Landiolol in Mitral Valve Surgery (LUNA)

The Use of Landiolol in Mitral Valve sUrgery: a raNdomized, Controlled, Double-blind triAl (LUNA)

Chronic mitral regurgitation is the most common valvular abnormality worldwide, it occurs in 10% of the general population and its prevalence increases with age. When left untreated, it can lead to left ventricular dysfunction and cause disabling symptoms (e.g., fatigue and dyspnea), life-threatening complications (e.g., ventricular dilation, congestive heart failure) and death. Surgical correction of chronic mitral regurgitation before irreversible changes happen can be curative. Open surgical valve repair or replacement are accomplished through cardiopulmonary bypass and cardioplegic arrest. Myocardial protection is essential to guarantee an uneventful perioperative course since a not-well protected heart may lead to postoperative low-cardiac output syndrome. This occurs in 30% of high-risk patients who undergo elective cardiac surgery and is associated with 20% mortality. Cardioplegia preserves the heart during ischemic arrest by reducing its metabolic demand. The most effective cardioplegia for protection in adult cardiac surgery remains unknown and improving the protection of the heart during the ischemic arrest may potentially improve patients' postoperative outcomes. Pharmacological adjuvants to the cardioplegic solutions have been tested to mitigate the ischaemic-reperfusion injury following cardiac surgery. Ultra-short acting beta-blockers (e.g., esmolol, landiolol) decrease intraoperative myocardial metabolic demand and suppress the sympathetic response to surgical stimuli while exhibiting limited adverse effects. Few studies with limited sample size investigated the role of ultra-short acting beta-blockers in reducing perioperative ischaemia and arrhythmia after cardiac surgery. When ultra-short acting beta-blockers were administered before aortic cross-clamping and as cardioplegia adjuvant we observed a trend towards a reduction in postoperative low-cardiac output syndrome (13/98 vs 6/102; p=0.08) and in the rate of hospital re-admission at one year (26/95 v 16/96, p=0.08) with an increase in the number of patients with ejection fraction >60% at hospital discharge (4/95 vs 11/92, p=0.06) (Zangrillo 2021). However, despite a growing body of literature exploring the role of ultra-short acting beta-blockers in enhancing myocardial protection during on-pump cardiac surgery, further high-quality evidence is needed before this practice can be established as standard routine care. Hence, we designed a randomized, placebo-controlled trial involving 1500 patients undergoing open mitral valve surgery to assess the effect of administering landiolol as cardioplegia adjuvant to reduce the occurrence of postoperative low-cardiac output syndrome. Successful results would have a significant impact on short and long-term complications.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Failure; Low Cardiac Output Syndrome
• Intervention / Treatment: Drug: Landiolol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 1500
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Fabrizio Monaco, MD; Phone Number: +39 0226436154; Email: monaco.fabrizio@hsr.it
• Study Contact Backup: Name: Giovanni Landoni, Prof.; Phone Number: +39 0226436154; Email: landoni.giovanni@hsr.it

Study Locations

• Italy
  • Alessandria, Italy
    • Recruiting
    • AOU di Alessandria
    • Contact: Andrea Aduo, MD; Email: aaudo@ospedale.al.it
  • Catania, Italy, 95123
    • Recruiting
    • Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco"
    • Contact: Cristina Santonocito; Phone Number: +393496332052; Email: cristina.santonocito@gmail.com
  • Florence, Italy
    • Recruiting
    • AOU Careggi
    • Contact: Raffaele Mandarano, MD; Email: mandaranor@aou-careggi.toscana.it
  • Foggia, Italy
    • Recruiting
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia
    • Contact: Domenico Paparella, MD; Email: domenico.paparella@unifg.it
  • Genova, Italy
    • Recruiting
    • IRCCS San Martino di Genova
    • Contact: Simona Silvetti, MD; Email: lu.simo@icloud.com
  • Milan, Italy, 20132
    • Recruiting
    • Ospedale San Raffaele
    • Contact: Fabrizio Monaco, MD; Phone Number: +39 0226436154; Email: monaco.fabrizio@hsr.it
    • Contact: Giovanni Landoni, prof; Phone Number: +39 0226436154; Email: landoni.giovanni@hsr.it
    • Principal Investigator: Fabrizio Monaco, MD
  • Milan, Italy
    • Recruiting
    • ASST Grande Ospedale Metropolitano Niguarda
    • Contact: Marcello Guarnieri, MD; Email: marcello.guarnieri@ospedaleniguarda.it
  • Palermo, Italy
    • Recruiting
    • AOU Policlinico Paolo Giaccone
    • Contact: Andrea Cortegiani, MD; Email: andrea.cortegiani@unipa.it
  • Pisa, Italy
    • Recruiting
    • Azienda Ospedaliero Universitaria Pisana
    • Contact: Fabio Guarracino, MD; Email: fabioguarracino@gmail.com
  • Potenza, Italy
    • Recruiting
    • AOR San Carlo
    • Contact: Gianluca Paternoster, Prof; Email: paternostergianluca@gmail.com
  • Ravenna, Italy
    • Recruiting
    • Maria Cecilia Hospital S.p.A.
    • Contact: Lorenzo Mantovani, MD; Email: lmantovani@gvmnet.it
  • Piedmont
    • Alessandria, Piedmont, Italy, 15121
      • Recruiting
      • Ospedale Cesare Arrigo
      • Contact: Giulia Maj, MD; Email: giulia.maj@ospedale.al.it
      • Contact: Giulia Maj, MD
  • TO
    • Torino, TO, Italy
      • Recruiting
      • A. O. Ordine Mauriziano di Torino
      • Contact: Marco Comis, MD; Email: comismarco@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Older than 18 years;
• Elective mitral valve repair or replacement surgery with planned cardiopulmonary bypass via midline sternotomy or minithoracotomy;
• Preoperative evidence of left ventricular end-systolic diameter >40 mm and/or left ventricular end-diastolic diameter >60 mm and/or left ventricular ejection fraction<60%;
• Signed informed consent.

