Botulinum Toxin for AF After Cardiac Surgery: Mixed Results Yield Patient-Selection Insights

December 04, 2018

A strategy aimed at preventing atrial fibrillation (AF) after cardiac surgery remains tantalizing as two research teams have now published randomized experiences that seem to contradict each other in some ways, but also may be complementary.

In one of the reports, patients who received epicardial-fat-pad injection of botulinum toxin during coronary bypass surgery (CABG) showed significant, steep, and sustained reductions in prevalence and burden of atrial tachyarrhythmias over 3 years, compared with a control CABG group.

The effect was especially evident during the first year of follow-up, and was accompanied by a significant drop in risk for hospitalization over the long term, reported the authors, led by Alexander Romanov, MD, Meshalkin National Medical Research Center, Novosibirsk, Russian Federation.

A separate randomized experience, in this case with patients undergoing CABG, valve surgery, or both, failed to show a significant difference in postoperative AF incidence or length of hospital stay for those getting the botulinum epicardial-fat-pad injections.

But as the report on that study notes, compared with the Romanov et al experience, its patients were arguably higher risk and their AF was assessed differently and might not have had the same underlying causes.

Those differences and others complicate comparisons between the two studies, note the second report's authors, led by Nathan H. Waldron, MD, MHS, Duke University Medical Center, Durham, North Carolina.

Both experiences were published online November 7 in Heart Rhythm and had been previously covered at meetings by theheart.org | Medscape Cardiology: Romanov et al in May 2015 and May 2018 and Waldron et al in November 2017.

As previously described, the treatment calls for intraoperative injections of botulinum toxin into epicardial fat pads known to contain ganglion plexi that help manage parasympathetic and sympathetic control of the heart.

Romanov and colleagues injected incobotulinumtoxinA (Xeomin, Merz Pharma) into four epicardial fat pads during the same procedure but immediately after isolated CABG.

Speaking to theheart.org | Medscape Cardiology, Waldron noted that his group, in contrast, injected onabotulinumtoxinA (Botox, Allergan) into the same four fat pads plus the anterior epicardial fat pad.

Perhaps more tellingly, Romanov and colleagues entered only patients with known paroxysmal AF undergoing CABG, whereas the other study entered a broader mix of patients undergoing CABG, valve procedures, or both who were without a history of persistent AF.

Paroxysmal AF, "in and of itself as a subtype of atrial fibrillation is probably more likely to be autonomically mediated than your standard post-cardiac surgery atrial fibrillation, which — without a uniting mechanistic explanation — is probably some combination of inflammation, autonomic derangement, catecholamine surge, and actual ischemic damage to the atrium from cardiopulmonary bypass," Waldron said.

Therefore, the contrasting results of the two studies "may reflect differing efficacy in various subtypes of atrial fibrillation after heart surgery."

Also likely involved, Waldron said, is that his study primarily looked at time to an episode of postoperative AF lasting at least 30 seconds by telemetry during the hospitalization for the surgery, which averaged about 6 days. But the Romanov group's main end points were AF incidence and burden over 36 months as measured by implantable loop recorder.

Waldron and associates randomly assigned 63 patients to receive the botulinum injections and 67 to corresponding placebo injections, delivered after the start of cardiopulmonary bypass support but before the main surgery itself.

Postoperative AF was observed in 36.5% of actively treated patients and 47.8% of the control subjects, corresponding to a hazard ratio (HR) of 0.69 (95% CI, 0.41 - 1.19; = .18), which was not significant.

Nor was the difference significant after adjustment for baseline ACE inhibitor use, age, history of AF, presence of chronic obstructive pulmonary disease, or whether the procedure included valvular surgery: HR, 0.71 (95% CI, 0.41 - 1.22; P = .21).

Among those who developed postoperative AF, actively treated patients showed a significantly shorter AF-episode duration than those in the control group (median, 1.9  vs 5.5 hours; P = .007), "with no difference in initial ventricular rate, total duration of postoperative AF, or postoperative AF burden," the group writes.

Romanov and colleagues, in contrast, observed significant reductions in AF incidence and burden throughout the 3-year follow-up in the patients who had received botulinum injections. The risk for hospitalization from any cause was also reduced in the active-therapy group.

They had randomly assigned 60 patients with a history of paroxysmal AF undergoing standard CABG to receive active or placebo botulinum fat-pad injections.

The previously reported benefits in the actively treated group over the shorter term were sustained at 36 months, with an HR of 0.36 (95% CI, 0.14 - 0.88; P = .02) for AF incidence. AF burden was also reduced (1.3% vs 6.9% of monitoring; P = .007), as was hospitalization for any cause (7% vs 33%; P = .02).

Those long-term results, propose the authors, suggest that "autonomic remodeling plays a crucial role in the progression of AF and that suppression of autonomic remodeling may prevent electrical remodeling, and subsequently prevents AF from perpetuating itself."

Based on the two studies together, "it seems that botulinum toxin type A suppresses postoperative AF in patients with pre-existent paroxysmal AF but does not prevent it in patients without AF undergoing cardiac surgery," an accompanying editorial states.

On average, writes Joris R. de Groot, MD, PhD, University of Amsterdam, patient mean left-atrial size was "remarkably" larger in the Romanov et al experience. That, along with the two studies' other differences, suggests they started with more atrial remodeling.

"One could speculate that suppression of postoperative AF is related in part to the interplay between autonomic dysbalance and structural remodeling in those patients," he writes.

Identification of patients most likely to respond to the treatment should be one goal for this line of research, Waldron said.

"If we were able to harness heart-rate variability, or catecholamine sampling, or something else that would speak to a preoperative autonomic derangement, or some kind of vulnerable cohort, we may be able to use that as a relatively reliable, cheap screening technique as this technology advances."

In the report from Waldron et al, botulinum toxin type A was provided by Allergan, for which Waldron discloses serving on an advisory board. Disclosures for the other authors are in the report. Romanov had no disclosures; industry relationships for the other authors are in the report. de Groot states that the contents of his article was partially supported by a research grant from AtriCure.

Heart Rhythm. Published online November 7, 2018. Romanov abstract, Waldron abstract, Editorial

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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