ANAHEIM, CA — New research suggests epicardial botulinum toxin injections may reduce the all-too-common complication of postoperative atrial fibrillation (POAF), known to increase morbidity and affect 30% to 50% of patients after cardiac surgery[1].
Dr Nathan H Waldron
The researchers turned to the neurotoxin, which reduces the release of acetylcholine from nerve terminals, because of the role autonomic imbalance plays in the development of AF.
When injected near cardiac autonomic nerves in epicardial fat pads, botulinum toxin acts in an anticholinergic fashion on the atrium, shortening atrial effective refractory periods and blocking induction of AF, explained author and anesthesiologist Dr Nathan Waldron (Duke University School of Medicine, Durham, NC).
The novel strategy showed promise in a prior first-in-human study, reducing the risk of recurrent AF after CABG in patients with paroxysmal AF compared with saline when injected into the four major epicardial fat pads (30% vs 7%; P=0.024)[2].
Based on these results, the TNT-POAF study randomized a larger, higher-risk cohort of 130 patients undergoing CABG, valve surgery, or both to receive either 50 U of Onabotulinum toxin A (Botox, Allergan) or 1-mL sterile saline injected into five epicardial fat pads—the anterior fat pad and the four pads associated with right and left pulmonary veins. Of the 2017 patients screened, only 130 (6.4%) were treated, with most exclusions due to nontarget procedures, Waldron said.
The 63 botulinum toxin and 67 placebo patients were generally balanced, but controls were more likely to be on preoperative ACE inhibitors (46% vs 29%), to have a history of AF (5% vs 2%) or chronic obstructive pulmonary disease (22% vs 11%), and to undergo combination CABG and valve surgery (18% vs 8%).
The risk of POAF during hospitalization was numerically lower in patients receiving botulinum toxin rather than saline (36.5% vs 47.8%) but the difference failed to reach statistical significance in unadjusted (hazard ratio 0.69; P=0.18) or multivariate adjusted (HR 0.70; P=0.21) analysis, presented here at the American Heart Association 2017 Scientific Sessions.
The duration of the first episode of POAF was lower with the neurotoxin (1.9 h vs 5.5 h; P=0.01), although overall POAF burden, treatment of POAF with amiodarone or cardioversion, and length of stay were not significantly different.
“A number of groups have shown that heart-rate variability is a potentially promising marker of autonomic instability or derangement at the cardiac level. So integrating this into a preoperative screening may be a promising way of flushing out patients who may or may not better respond to epicardial botulinum toxin,” Waldron said during a press conference.
Invited discussant Dr Renate Schnabel (Universitätsklinikum Hamburg-Eppendorf, Germany) remarked, “At present I very much like the concept and think the authors presented a promising inoperative way of possibly reducing atrial-fibrillation burden. I’m looking forward to more results, maybe more explosive results.”
She suggested the results may have been diluted by baseline differences and that the study was “very optimistically powered for a 40% risk reduction” in POAF.
The mechanisms underlying the transient nature of postoperative AF are unknown, said Schnabel, observing that patients who develop AF postoperatively are also at high risk for developing atrial fibrillation in the long run, “so we might need more sustainable procedures.”
Follow-up out to 4 months revealed no between-group differences, Waldron said in an interview, but he agreed that the study of epicardial fat pads and atrial autonomic innervation is still relatively germinal.
“There are good data that denervating part of the left atrium induces susceptibility to reentrant arrhythmias, so in terms of biasing autonomic tone toward one of less atrial reentry, you need a more complete degree of autonomic blockade,” he said. “It could be that the addition of that fifth anterior fat pad played some role in the differences between our study and the [earlier] Pakoushalov study and our findings, although there are so many cohort differences between our study and theirs, it’s hard to interpret.”
In terms of safety, there were no differences between the botulinum toxin and placebo groups in duration of intubation (6 h vs 6.8 h), any adverse event (69.8% vs 70.1%), any serious adverse event (42.9% vs 44.8%), or perioperative mortality (1.6% vs 1.5%).
“If our results carry over into larger clinical trials, the magnitude of risk reduction would be on par with that of amiodarone; the number needed to treat would be off by 1.7 patients without a lot of the adverse effects associated with amiodarone use,” Waldton said.
Commenting to theheart.org | Medscape Cardiology, Dr Ivor Benjamin (Medical College of Wisconsin, Milwaukee), who was not involved in the study, said, “We hear a lot about precision medicine, personalized medicine, but not all comers may necessarily have autonomic imbalance. We have to work on better trial design by doing a better job of identifying the people who may have the highest likelihood of getting a benefit, and that requires a bit more preclinical screening.
“But it’s very catchy and it’s very interesting that you can basically apply Botox for atrial fibrillation.”
The study was funded by a grant from the American Heart Association. Waldron had no relevant financial relationships. Disclosures for the coauthors are listed in the abstract.
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