Clinical trial NCT04607122: Prevention of Atrial Fibrillation by Low-dose Landiolol Administration After Cardiac Surgery
Official title: Interest of Low-dose Landiolol Administration After Cardiac Surgery for the Prevention of Postoperative Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atrial Fibrillation
Cardiac Surgery
Keywords: Postoperative atrial fibrillation
Cardiac surgery
Landiolol hydrochloride
Low dose
Prophylactic administration
Lead sponsor: CMC Ambroise Paré
Sponsor class: OTHER
First posted: 2020-10-29
Enrollment: 400
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Postoperative atrial fibrillation (POAF) is a common complication that occurs in 30-50% of patients after cardiac surgery and increases morbidity and mortality and hospital length of stay. During the perioperative period, the discontinuation of beta-blocker treatment is known to be a risk factor for developing POAF in patient undergoing cardiac surgery. Early beta-blocker reintroduction is associated with lower incidence of POAF. Unfortunately, side effects of currently available beta-blockers (including esmolol), such as low blood pressure and excessive bradycardia and/or their extended duration of action, limit their use in the post-operative period especially for prevention.

Landiolol, an ultra-short acting injectable beta-blocker, offers the advantage of significantly limiting low blood pressure events while increasing therapeutic efficacy in the treatment of POAF in cardiac and non-cardiac surgery. Landiolol, when used at low dose in the postoperative period, has been showed to reduce the incidence of POAF with no increased incidence of side effect as compared to standard of care. The limitation is that these promising data come from single center studies with limited samples and conducted exclusively in Japanese population. If landiolol is approved for use in the treatment of atrial fibrillation in non-Asian patients, there are no data on the prevention of POAF in cardiac surgery.

The objective of this multicenter, double-blind, randomized, placebo- controlled phase III trial is to confirm that landiolol postoperative infusion is associated with lower incidence of POAF without excess of adverse events as compared to standard of care in a non-Asian population after cardiac surgery with sternotomy.

Detailed description: This is a multicenter, randomized, double-blind, parallel-group controlled, Landiolol vs Placebo (saline), phase III trial assessing the efficacy and the safety of landiolol postoperative treatment on POAF occurrence within 7 days of surgery in patients undergoing cardiac surgery with sternotomy.

Subjects are randomly assigned in a 1:1 ratio to receive either Landiolol or Placebo (saline). A stratification of the randomization is planned according to the hospital and the age of the patient (65 ≤ age ≤ 70 and age \> 70).

A preventive treatment is infused during at least the first 24 hours after surgery (in ICU) to each patient included in the study until the optimal oral betablocker dose. Continuous infusion of landiolol at 2 µg/kg/min (1.2 ml/h, for a 60 kg patient) in Landiolol group or continuous infusion of saline (at 1.2 ml/h for a 60 kg patient) in Placebo group is administrated until restoration of an effective oral beta-blocker treatment.

Treatment:

Treatment is initiated after the surgery, on arrival at the ICU (Day-0) in the absence of a contraindication. The target of continuous intravenous infusion of landiolol is 2 µg/kg/min (1.2 ml/h for a 60 kg patient), or placebo (saline) at the same infusion rate as landiolol.

The modalities for initiating the treatment are as follows:

* No bolus is performed,
* Continuous infusion starting at the lowest dosage (1 µg/kg/min),
* Increasing in increments every 10 to 15 minutes until 2 µg/kg/min by maintaining a MAP ≥ 65 mmHg and HR ≥ 50/min.

Relay with oral betablocker treatment:

The relay with oral betablocker treatment, bisoprolol (1.25 mg x 2/day) for initial introduction (target HR \< 100/min) or with the patient's preoperative beta-blocker in case of preoperative treatment, is resumed on Day-1 if possible or as soon as possible.

The dosage of landiolol can be reduced as follows:

* Within the first hour after the first dose of the alternative medicinal product has been administered, the infusion rate of landiolol should be reduced by one-half (e.g. from 2 to 1 µg/kg/min).
* After administration of the second dose of the alternative medicinal product (12 hours later), the patient's response should be supervised and if satisfactory control is maintained for a least one hour, the landiolol infusion can be discontinued.

Maximal duration of continuous intravenous treatment before oral betablocker relay is 5 days, exclusively administrated in ICU for safety reasons.

