Effect Levosimendan Administration on Postoperative NT-proBNP in Cardiac Risk Patients

NCT04329624 | Completed Phase 3 DMC

• 1 other identifier: IMPROVE_2.2
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective randomised trial investigating the effect of a preemptive administration of levosimendan on postoperative cardiac NT-proBNP concentrations.

Conditions

Cardiovascular Risk Factor

Keywords

Levosimendan; NT-proBNP; MINS; Cardiovascular Disease

Outcome Measures

Primary Outcomes (1)

• Postoperative maximum NT-proBNP concentration

  The administration of levosimendan improves LVEF and myocardial oxygen perfusion, which will be reflected in a decrease of postoperative NT-proBNP concentration.Since NT-proBNP is a strong predictor for postoperative cardiovascular complications in patients undergoing noncardiac surgery, we want to test the efficiency of levosimendan to decrease postoperative maxNT-proBNP concentrations in patients with increased cardiac risk factors undergoing moderate- to high-risk noncardiac surgery.

  First 5 Postoperative Days

Secondary Outcomes (5)

• Postoperative maximum troponin T concentration

  First five postoperative days

• Incidence of MINS (myocardial injury in non cardiac surgery)

  First three postoperative days

• Myocardial Infarction

  30 days and 1 year after surgery

• Disability

  30 days and 1 year after surgery

• NT-proBNP Mortality

  30 days and 1 year after surgery

Other Outcomes (4)

• Sub-Study I: Fluid status determination

  within 5 days after surgery

• Sub-Study II: Acute Kidney Injury

  within 5 days after surgery

• Sub-Study III: Inflammatory Response

  within 5 days after surgery

Study Arms (2)

Levosimendan

ACTIVE COMPARATOR

Patients receive a continuous infusion of 12.5mg solved in 50mL Levosimendan for up to 24 hours. Infusion will be started with surgical skin incision.

Drug: Levosimendan

Placebo

PLACEBO COMPARATOR

Patients receive a continuous infusion containing a placebo solved in 50mL for up to 24 hours. Infusion will be started with surgical skin incision.

Drug: Placebo

Interventions

Levosimendan DRUG

Levosimendan 2.5 mg/ml injection contains levosimendan 2.5 mg, povidone 10.0 mg, citric acid, anhydrous 2.0 mg and ethanol, anhydrous to 1.0 mL. Levosimendan injection is a clear, yellow to orange solution. Immediately after skin incision patients allocated to the verum group will receive a dose of 12.5 mg in 500 mL of levosimendan.

Levosimendan

Placebo DRUG

Placebo 2.5 mg/ml injection contains riboflavine sodium phosphate 0.4 mg, dehydrated alcohol 100 mg and water for injection to 1 mL. Immediately after skin incision patients allocated to the placebo group will receive 500 mL of 5% Glucose.

Placebo

Eligibility Criteria

• Age: 65 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Undergoing major surgery planned for more than 2 hours
• ≥ 65 years of age and ≤ 85 years of age
• Provide written informed consent AND
• Fulfill ≥ 2 of the following criteria (A-E)
• A) NT-proBNP ≥ 200 ng/L
• B) History of coronary artery disease defined as 1 of the following 7 criteria (I to VII):
• I) History of angina
• II) History of myocardial infarction or acute coronary syndrome
• III) History of a segmental cardiac wall motion abnormality on echocardiography/radionuclide imaging
• IV) History of positive myocardial stress test (echocardiographic or radionuclide)
• V) History of a coronary artery stenosis \> 50%
• VI) ECG with pathological Q waves in any two contiguous leads
• VII) History of previous artery revascularizations
• C) History of permanent/paroxysmal atrial fibrillation diagnosed by physician/specialist
• D) History of peripheral arterial disease as defined by a physician/specialist diagnosis of a current, or prior history of any 1 of the following 5criteria (I-V)

You may not qualify if:

• A) Previous adverse response and/or allergy to levosimendan B) ICU Patients undergoing surgery C) Preoperative Sepsis/SIRS needing ICU treatment D) Preoperative hemodynamically instable patients, who requirevasopressor or inotropic support E) Renal or liver transplantation F) History of severe heart failure (e.g. LVEF \< 30%) G) Patients undergoing surgery for pheochromocytoma H) Liver cirrhosis I) Pulmonary hypertension (mPAP \> 25 mmHg) J) Severe Renal Failure defines as creatinine clearance ≤ 30ml/min

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University of Vienna

Vienna, Vienna, 1100, Austria

Location

Related Publications (7)

• Rodseth RN, Biccard BM, Chu R, Lurati Buse GA, Thabane L, Bakhai A, Bolliger D, Cagini L, Cahill TJ, Cardinale D, Chong CP, Cnotliwy M, Di Somma S, Fahrner R, Lim WK, Mahla E, Le Manach Y, Manikandan R, Pyun WB, Rajagopalan S, Radovic M, Schutt RC, Sessler DI, Suttie S, Vanniyasingam T, Waliszek M, Devereaux PJ. Postoperative B-type natriuretic peptide for prediction of major cardiac events in patients undergoing noncardiac surgery: systematic review and individual patient meta-analysis. Anesthesiology. 2013 Aug;119(2):270-83. doi: 10.1097/ALN.0b013e31829083f1.

