One Round of Botulinum Pacifies Postoperative AF for Up to 3 Years in Pilot Study

May 15, 2018

BOSTON — One promising strategy for suppressing atrial fibrillation (AF) after cardiac surgery calls for poisoning the neuronal system responsible for it, researchers say.

It seems that the temporary poisoning — intraoperative injections of botulinum toxin A into epicardial fat pads — may "reset" the neurohormonal underpinnings of postoperative AF with a lasting stabilizing effect, researchers speculate based on growing evidence.

Impressive declines in AF burden seen 1 month and 1 year after the treatment delivered during coronary artery bypass grafting (CABG) persisted for at least 3 years in a small, placebo-controlled pilot study that has set the stage for a planned much larger randomized trial.

The presence of any atrial tachyarrhythmia at 3 years was detected by implantable loop recorder in 23.3% of the 30 patients who received the botulinum injections into four epicardial fat pads during their CABG operation.

That compares to 50% of the same number of patients whose placebo injections contained saline, for a hazard ratio of 0.36 (95% CI, 0.14 - 0.88; P = .019), reported Alexander B. Romanov, MD, PhD, from the Meshalkin National Medical Research Center, Novosibirsk, Russia.

Moreover, patients who had received the active injections showed a significantly reduced AF burden after 3 years, 1.3% of the time compared with 6.9% in the control group (P < .007), Romanov said when presenting the results here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions.

There were three hospitalizations in two patients who had received the botulinum injections, compared with 21 hospitalizations in 10 of the control patients (P < .001). And significantly more of the latter group were receiving antiarrhythmic medications at 3 years (P = .029), he reported.

With only 60 patients, the current study is far too underpowered for conclusions about clinical outcomes, Romanov observed for the theheart.org | Medscape Cardiology, but the reductions in AF burden with the active treatment are promising.

Such reductions appear to cut the risk for clinical events in other forms of the arrhythmia, he pointed out, referencing an earlier presentation at the HRS sessions suggesting as much after catheter ablation in the CASTLE-AF trial.

That the AF suppression lasted years after the single injections, long after the well-recognized short-term effects of botulinum toxin would have faded, he said, suggests the poison "temporarily blocks and resets" aspects of the autonomic nervous system related to postoperative AF.

That such "autonomic reverse-remodeling" may be the mechanism behind the observed benefit is supported by animal studies that tracked acetylcholine changes associated with the procedure, among other indicators, Romanov said.   

Moreover, it's well recognized that the epicardial fat pads secrete proinflammatory cytokines and contain ganglionic plexi that support vagal innervation; the ganglia are sometimes targeted during surgical AF ablation.

Patients in the study received the commercial botulinum toxin preparation incobotulinumtoxinA (Xeomin, Merz), which has effects similar to those of the more famous  onabotulinumtoxinA (Botox, Allergan).

The beauty of using botulinum toxin injections, which could be delivered by catheter or other minimally invasive techniques, is that "we don't destroy anything," Romanov said. This distinguishes the approach from surgical or catheter-based ablation for AF.

But the proposed mechanisms are largely speculative. Besides the low patient numbers, another reason "why this isn't conclusive, but extremely exciting, is because the biologic measures of how it works are not fully understood," observed Andrew D. Krahn, MD, Sauder Family and Heart & Stroke Foundation, Vancouver, British Columbia, Canada, about the study.

There is an array of biomarkers and other indicators of neurohormonal and electrophysiologic function "that need to be measured and understood on a large scale" before it's really understood why the procedure seems to make such a difference, said Krahn at a media briefing on the study. He had earlier co-moderated the session that featured Romanov's report.

After that earlier presentation, invited discussant Kalyanam Shivkumar, MD, PhD, University of California Los Angeles, agreed that neuromodulation, by "actually resetting the entire nervous system so that it remodels," probably is the mechanism.

"We don't know why it works, but it's a fascinating new approach that is worthy of further studies."

Also at the media presentation, Romanov described a larger Allergan-sponsored randomized trial in the works, with a target enrollment of about 300 patients, that will be better powered for outcomes. It will test essentially the same technique for delivering botulinum toxin A to patients undergoing CABG or valve surgery, he said.

The trial, with one placebo arm and two arms of botulinum-toxin delivery at different dosages, is scheduled to launch "at the end of 2018," he said.

In the current study, as previously described by theheart.org | Medscape Cardiology, the 60 patients had been randomly assigned at two centers to receive injections of botulinum toxin type A or placebo into four posterior epicardial fat pads during CABG. Each pad received 50 U/mL or 1 mL of 0.9% normal saline.

Table 1. Monitored Burden of AF After Injection of Botulinum Toxin Type A or Placebo

Time of Follow-up Botulinum Toxin (n = 30) (% Time) Placebo (n = 30) (% Time) P Value
12 mo 0.22 1.9 .003
24 mo 1.6 9.5 <.001
36 mo 1.3 6.9 <.007

 

The two randomization groups, 30 patients in each, didn't differ significantly in number or type of grafts, how many surgeries were performed off-pump, aortic cross-clamp time, or duration of intubation. All patients received implantable loop recorders, and none were lost to follow-up.

Table 2. Clinical Findings After Injection of Botulinum Toxin Type A or Placebo

Endpoint Botulinum Toxin (n = 30) (%) Placebo (n = 30) (%) P Value
Patients hospitalizeda 7 33 .02
Use of antiarrhythmic agents 20 50 .029
aThree hospitalizations in 2 actively treated patients vs 21 hospitalizations in 10 control patients (P < .001).

 

The technique is fairly advanced in small, mostly ongoing studies. Results so far have been mixed. In a recent study trial that randomly assigned 130 patients undergoing CABG or valve surgery to receive a similar botulinum toxin type A or placebo injections into epicardial fat pads, there was no significant difference in AF burden during the hospitalization.

The same group that conducted the current pilot study has registered other randomized trials that are apparently nearing completion, including one with a projected 170 patients undergoing CABG or valve repair or replacement, and another with a target of about 180 patients with a history of drug-refractory paroxysmal AF scheduled for such cardiac surgery.

Other studies, each with similar numbers of patients, will be comparing the technique to catheter ablation. One is a straight comparison of the technique to AF ablation with pulmonary-vein isolation (PVI), and the other compares the botulinum toxin injections to placebo on top of AF ablation with PVI.

Romanov discloses serving on a speakers' bureau for Medtronic, Boston Scientific, and Biosense Webster and receiving research grants from Spectrum Dynamics, EP Dynamics, Biosense Webster, and Boston Scientific. Shivkumar had no disclosures. Krahn discloses receiving compensation for services for Medtronic and receiving research grants from Boston Scientific and Medtronic.

Heart Rhythm Society (HRS) 2018 Scientific Sessions. B-LBCT02-01. Presented May 11, 2018.  

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