Precautions for patient safety:

The landiolol infusion should be decreased half and progressively re-increased every 15 min by step of 0.5 µg/kg/min and/or discontinued temporarily or permanently in case of:

* Bradycardia defined by HR \< 50 /mim
* Hypotension defined by SAP \< 90 mmHg or MAP \< 65 mmHg
* Atrioventricular conduction treated by pacing
* Norepinephrine increase \> 50% after introduction of landiolol infusion

In case of POAF event:

Patients will benefit from the usual care:

* Intravenous magnesium sulfate injection: 3 g over 1 hour
* Intravenous or per os treatment with amiodarone depending on patient's condition:

  * Intravenous: IV bolus of 300 mg over 1 hour; then IV infusion pump of 150-600 mg per day
  * Per os: loading dose with 4-6 tablets of 200 mg; then 2 tablets per day during one week
* If AF persists, cardioversion
* Anticoagulant therapy if required Treatment with landiolol or placebo is continued and the infusion rate is adjusted if needed as described above.

Primary endpoint: Continuous monitoring of heart rate is performed in ICU and POAF event \> 5 minutes and/or requiring medical treatment and/or cardioversion is recorded during the ICU stay and reported.

Eligibility criteria: Inclusion Criteria:

* Non-Asian,
* Undergoing cardiac surgery with CPB,
* Left ventricular ejection fraction (LVEF) ≥ 40%,
* Having signed a written informed consent form,
* Affiliation to the social security system.

Preoperative Exclusion Criteria:

* Paroxystic or persistant atrial fibrillation before surgery,
* Preoperative contraindication to beta-blockers,
* Known hypersensitivity to landiolol,
* Severe conduction disorders (atrio-ventricular conduction block),
* A mental or linguistic inability to understand the study,
* Dying patient,
* Patient under protection of the adults (guardianship, curators or safeguard of justice),
* Patient included or planning to be included in another research protocol relating to medications.

Postoperative Exclusion Criteria:

- Postoperative contraindication to beta-blockers: severe sinus bradycardia requiring pacing, postcardiotomy low cardiac output requiring inotropic agents (noradrenaline being not considered as an inotropic agent), severe hypotension, severe acute pulmonary hypertension, reoperation for significant bleeding (\> 200 ml/h), acute respiratory distress syndrome defined by increased oxygen dependence, a PaO2/FiO2 ratio \< 200, polypnea \> 30 /min, signs of respiratory distress (retractions, thoraco-abdominal asynchrony).

Primary outcomes:
measure: POAF occurrence in Intensive Care Unit (ICU)
timeFrame: 7 days
Secondary outcomes:
measure: Duration of POAF episode
timeFrame: 30 days
measure: Day-30 POAF free days
timeFrame: 30 days
measure: Need for cardioversion for POAF treatment
timeFrame: 30 days
measure: Need for medical treatment for POAF treatment
timeFrame: 30 days
measure: Delay between ICU admission and the first event of POAF
timeFrame: 30 days
measure: Delay between the first event and the recidive of POAF
timeFrame: 30 days
measure: Delay for discharge because of POAF event
timeFrame: 30 days
measure: All-cause mortality
timeFrame: 30 days
measure: In-ICU death
timeFrame: 30 days
measure: In-hospital death
timeFrame: 30 days
measure: Day-30 hospital free days
timeFrame: 30 days
measure: Day-30 ICU free days
timeFrame: 30 days
measure: Day-30 ventilator-free days
timeFrame: 30 days
measure: Day-30 renal replacement therapy-free days
timeFrame: 30 days
measure: Occurrence of major cardiovascular events
timeFrame: 30 days
measure: Occurrence of drug adverse events
timeFrame: 7 days
measure: Total hospital cost
timeFrame: 30 days
Other outcomes:
Locations:
city: Massy
country: France
facility: Hôpital Privé Jacques Cartier
city: Neuilly-sur-Seine
country: France
facility: CMC Ambroise Paré
city: Saint-Denis
country: France
facility: Centre Cardiologique du Nord
Study officials:
affiliation: Hôpital Privé Jacques Cartier, Massy, France
name: Julien Amour, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CMC Ambroise Paré, Neuilly-sur-Seine, France
name: Pierre Squara, MD
role: STUDY_CHAIR
References: