Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF) (BOTAF)

Prevention of Post-operative Atrial Fibrillation by BOTulinum Toxin Injections Into Epicardial Fat Pads Around Pulmonary Veins in Patients Undergoing Cardiac Surgery"

Over the past few years, research has focused on the prevention of atrial fibrillation (AF) after cardiac surgery, but highly effective interventions are still missing. Postoperative AF remains the most common complication after cardiac surgery, with an incidence of 10 to 50%. This complication is usually a transient condition that resolves spontaneously but it has major adverse consequences for patients and the health care system, including increased rates of death, complications (strokes), and hospitalisations with inflated costs.

Recently, animal studies have demonstrated that neurotoxins such as botulinum toxin (BTX) injected into fat pads could suppress AF inducibility by parasympathetic activation. Botulinum toxin injection in fat pads has been studied in the dog's heart and could be associated with the reduction of atrial fibrillation in postoperative cardiac surgery. One pilot study has demonstrated the feasibility and safety of this technique in the human heart.

The investigators hypothesize that botulinum toxin injection may substantially reduce postoperative AF during the first postoperative month after cardiac surgery without any serious adverse events. By the suppression of ganglionic plexi (GP) activity in the epicardial fat pads, mild term antiarrhythmic effects can be achieved with fewer antiarrhythmic drugs and anticoagulant treatment.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Surgery
• Intervention / Treatment: Drug: Botulinum Toxin Type A Injection [Xeomin]; Other: Drug placebo

Detailed Description

Botulinium toxin use has been developed with success in wide-ranging fields (neurology, otorhinolaryngology, gynaecology, urology, plastic surgery, pain therapy), but not in cardiology.

In the cardio-vascular field, only one pilot study on man has shown its utility in the prevention of atrial fibrillation by blocking the triggering through the sympathic and parasympathic systems. The investigators need to assess its potential benefits to prevent postoperative atrial tachyarrhythmia in a randomised multicentre study, with an expected impact of approximately 30,000 patients per years in France undergoing these types of cardiac surgery.

The investigators hypothesize that botulinum toxin injection may substantially reduce postoperative AF during the first 3 weeks after cardiac surgery without any serious adverse events. By the suppression of ganglionic plexi (GP) activity in the epicardial fat pads, mild term antiarrhythmic effects can be achieved with fewer antiarrhythmic drugs and anticoagulant treatment.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emmanuelle FLORENS, MD; Phone Number: +33(0)1 56 09 31 55; Email: emmanuelle.florens@aphp.fr
• Study Contact Backup: Name: Laura LE MAO, MSc; Phone Number: +33(0)1 56 09 54 97; Email: laura.le-mao@aphp.fr

Study Locations

• France
  • Issy-les-Moulineaux, France
    • Active, not recruiting
    • Corentin Celton
  • Le Plessis-Robinson, France
    • Active, not recruiting
    • Hopital Marie Lannelongue
  • Limoges, France
    • Active, not recruiting
    • CHU Limoges
  • Ile-de-France
    • Neuilly-sur-Seine, Ile-de-France, France, 92200
      • Active, not recruiting
      • Clinique Ambroise Pare
    • Paris, Ile-de-France, France, 75014
      • Recruiting
      • Institut Mutualiste Montsouris
      • Contact: Milena NOGHIN; Email: milena.noghin-gulivati@imm.fr
    • Paris, Ile-de-France, France, 75015
      • Recruiting
      • Hopital Europeen Georges Pompidou
      • Contact: Emmanuelle FLORENS; Email: emmanuelle.florens@aphp.fr
    • Paris, Ile-de-France, France, 75877
      • Withdrawn
      • Hôpital Bichat
    • Saint-Denis, Ile-de-France, France, 93200
      • Withdrawn
      • Centre Cardiologique du Nord
  • Provence-Alpes-Côte d'Azur
    • Marseille, Provence-Alpes-Côte d'Azur, France, 13008
      • Active, not recruiting
      • Höpital Saint-Joseph

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Indication for cardiac surgery (CABG, aortic valve repair or aortic valve replacement excluding the sutureless valve, ascending aorta surgery), according to the European Heart Association guidelines.
• Patients in hemodynamically stable condition.
• Sinus rhythm at moment of randomisation (ECG).
• Age: ≥18 to ≤80 years old.
• Negative serum or urinary β-hCG for women of child-bearing potential.
• Patients able to attend several consultations at the centre.
• Informed consent signed.
• Affiliation to French social security regime.