Exclusion Criteria:

• Need for preoperative dialysis;
• Hepatic dysfunction (defined as Child-Pugh class C);
• History of previous unusual response to beta-blockers;
• Urgent or emergency surgery;
• Patient already in need of mechanical circulatory support before surgery (except for IABP);
• Pregnancy as documented by a pregnancy test performed in the last 72h before surgery;
• Patients with preoperative evidence of hypernatremia (serum sodium concentration: > 160 mmol/L);
• Patients with preoperative evidence of hyperchloremia (serum chloride concentration: >115 mmol/L);
• Patients with hypersensitivity to the active substance or to any of the excipients;
• Patients with severe bradycardia (less than 50 beats per minute) sick sinus syndrome, severe atrioventricular nodal conductance disorders or 2nd -3rd degree atrioventricular block and without a pacemaker;
• Patients with cardiogenic shock, severe hypotension (MAP<50 mmHg), decompensated heart failure or severe pulmonary hypertension (PAPs >70 mmHg);
• Patients with non-treated phaeochromocytoma;
• Patients with acute asthmatic attack;
• Patients with severe, uncorrectable metabolic acidosis.
• Participation in a clinical trial in which an investigational drug was administered within 30 days of screening or within the 5 half-lives of the study drug, whichever is longer.
• Planned use of ultra-short acting beta-blockers as intraoperative cardiac protective strategy.
• Refusal or inability to sign the informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Landiolol; intraoperative landiolol, first as low-dose continuous infusion (5 mcg/kg/min) until aortic cross clamping, followed by an intravenous bolus (0.3 mg/kg) after aortic cannulation (but still before aortic cross-clamping) and a further intravenous bolus dose of 0.3 mg/kg as cardioplegia adjuvant added to the first administered cardioplegic solution.	Drug: Landiolol; Intravenous infusion of landiolol
Placebo Comparator: Placebo; intraoperative equivolume placebo normal saline solution, first as low-dose continuous infusion until aortic cross clamping, followed by an intravenous bolus after aortic cannulation and a further equivolume quantity added to the first administered cardioplegic solution.	Drug: Placebo; Intravenous infusion of saline solution of NaCl 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of the occurrence of postoperative low-cardiac output syndrome (LCOS)	The primary outcome will be the reduction of the occurrence of postoperative low-cardiac output syndrome, defined following Cholley et al. 2017 JAMA as the presence of at least one of the following: need of prolonged catecholamine infusion (persisting beyond 48 hours after the initiation of the study drug);; need of circulatory mechanical assist devices in the postoperative period (if an intra-aortic balloon pump was inserted preventively, the criteria will be met if patients are not weaned from the balloon within 96 hours);; need for renal replacement therapy at any time during the intensive care unit stay.	Until ICU discharge, an average of 4 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Death	1 year
Patients requiring prolonged (>48 h) catecholamine infusion	Until ICU discharge, an average of 4 days
Patients with increased postoperative cardiac biomarkers (Troponin I or T)	Up to 48 hours.
Patients with a reduction in left ventricular ejection fraction	Until hospital discharge, an average of 10 days
Number of patients readmitted to hospital for cardiac reasons	1 year
EQ-5D-5L questionnaire	1 year

Collaborators and Investigators

• Sponsor: Università Vita-Salute San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 15, 2025
• First Submitted That Met QC Criteria: January 23, 2025
• First Posted (Actual): January 27, 2025

Study Record Updates

• Last Update Posted (Actual): December 29, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Heart Failure; Cardiac Output, Low; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Anti-Arrhythmia Agents; Adrenergic Agents; Adrenergic beta-Antagonists; Adrenergic Antagonists; landiolol
• Other Study ID Numbers: PNRR-MCNT2-2023-12377946

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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