Prevention Atrial Fibrillation by BOTulinum Toxin Injections (BOTAF)

Cardiac Surgery Clinical Trial

— 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"

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04075981
• Other study ID #: P170912J
• Secondary ID: PHRCN-17-0371
• Status: Recruiting
• Phase: Phase 3
• Start date: September 30, 2019
• Est. completion date: September 1, 2023

Study information

• Verified date: November 2021
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Emmanuelle FLORENS, MD
• Phone: +33(0)1 56 09 31 55
• Email: emmanuelle.florens[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: September 1, 2023
• Est. primary completion date: October 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 ß-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)

Related Conditions & MeSH terms

• Atrial Fibrillation
• Cardiac Surgery

Intervention

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:
• 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).

Locations

Country	Name	City	State
France	Corentin Celton	Issy-les-Moulineaux
France	Hôpital Marie Lannelongue	Le Plessis-Robinson
France	CHU Limoges	Limoges
France	Hôpital Saint-Joseph	Marseille	Provence-Alpes-Côte d'Azur
France	Clinique Ambroise Paré	Neuilly-sur-Seine	Ile-de-France
France	Hôpital Bichat	Paris	Ile-de-France
France	Hôpital Européen Georges Pompidou	Paris	Ile-de-France
France	Institut Mutualiste Montsouris	Paris	Ile-de-France
France	Centre Cardiologique du Nord	Saint-Denis	Ile-de-France

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Merz Pharmaceuticals, Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 ECG recorder during the first 21 days post-op (Spiderflash-t).	3 weeks
Secondary	Death rate	Death rate at 12 months	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Readmission rate	Unplanned readmission rate at 3 months and 12 months for cardiovascular cause or haemorrhage.	3 and 12 months
Secondary	Antiarrhythmic drugs	Number of antiarrhythmic drugs and curative anticoagulation within 3 months following cardiac surgery.	3 months
Secondary	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