Exclusion Criteria:

• Previous cardiac surgery.
• Persistent AF or atrial tachycardia.
• Planned maze procedure or pulmonary vein (PV) isolation.
• Use of class I or III antiarrhythmic drugs within 5 elimination half-life of the drug (for amiodarone: one year).
• Mitral or tricuspid valve surgery.
• Congenital cardiomyopathy.
• Neuro-muscular disease (including disorders of pre-operative swallowing).
• Protected populations e.g. minor patient, breastfeeding women, patients under legal guardianship, curatorship or legal protection. .
• Participation in another interventional trial.
• Unwillingness to participate.
• Contraindications to botulinum toxin under investigation or to the excipients: known hypersensitivity.
• Patient with active endocarditis Minimal invasive surgery (ministernotomy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botulinum toxin; All patients from the experimental group will receive botulinum toxin (Xeomin®, incobotulinumtoxin A, Merz Pharma GmbH & Co KGaA, Germany; 200 U dissolved in 4 mL of 0.9% normal saline and 50 U/1 mL will be injected at each fat pad). Botulinum toxin will be injected into the entire visible area of the 4 major epicardial fat pads, during extra corporal circulation and before aortic cross clamping in order to reduce the time of ischemia. The whole estimated dosage would be therefore 200 units of incobotulinumtoxin A,	Drug: Botulinum Toxin Type A Injection [Xeomin]; Before the main stage of the surgery, botulinum toxin will be injected into the entire visible area of the 4 major epicardial fat pads, during extra corporal circulation and before aortic cross clamping in order to reduce the time of ischemia.; Other Names: Xeomin
Placebo Comparator: Placebo; All patients from the control group will receive placebo. Before the main stage of the surgery, during extra corporal circulation and before aortic cross clamping, the placebo dissolved in 4 mL of 0.9% normal saline will be injected into the entire visible area of the 4 major epicardial fat pads as follows (1 mL at each fat pad).	Other: Drug placebo; All patients from the control group will receive placebo. Before the main stage of the surgery, during extra corporal circulation and before aortic cross clamping, the placebo will be injected into the entire visible area of the 4 major epicardial fat pads as follows (1 mL at each fat pad).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 weeks after cardiac surgery	An episode of AF will be considered part of the primary outcome analyses if it last at least 30 seconds continuously within 21 days after cardiac surgery and is documented by any form of monitoring, regardless of symptoms. The definition of atrial fibrillation (at least 30 seconds continuously) results from recent publications and AF definition in the cardiovascular field64. This endpoint will be measured through both holter ECG Spiderflash-t recorder during the first 21 days post-op and ECG daily monitoring during the first 7 days after surgery.	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death rate	Death rate at 12 months	12 months
Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 monthes after cardiac surgery	Incidence of rhythm disorders of postoperative AF in patients undergoing cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.	3 months
Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events	conduction troubles such as atrioventricular block or the need for transient or permanent placement of a pacemaker, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events.cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.	3 months
Incidence of atrial tachyarrhythmia / Flutter	Incidence of all atrial tachyarrhythmia including atrial fibrillation, but also atrial flutter and atrial tachycardia 3 months, and each arrhythmia taken individually between the two parallel groups.cardiac surgery at 3 months defined as atrial arrhythmia during at least 30 seconds continuously.	3 months
New onset of postoperative AF	Incidence of new onset of postoperative AF depending on the following subgroups: age, gender, heart failure, left atrial enlargement, Euro SCORE 2, renal function, type of surgery	3 months
End of surgery until discharge (intervals from end of surgery to extubation, in hours)	Mechanical ventilation duration and postoperative length of stay in intensive care unit and in hospital	10 days
Readmission rate	Unplanned readmission rate at 3 months and 12 months for cardiovascular cause or haemorrhage.	3 and 12 months
Antiarrhythmic drugs	Number of antiarrhythmic drugs and curative anticoagulation within 3 months following cardiac surgery.	3 months
total hospital cost	Initial admission and readmissions for cardiovascular cause, and Incremental cost effectiveness ratio (additional cost per additional survival, additional QALY or per additional adverse event recognised).	twelve months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France; Merz Pharmaceuticals
• Investigators: Principal Investigator: FLORENS Emmanuelle, MD, Assistance Publique Hopitaux de Paris (APHP)

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2019
• Primary Completion (Estimated): October 30, 2025
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: August 19, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (Actual): September 3, 2019

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Cardiac surgery; Botox; Botulinum; Xeomin®
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Neurotransmitter Agents; Membrane Transport Modulators; Cholinergic Agents; Neuromuscular Agents; Acetylcholine Release Inhibitors; Botulinum Toxins, Type A; abobotulinumtoxinA; Botulinum Toxins; incobotulinumtoxinA
• Other Study ID Numbers: P170912J; PHRCN-17-0371 (Other Identifier: Ministry of health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individuel participant data that underlie results in publication could be shared Individuel participant data detailed in meta analysis protocol could be shared
• IPD Sharing Time Frame: one year after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on scientific project and scientific involvement of the PI team.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No