  PMID: 23528538 BACKGROUND

• Writing Committee for the VISION Study Investigators; Devereaux PJ, Biccard BM, Sigamani A, Xavier D, Chan MTV, Srinathan SK, Walsh M, Abraham V, Pearse R, Wang CY, Sessler DI, Kurz A, Szczeklik W, Berwanger O, Villar JC, Malaga G, Garg AX, Chow CK, Ackland G, Patel A, Borges FK, Belley-Cote EP, Duceppe E, Spence J, Tandon V, Williams C, Sapsford RJ, Polanczyk CA, Tiboni M, Alonso-Coello P, Faruqui A, Heels-Ansdell D, Lamy A, Whitlock R, LeManach Y, Roshanov PS, McGillion M, Kavsak P, McQueen MJ, Thabane L, Rodseth RN, Buse GAL, Bhandari M, Garutti I, Jacka MJ, Schunemann HJ, Cortes OL, Coriat P, Dvirnik N, Botto F, Pettit S, Jaffe AS, Guyatt GH. Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery. JAMA. 2017 Apr 25;317(16):1642-1651. doi: 10.1001/jama.2017.4360.

  PMID: 28444280 BACKGROUND

• Sessler DI, Meyhoff CS, Zimmerman NM, Mao G, Leslie K, Vasquez SM, Balaji P, Alvarez-Garcia J, Cavalcanti AB, Parlow JL, Rahate PV, Seeberger MD, Gossetti B, Walker SA, Premchand RK, Dahl RM, Duceppe E, Rodseth R, Botto F, Devereaux PJ. Period-dependent Associations between Hypotension during and for Four Days after Noncardiac Surgery and a Composite of Myocardial Infarction and Death: A Substudy of the POISE-2 Trial. Anesthesiology. 2018 Feb;128(2):317-327. doi: 10.1097/ALN.0000000000001985.

  PMID: 29189290 BACKGROUND

• Rodseth RN, Biccard BM, Le Manach Y, Sessler DI, Lurati Buse GA, Thabane L, Schutt RC, Bolliger D, Cagini L, Cardinale D, Chong CP, Chu R, Cnotliwy M, Di Somma S, Fahrner R, Lim WK, Mahla E, Manikandan R, Puma F, Pyun WB, Radovic M, Rajagopalan S, Suttie S, Vanniyasingam T, van Gaal WJ, Waliszek M, Devereaux PJ. The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis. J Am Coll Cardiol. 2014 Jan 21;63(2):170-80. doi: 10.1016/j.jacc.2013.08.1630. Epub 2013 Sep 26.

  PMID: 24076282 BACKGROUND

• Duceppe E, Parlow J, MacDonald P, Lyons K, McMullen M, Srinathan S, Graham M, Tandon V, Styles K, Bessissow A, Sessler DI, Bryson G, Devereaux PJ. Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery. Can J Cardiol. 2017 Jan;33(1):17-32. doi: 10.1016/j.cjca.2016.09.008. Epub 2016 Oct 4.

  PMID: 27865641 BACKGROUND

• Reiterer C, Kabon B, Taschner A, Graf A, Adamowitsch N, Horvath K, Emler D, Zotti O, Hantakova N, Hochreiter B, Fraunschiel M, Clement T, Fleischmann E. Levosimendan for postoperative subclinical heart failure after noncardiac surgery: a randomized, double-blinded, phase III trial. Nat Commun. 2025 Jul 1;16(1):5847. doi: 10.1038/s41467-025-60601-y.

  PMID: 40593481 DERIVED

• Reiterer C, Kabon B, Taschner A, Adamowitsch N, Graf A, Fraunschiel M, Horvath K, Kuhrn M, Clement T, Treskatsch S, Berger C, Fleischmann E. Effect of perioperative levosimendan administration on postoperative N-terminal pro-B-type natriuretic peptide concentration in patients with increased cardiovascular risk factors undergoing non-cardiac surgery: protocol for the double-blind, randomised, placebo-controlled IMPROVE trial. BMJ Open. 2022 Jan 21;12(1):e058216. doi: 10.1136/bmjopen-2021-058216.

  PMID: 35063963 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

Simendan

Intervention Hierarchy (Ancestors)

Hydrazones; Hydrazines; Organic Chemicals; Pyridazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ao. Univ. Prof. Dr. Edith Fleischmann

Study Record Dates

• First Submitted: March 27, 2020
• First Posted: April 1, 2020
• Study Start: October 10, 2020
• Primary Completion: November 7, 2023
• Study Completion: December 18, 2024
• Last Updated: May 8, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)