Landiolol for Prevention of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery

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.

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