Landiolol for Prevention of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery (LANDI-POAF)

A Prospective, Randomized, Double- Blind, Placebo- Controlled Study to Evaluate the Efficacy of Landiolol Hydrochloride for Prevention of Atrial Fibrillation in Patients Undergoing Cardiac Surgery

Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery with incidences ranging from 20% to 40% with the consequence of increasing mortality, morbidity, and hospital length of stay, as well as increasing the costs to the health care system. To prevent POAF the use of beta-blockers is suggested by the EACTA and ESC guidelines. Despite the prophylactic use, the discontinuation of beta-blockers in the perioperative period is a known risk factor that contributes to the occurrence of POAF. Due to the short half time and the highly beta-1-selective properties of Landiolol, it could be possible to initiate a betablocker for prevention in the immediate postoperative setting, without adverse effects like hypotension or severe bradycardia as seen with other betablockers like Metoprolol or even sometimes Esmolol.

Landiolol is already approved for the treatment of atrial tachycardias but is not yet approved for the use of prevention of POAF. In multiple previous studies the preventive potential of Landiolol in cardiac surgery could be proven in japanese study populations, with limitations due to limited sample sizes. In these trials the use of low-dose Landiolol effectively reduced the incidence of POAF without significant differences of increased side effects or in the hemodynamic stability compared to the placebo or standard of care groups.

The primary objective of this prospective, double-blind, randomized, placebo-controlled phase III trial is to prove that the postoperative application of low-dose Landiolol significantly reduces the incidence of POAF without increased adverse events or hemodynamic instability compared to the placebo group after cardiac surgery in a non-Asian population.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Complications; Atrial Fibrillation
• Intervention / Treatment: Drug: Landiolol HCl; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 164
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Andreas Binder; Phone Number: 0043 1 40400 64100; Email: andreas.binder@meduniwien.ac.at
• Study Contact Backup: Name: Barbara Steinlechner; Phone Number: 0043 1 40400 41850; Email: barbara.steinlechner@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • University Hospital Vienna
    • Contact: Andreas Binder, MD; Email: andreas.binder@meduniwien.ac.at
    • Contact: Barbara Steinlechner, Prof.; Email: barbara.steinlechner@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients ≥ 18 years old
2. Written informed consent from patient
3. Patients are in sinus rhythm
4. Oral Betablocker in the patients long-term medication

5. One of the following cardiac surgical procedures which is planned on cardiopulmonary bypass (CPB):

   1. Single valve surgery
   2. Single or multiple CABG procedures
   3. Single valve surgery in combination with one or multiple coronary artery bypass grafts (CABGs)
   4. Multiple valve surgery in combination with or without CABG
   5. Single or multiple valve surgery in combination with ascending aorta procedure with or without additional CABG
   6. Re-surgery of aortic valve, mitral valve, aortic arch or ascending aorta with or without CABG
6. Cardiac surgery is performed electively

Exclusion Criteria:

1. Bodyweight > 101kg and/or BMI ≥ 40
2. Cardiac surgery is planned as minimally invasive procedure (e.g., without thoracotomy or with lateral incision, minimal thoracotomy) or planned as off-pump surgery
3. Planned maze procedure, radiofrequency ablation, pulmonary vein ablation, resection of the atrial appendix or atrial resections during the surgery
4. Sinus bradycardia (resting heart rate < 50/min) at screening and before start of IMP treatment
5. Second- or third-degree atrioventricular block at screening and before start of IMP treatment
6. Clinical hypothyroidism or hyperthyroidism at screening
7. History of ventricular arrhythmia
8. Permanent atrial fibrillation or atrial fibrillation at time of screening and IMP administration
9. Emergency cardiac surgery
10. Requiring inotropic, vasopressor or requiring ventilatory support at time of screening
11. Circulatory shock requiring mechanical circulatory support before initiation of study medication
12. Distributive shock (cardiac index>2.2 L/min with norepinephrine dose > 0.3 µg/kg/min to reach mean arterial pressure > 65mmHg) before initiation of study medication
13. More than 5 units of RBC necessary to maintain a haemoglobin level >8mg/dl at the end of surgery
14. Prior cardiac surgery within the past 6 months
15. History of heart transplantation or planned heart transplantation

16. Any other disease or condition that is likely to interfere with the evaluation of the study drug, outcome assessment or satisfactory conduct of the study:

    1. Active infective endocarditis
    2. Stroke or transient ischemic attack (TIA) within the last 6 months
    3. Concomitant disease with a life expectancy of less than 6 months
    4. Cardiopulmonary resuscitation within the last 4 weeks
    5. Patients requiring renal replacement therapy
17. Active infection on current systemic antibiotics and/ or temperature greater than 38°C at time of screening and before start of surgery
18. Haemoglobin < 5 mmol/l (< 8.06 g/dl)
19. Any systemic anti-cancer therapy within past 3 months
20. Patients with known hypersensitivity to any constituent of the IMP

21. General exclusion criteria:

    1. Pregnant (in women of childbearing potential a urine or blood pregnancy test has to be performed) or breast-feeding women. Women with childbearing potential (defined as within two years of their last menstruation) not willing to practice appropriate contraceptive measures (e.g., implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy, abstinence) while participating in the trial
    2. Participation in any interventional clinical trial within the last one-month prior randomization in this clinicaltrial (screening failures can be rescreened, if appropriate)
    3. Alcohol, drug, or medication abuse
    4. Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, subinvestigators, or study nurse) or relationship to the sponsor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Landiolol group; Randomized patients receiving low dose landiolol after cardiac surgery	Drug: Landiolol HCl; continous 2mcg/kg/min low dose application of Landiolol HCl for 72 hours; Other Names: Rapibloc
PLACEBO_COMPARATOR: Placebo group; Randomized patients receiving 0,9% saline solution after cardiac surgery	Drug: Placebo; continous application of isotone saline solution for 72 hours; Other Names: Isotone saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary end point is a combined endpoint consisting of the occurrence of atrial fibrillation and mortality during the initial 72 hours period after surgery	Death from any reason or the occurence of atrial in the holter ecg within 3 days after operation.	3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence/ frequency of occurrence of atrial fibrillation during the first seven days after cardiac surgery	The occurence of AF in the holter ecg in the 7 days after the operation	7 days
Hemodynamic stability during treatment with IMP	Hemodynamic stability assessed with the need for vasoactive medication in the two groups within 7 days after operation	7 days
Length of ICU stay	Postoperative length of stay in days in the icu	30 days
Requirement of intensive respiratory and circulatory support	Length of invasive ventilation in hours or need for circulatory support	30 days
Peri- and postoperative mortality	Peri- and postoperative mortality	30 days
Assessment of biomarkers as surrogate parameters for cardiac dysfunction	Assessment of cardiac biomarkers to evaluate cardiac dysfunction	30 days
Biomarker Assessment for cardiac injury, remodelling and fibrosis	Biomarker assessment (TropT, CK, CK-MB, sST-2) for cardiac remodelling, fibrosis, apoptosis and ischemia reperfusion injury at time of start of the surgery, at ICU admission, 24 hours after ICU admission, 3 days and 7 days after surgery.	7 days
Incidence of serious adverse events	Incidence of serious adverse events	30 days
Echocardiographic assessment for left ventricular function	Echocardiographic assessment for left ventricular systolic, diastolic and valvular function 7 days after surgery	7 days

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Andreas Binder, Medical University of Vienna, Division of Cardiothoracic and Vascular Anesthesia

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 21, 2021
• Primary Completion (ANTICIPATED): November 1, 2023
• Study Completion (ANTICIPATED): June 1, 2024

Study Registration Dates

• First Submitted: May 18, 2021
• First Submitted That Met QC Criteria: October 6, 2021
• First Posted (ACTUAL): October 19, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2021
• Last Update Submitted That Met QC Criteria: October 21, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: landiolol
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Postoperative Complications; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Landiolol
• Other Study ID Numbers: LAN_POAF_01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No