Epicardial Injections of Botulinum Toxin Evaluated to Prevent Postoperative Atrial Fibrillation

Atrial fibrillation (AF) is a common complication after cardiac surgery. The incidence of postoperative AF (POAF) has been unchanged over the past few decades: 26% to 32% of cardiac surgeries and more than 40% of valve procedures result in this complication. POAF is associated with increased rates of neurologic, infectious, and renal complications; longer hospital stays; greater resource utilization; and increased in-hospital mortality.

Nathan H. Waldron, MD, of Duke, presented findings from the TNT-POAF trial (Temporary Neurotoxin Treatment to Prevent Postoperative Atrial Fibrillation) at the American Heart Association’s Scientific Sessions held November 11 to 15, 2017, in Anaheim, CA. Other investigators of the study included Mary Cooter, MS, John C. Haney, MD, Jacob N. Schroder, MD, Carmelo A. Milano, MD, Jonathan P. Piccini, MD, and Joseph P. Mathew, MD, of Duke.

Earlier studies showed preliminary success in modulating the cardiac autonomic nervous system to reduce AF. TNT-POAF is a double-blind, prospective, randomized controlled trial (N = 130) that assessed the safety and efficacy of botulinum toxin versus placebo in patients aged 51 to 89 years who underwent coronary artery bypass grafting (CABG), valve repair or replacement, or both. Five injections of botulinum toxin or saline were made near autonomic nerves in the epicardial fat pads of several regions of the heart.

The primary outcome of TNT-POAF was time from intensive care unit (ICU) admission to onset of first POAF episode, defined as 30 seconds of AF or atrial flutter on continuous telemetry. The protocol assumed the sample size would have 80% power to detect a 40% relative risk reduction in POAF. Secondary outcomes included incidence of POAF and in-hospital POAF burden, ICU and hospital length of stay, and postoperative adverse events.

Baseline characteristics varied between the botulinum toxin and control groups. For example, rates of previous myocardial infarction and diabetes were more pronounced in the botulinum toxin arm, and a history of AF and chronic obstructive pulmonary disease were more common in the control group. More patients in the investigative arm underwent CABG alone, whereas more patients in the control group underwent CABG plus a valve repair/replacement.

The cumulative incidence of POAF was 36.5% for botulinum toxin at 168 hours compared with 47.8% for controls. This equates to a hazard ratio (HR) for POAF risk of 0.69 compared with placebo (P = .18). The multivariate analysis did not reach statistical significance (HR 0.70; P = .21). On secondary outcomes, botulinum toxin significantly reduced the duration of first POAF episode at 1.9 hours compared with 5.5 hours for controls (P = .01). No differences were observed between the groups on total POAF duration, burden, and length of stay in the ICU and hospital.

There also were no differences between botulinum toxin and placebo related to safety. The most common safety events were acute kidney injury, infection/leukocytosis, and thrombocytopenia. Event rates were similar or lower in the botulinum toxin arm but did not achieve statistical significance.

Compared with the first-in-human study of botulinum toxin to reduce the risk of POAF, TNT-POAF enrolled higher-risk patients, including those with a history of AF; permitted valve surgery; and included the injection of botulinum toxin to an additional epicardial fat pad. It is unclear whether these differences affected TNT-POAF results. Further evaluation in a large study is warranted.

Source: Waldron NH, Cooter M, Haney JC, et al. Innovative therapies and novel applications: temporary neurotoxin treatment to prevent postoperative atrial fibrillation (TNT-POAF). Presented at: American Heart Association Scientific Sessions 2017; November 11-15, 2017; Anaheim, CA. Abstract LBS.07.