• Botulinum Toxin A Does Not Significantly Reduce Post-Operative AF, Phase 2 NOVA Study Finds

    Among patients undergoing cardiac surgery, botulinum toxin type A (AGN-151607) did not significantly reduce post-operative atrial fibrillation (POAF) events in the primary analysis of a phase 2 dose-ranging study.

    Jonathan Piccini, MD, MHS, of Duke Clinical Research Institute, Durham, North Carolina, presented these results Monday at the American Heart Association Scientific Sessions 2022 in Chicago.

    POAF is common condition seen after cardiac surgery that has a significant impact on patient outcomes. Certain pre-emptive interventions, such as amiodarone or beta blockers, are advised in high-risk patients; however, POAF events remain high. The NOVA study was undertaken, therefore, to evaluate whether botulinum toxin might help prevent POAF by acting on the cholinergic system, which is implicated in the mechanism of POAF

    Piccini and the NOVA investigators studied the effect of botulinum toxin type A in a Phase 2 trial. Cardiac surgery patients were given placebo, 125U botulinum toxin or 250U botulinum toxin  (1:1:1). Notably, patients were excluded if their left atrial diameter was >55 mm or left ventricular ejection fraction was <25% and if they any instance of second  or third-degree heart block in the previous 30  days. The primary endpoint was percentage of participants with at least one continuous AF episode ≥30 seconds.

    The cohort consisted of 323 randomized patients. Their mean age was 67 years in the placebo and 125U groups and 66 years in the 250U group; the study population was predominantly male (placebo 86.7%, 125U 83.8%, 250U 79.8%) and white  (placebo and 125U both 97.1%, 250U 96.3%); roughly 30% had diabetes (placebo 32.4%, 125U 28.6%, 250U 30.3%). Most patients in all three groups underwent coronary artery bypass grafting (CABG; placebo 61.9%, 125U 64.8%, 250U 64.2%), about a quarter underwent valvular surgery (placebo 25.7%, 125U 22.9%, 250U 24.8%, roughly one eighth underwent both CABG and valvular surgery (placebo 12.4%, 125U 12.4%, 250U 11.0%).

    The primary endpoint rate was not different among the three groups The relative risk (RR) of experiencing at least one AF episode of 30 seconds or greater at 30 days was nonsignificantly lower in the 125U group compared to placebo (RR 0.80, 95% confidence interval [CI]: 0.58-1.10; p=0.16) and roughly the same in the 250U group compared to placebo (RR 1.04, 95% CI: 0.79-1.37; p=0.78).

    Secondary endpoints measuring percentage of patients with ≥2 minutes AF or ≥5 minutes AF were also not significantly different in the primary analysis. Subgroup analysis showed a trend toward significant reduction in AF ≥30 seconds in isolated CABG patients treated with 125U (RR: 0.71, 95% CI:0.44-1.15; p=0.16) but not 250U (RR: 0.89, 95% CI: 0.58-1.37; p=0.60). In patients ≥65 years of age , there was also a signal for benefit in patients receiving 125U (RR: 0.64, 95% CI: 0.43-0.94, p=0.02) but not with the 250U dose (RR: 0.93, 95% CI: 0.68-1.28; p=0.67). Adverse events were similar among the groups.

    Piccini noted several limitations to this study. They emphasized that this was a phase 2 dose finding, proof of concept study, not powered to demonstrate superiority for all clinically relevant differences in AF occurrence. Further, subgroups analyses were not adequately powered.

    Piccini concluded that there were no significant differences in POAF with either the lower or higher dose of botulinum toxin compared to placebo at 30 days but that subgroup analyses suggest a potentially lower rate of POAF and rehospitalization in patients undergoing isolated CABG and patients older than 65 years who received 125U of botulinum toxin.

    The NOVA study was funded by AbbVie, manufacturer of botulinum toxin A.

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