Epicardial botulinum toxin injection for now does not lower burden of postoperative AF
Temporary Neurotoxin Treatment to Prevent Postoperative Atrial Fibrillation
Presented at AHA 2017 Scientific Sessions in Anaheim, CA, USA by Nathan Waldron (Duke University Medical Center, Durham, NC, USA
Postoperative atrial fibrillation (POAF) is a very common complication after cardiac surgery, and despite multiple refinements in perioperative care, the incidence is unchanged over the last 20 years at about 26-40%. POAF is associated with increased morbidity, including stroke and renal failure, prolonged length of stay (LOS) and increased in-hospital mortality. Moreover, it is associated with worse long-term outcomes, including a higher risk of AF and death.
Cardiac autonomic dysregulation has long been implicated in the pathogenesis of AF, with both animal and human data suggesting a role for the parasympathetic and the sympathetic nervous system. Clinical efforts to modulate the cardiac autonomic nervous system (catheter-based and surgical techniques) have shown some preliminary promise in reducing AF.
Botulinum toxin is a neurotoxin that reduces release of acetylcholine from nerve terminals, and when injected near cardiac autonomic nerves, acts in an anticholinergic fashion on the atrium, reducing dispersion of atrial effective refractory periods and blocking induction of AF. A pilot trial was published in 2014 showing a profound reduction (78%) in recurrent atrial dysrhythmias after CABG when patients received injection of botulinum toxin into epicardial fat pads containing cardiac autonomic nerves.
Given the preliminary promise of this solution, a randomized clinical trial was set up to examine the efficacy and safety of epicardial botulinum toxin injection, hypothesizing that this would safely reduce the risk of POAF in a larger, higher risk cohort of patients undergoing CABG or valve surgery, or both. The primary outcome was time to onset of first POAF episode (>30 seconds of AF/AFL on continuous telemetry). 63 patients were randomized to botulinum toxin, and 67 to placebo. A significant imbalance in the proportion of patients receiving preoperative ACEi was seen at baseline (29% in those receiving botulinum toxin, 46% in those on placebo). Non-significantly higher proportions of patients in the placebo group had a history of pAF, history of COPD, or received a combination of CABG + valve surgery.
- No significant difference was seen in the risk of POAF between patients receiving epicardial botulinum toxin and placebo (HR: 0.69- 95%CI: 0.40-1.18, P=0.18).
- Adjusted analyses accounting for preoperative risk factors for POAF and ACEi usage, did not show significant difference in the primary outcome either (HR: 0.70, 95%CI: 0.41-1.21, P=0.21).
- Secondary efficacy outcomes showed a significantly shorter duration of first episode of POAF in patients receiving epicardial botulinum toxin (1.9 hours vs. 5.5 hours, P=0.01), a non-significantly numerically lower POAF incidence (23% vs. 32%, P=0.19).
- No significant differences were seen in total POAF duration (15.4 hours vs. 17.3 hours, P=0.70), overall POAF burden (8.2% vs. 8.7%, P=0.83), treatment of POAF (amiodarone: 87% vs. 94%, P=0.64, electrical cardioversion 9% vs. 19%, P=0.30), or LOS (ICU: 25.7 vs. 23.1 hours, P=0.16, post-surgery LOS (6.0 vs. 6.2 days, P=0.51).
- No significant difference was seen between groups in the primary safety outcome of duration of postoperative intubation (6.0 vs. 6.8 hours, P=0.06), nor in the incidence of any adverse events (AEs, 69.8% vs. 70.1%, P=0.97) or any serious AEs (42.9% vs. 44.8%, P=0.83).
- No significant differences were seen in the incidence of serious AEs that prolong LOS.
This study shows that patients receiving epicardial botulinum toxin injection had a numerically lower risk of POAF that did not reach statistical significance, along with a shorter duration of first POAF episode without resultant changes in burden or treatment of POAF. From a safety standpoint, no significant differences were detected in duration of postoperative mechanical ventilation, length of stay, or postoperative adverse events.
It should be noted that this study included a heterogeneous group of high-risk patients, undergoing multiple types of surgery. Based on the findings of the pilot study, this study was powered (80%) to detect 40% reduction, thus it was underpowered to detect smaller, but clinically significant reductions in POAF. The current study differed from the pilot study in that the latter enrolled patients with a known history of pAF, only undergoing CABG, and the current population was at higher risk, given the inclusion of valvular procedures and the higher mean age and prevalence of COPD. Also some procedural aspects were different.
Overall, Waldron concluded that these findings warrant further study in larger trials, to further evaluate the potential protective ability of this strategy.
Discussant Renate B. Schnabel agreed that we are in need of a means to temporary block autonomic activation to prevent POAF. Botulinum toxin injection has been shown to be effective in a small study, both immediately post-operatively and in longer-term follow-up. She notes that the current study was quite optimistically powered to detect 40% reduction.
Critical points include that only 6.4% of patients screened were considered eligible, which may have induced bias. For instance, patients with LVEF <25% were excluded, which represents a common group of patients who undergo cardiac surgery. The fact that prior AF was permitted may have diluted the effect. At present, she thinks that this study does not help us to understand the transient nature of POAF. It does, however, give insight into the role of autonomic imbalance, particularly parasympathetic activation in POAF. She appreciates this innovative way of possibly reducing POAF burden, and anticipates more explosive results in the future.
- Our reporting is based on the information provided at the AHA 2017 congress -