Author + information
- Evgeny Pokushalov, MD∗ ( )(, )
- Boris Kozlov, MD,
- Alexander Romanov, MD,
- Artem Strelnikov, MD,
- Sevda Bayramova, MD,
- David Sergeevichev, PhD,
- Alexander Bogachev-Prokophiev, MD,
- Sergey Zheleznev, MD,
- Vladimir Shipulin, MD,
- Nariman Salakhutdinov, PhD,
- Vladimir V. Lomivorotov, MD,
- Alexander Karaskov, MD,
- Sunny S. Po, MD and
- Jonathan S. Steinberg, MD
- ↵∗State Research Institute of Circulation Pathology, Arrhythmia Department, Rechkunovskaya 15, 630055 Novosibirsk 55, Russia
Atrial fibrillation (AF) is a common complication of cardiac surgery. The incidence of post-operative AF is 10% to 50%, usually occurring 2 to 5 days after surgery (1). In light of the increased short- and long-term risks of patients who develop post-operative AF, it is of particular importance to consider ways to reduce its burden.
Animal models suggest that botulinum toxin injection into the epicardial fat pads suppresses AF inducibility (2). The aim of this prospective, randomized double-blind pilot study (Botulinum Toxin Injection in Epicardial Fat Pads To Treat Atrial Fibrillation After Cardiac Surgery; NCT01842529) was to compare the efficacy and safety of botulinum toxin injection into epicardial fat pads for the prevention of recurrences of atrial tachyarrhythmia in the post-operative period in patients with paroxysmal AF (PAF) undergoing coronary artery bypass graft (CABG) surgery.
This parallel-group, 2-center study compared treatment with botulinum toxin to 0.9% normal saline (placebo). The inclusion criteria were pre-operative history of PAF and an indication for CABG, according to the American College of Cardiology/American Heart Association guidelines.
The exclusion criteria were previous heart surgery or AF ablation procedure; emergency CABG; unstable angina or heart failure; persistent AF or AF at the time of screening; planned Maze procedure or pulmonary vein isolation; use of class I or III antiarrhythmic drugs within 5 elimination half-lives of the drug (or within 2 months for amiodarone); need for concomitant valve surgery; and unwillingness to participate.
Patients were randomized to a botulinum toxin (Xeomin, incobotulinumtoxin A, Merz Pharma GmbH & Co KGaA, Frankfurt am Main, Germany) (n = 30) or 0.9% normal saline (control; n = 30) injection into epicardial fat pads. Patients were followed for 30 days to assess maintenance of sinus rhythm.
Our hypothesis was that a botulinum toxin injection into epicardial fat pads could prevent recurrences of atrial tachyarrhythmia in the post-operative period in patients undergoing CABG surgery. The primary endpoint was recurrence of >30 s of any atrial tachyarrhythmia, including AF and atrial flutter/tachycardia, after a CABG procedure with no antiarrhythmic drug. The secondary endpoints included time intervals from end of surgery to extubation and discharge from the intensive care unit (ICU), creatine kinase-myocardial band (CK-MB) levels, post-CABG length of stay, congestive heart failure, sustained ventricular arrhythmias, myocardial infarction, infection, renal failure, respiratory failure, stroke or transient ischemic attack, rehospitalization, ICU readmission, and death within 30 days.
All patients underwent conventional CABG. After surgery, botulinum toxin (50 U/ml at each fat pad) or 0.9% normal saline (1 ml at each fat pad; placebo group) was injected into the entire visible area of the 4 major epicardial fat pads. Technically, injections were performed using a conventional insulin syringe (1 ml) in 2 stages. The first stage was a needle puncture at 45° relative to the surface of the fat pad at a depth of 2 mm; the second had an additional 2-mm advancement of the needle, parallel to the surface of the pad. After needle placement, adipose tissue infiltration was performed by injection of solution at volumes 0.2 to 0.3 ml per puncture. Infiltration zone had a distinctive whitish color and clear boundary, and was 5 to 6 mm in diameter. To cover the entire surface of the fat pad, it was necessary to create 3 to 5 infiltration zones.
Weekly electrocardiograms (ECGs) and 24-h Holter monitor recordings were performed at 7, 14, 21, and 30 days. Patients were instructed to report symptoms suggestive of AF and to undergo prompt ECG recording.
In the study, 60 patients were enrolled (30 in each arm). There were no baseline differences between groups. Most patients were male (80%), with an average age of 62.3 years. There were no differences in the number of grafts placed (venous or arterial), duration of aorta cross-clamping, or number of off-pump CABG surgeries performed between groups (all p > 0.05). There were no significant differences in the median time to extubation, or intervals from the end of surgery to eligibility for and to actual discharge from the ICU (all p > 0.05). There were no significant differences in CK-MB levels in the post-operative period.
Overall, the incidence of post-operative AF was 18% (11 of 60 patients). Post-operative AF occurred in 2 (7%) of 30 patients in the botulinum toxin group and in 9 (30%) of 30 patients in the placebo group (log-rank test p = 0.024) (Fig. 1). The AF burden on 24-h Holter also favored the botulinum toxin group, 0.3% versus 2.5% (p = 0.08). The mean duration of AF episodes were 0.94 ± 1.1 h in the botulinum toxin group and 2.83 ± 6.6 h in the placebo group (p = 0.17).
There was no significant difference in the post-operative hospital length of stay between groups (p = 0.12), with a median (25th to 75th percentile) length of stay of 6 (5 to 8) days in the botulinum toxin group versus 6 (4 to 8) days in the placebo group. Other post-operative complications, including death, were similar between groups (all p > 0.05).
The main findings of this study were botulinum toxin injection into the epicardial fat pads prevented recurrences of atrial tachyarrhythmia in the post-operative period in patients with prior PAF undergoing CABG; and the botulinum toxin injection did not alter timing of discharge from the ICU, nor enhance post-operative hospital length of stay or any other post-operative complication.
Because in the vast majority of these patients, post-operative AF is a transient phenomenon, permanent ganglionated plexi (GP) destruction should not be the method of choice. Temporary autonomic blockade without permanent destruction of the GP during the post-operative period would be expected to produce favorable results in the short term, coinciding with post-operative risk of AF. Our study strongly supports this hypothesis by utilizing a novel therapy.
This is a “first-in-man” study of botulinum toxin injection into the epicardial fat pads, resulting in the enrollment of a limited number of patients. Although the study was randomized, double-blind, and prospective, the results will require validation in larger trials. The major limitation of the study is the failure to clarify the mechanisms underlying the transient nature of post-operative AF and the ability of GP inactivation by botulinum toxin to attenuate post-operative AF. Perhaps this study will initiate additional studies utilizing this new treatment.
- American College of Cardiology Foundation
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