Clinical trial NCT04075981: Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF)
Official title: Prevention of Post-operative Atrial Fibrillation by BOTulinum Toxin Injections Into Epicardial Fat Pads Around Pulmonary Veins in Patients Undergoing Cardiac Surgery"
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cardiac Surgery
Keywords: Xeomin®
Botox
Botulinum
Atrial Fibrillation
Cardiac surgery
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Merz Pharmaceuticals
name: Ministry of Health, France
First posted: 2019-09-03
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study is a double-blind multicenter randomized trial comparing treatment with botulinum toxin to normal saline (placebo) on top of usual treatment to prevent atrial fibrillation in patients undergoing cardiac surgery (coronary artery bypass graft surgery (CABG), aortic valve surgery, or ascending aorta surgery).
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 weeks after cardiac surgery
timeFrame: 3 weeks
Secondary outcomes:
measure: Death rate
timeFrame: 12 months
measure: Number of participants presenting at least one episode of atrial fibrillation (more than 30 seconds), during the first 3 monthes after cardiac surgery
timeFrame: 3 months
measure: Number of patients presenting a cardiovascular event as conduction troubles, congestive heart failure, major bleeding, stroke, and arterial thromboembolic events
timeFrame: 3 months
measure: Incidence of atrial tachyarrhythmia / Flutter
timeFrame: 3 months
measure: New onset of postoperative AF
timeFrame: 3 months
measure: End of surgery until discharge (intervals from end of surgery to extubation, in hours)
timeFrame: 10 days
measure: Readmission rate
timeFrame: 3 and 12 months
measure: Antiarrhythmic drugs
timeFrame: 3 months
measure: total hospital cost
timeFrame: twelve months
Other outcomes:
Locations:
city: Neuilly-sur-Seine
country: France
facility: Clinique Ambroise Paré
state: Ile-de-France
city: Paris
country: France
facility: Institut Mutualiste Montsouris
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
state: Ile-de-France
city: Paris
country: France
facility: Hôpital Bichat
state: Ile-de-France
city: Saint-Denis
country: France
facility: Centre Cardiologique du Nord
state: Ile-de-France
city: Marseille
country: France
facility: Hôpital Saint-Joseph
state: Provence-Alpes-Côte d'Azur
city: Issy-les-Moulineaux
country: France
facility: Corentin Celton
city: Le Plessis-Robinson
country: France
facility: Hôpital Marie Lannelongue
city: Limoges
country: France
facility: CHU Limoges
Study officials:
affiliation: Assistance Publique Hopitaux de Paris (APHP)
name: FLORENS Emmanuelle, MD
role: PRINCIPAL_INVESTIGATOR
References: