called the dose data “interesting” and said he was somewhat surprised to see that the lower dose of the study drug had a greater potential effect on postoperative AF compared with the higher dose. “This is unexpected at first glance, but it may also suggest that excessive cholinergic inhibition could be counterproductive,” he suggested. Discussing the study after the presentation, Usha Tedrow, MD (Brigham and Women’s Hospital, Boston, MA), said that because not a single indication of benefit was seen for the 250-unit dose of botulinum toxin type A, it “raises some questions about the mechanism of reductions in atrial fibrillation events’. Also, he said, “a reduction in inflammatory markers was observed for both doses and raises the question of whether the reduction in AF may not have been specifically mediated by inflammation.” Tedrow said that in the future she would like to see more information on the patient’s heart rate variability or other forms of self-assessment in order to better understand the mechanism of action of how botulinum toxin affects the onset of AF. For Siontis, a closer look at the reduction in all-cause hospitalizations would be a useful way to determine whether the reduction was due to fewer arrhythmias or perhaps “other side benefits” to the botulism toxin. In addition, he continued, “it would be great to see larger, well-powered clinical trials that can address major arrhythmia-related clinical endpoints, with a focus on higher-risk patients, including those over 60-65 years of age. also [welcome are] more clinical trials testing noninvasive, extracardiac autonomic modulation to reduce postoperative AF after cardiac surgery.
