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

Phase 3

Active, not recruiting

• Conditions: Cardiovascular Risk Factor
• Interventions: Drug: Placebo; Drug: Levosimendan

• Registration Number: NCT04329624
• Lead Sponsor: Medical University of Vienna

Brief Summary

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

Detailed Description

Major cardiovascular complications occur in about 3 % of all patients undergoing noncardiac surgery and are even higher in patients with increased preoperative risk factors. N-terminal pro brain natriuretic peptide (NT-proBNP) increases in over two third of patients undergoing surgery and is a strong predictor for perioperative myocardial complications. Levosimendan is a positive inotropic Ca2+ sensitizer and significantly reduces postoperative BNP concentration in cardiac surgery. The evidence in the non-cardiac surgery setting, however, is weak. Therefore, we will test our primary hypothesis that the perioperative administration of levosimendan significantly will reduce postoperative NT-proBNP concentrations in patients undergoing moderate- to high-risk non-cardiac surgery. We will also test the secondary hypotheses that levosimendan will reduce postoperative maximum troponin T (maxTnT) concentration, the incidence of myocardial injury after noncardiac surgery (MINS), myocardial infarction and death within 30 days and one year after surgery.

Study Timeline

• Study First Submitted: 2020-03-27
• Study First Submitted QC: 2020-03-30
• Study First Posted: 2020-04-01
• Study Start: 2020-10-10
• Primary Completion: 2023-11-07
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-23
• Last Update Posted: 2024-03-26
• Study Completion: 2024-11-02

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 230

Inclusion Criteria

All patients need to meet all of the following criteria for inclusion (1-4):

1. Undergoing major surgery planned for more than 2 hours
2. ≥ 65 years of age and ≤ 85 years of age
3. Provide written informed consent AND
4. 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)

• I) Intermittent claudication
• II) Stenosis ≥ 70 % detected by angiography or doppler
• III) Stenosis ≤ 70% detected by angiography or doppler AND requiring medical treatment e.g. ASA or other platelet inhibitor
• IV) History of stroke or TIA - diagnosed by physician or CT/MRI
• V) Diagnosed cerebral arteriovascular disease (cAVK) diagnosed by a physician/specialist

E) Any 3 of 10 of the following risk criteria (i - x).

• i. History of congestive heart failure defined as a physician diagnosis of a current or prior episode of congestive heart failure OR prior radiographic evidence of vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary edema;
• ii. History of a transient ischemic attack;
• iii. Diabetes and currently taking an oral hypoglycemic agent or insulin;
• iv. History of hypertension;
• v. Hyperlipidemia and currently taking a lipid lowering agent;
• vi. Documented chronic kidney disease diagnosed by physician/specialist and creatinine clearance > 30 ml/min
• vii. History of smoking within 2 years of surgery
• viii. Diastolic dysfunction (≥ grade 1) documented by echocardiography
• ix. Age ≥ 70 years
• x. Preoperative Troponin T (5th generation) ≥ 25ng/dL

Read More

Exclusion Criteria

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Postoperative maximum NT-proBNP concentration	First 5 Postoperative Days	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.

Secondary Outcome Measures

Name	Time	Method
Postoperative maximum troponin T concentration	First five postoperative days	Levosimendan improves myocardial perfusion and might therefore reduce the postoperative maximum rise in TnT
Incidence of MINS (myocardial injury in non cardiac surgery)	First three postoperative days	Levosimendan decreases the incidence of MINS during the first 3 postoperative days as compared to placebo in patients with increased cardiovascular risk factors undergoing moderateto high-risk noncardiac surgery. MINS is defined as: (i) a non-high-sensitivity troponin T \>_30ng/L2 and (ii) a high-sensitivity troponin T (hsTnT) of 20 to \<65 ng/L with an absolute change of at least 5 ng/L-this change threshold is independently associated with 30-day mortality \[hazard ratio (HR) 4.69; 95% confidence interval (CI) 3.52-6.25\]-or an hsTnT level \>_65ng/ L. Furthermore, an absolute change of at least 5 ng/L is independently associated with 30-day mortality and will also be defined as MINS. TnT will be measured within 2 hours after surgery, on the first, second and third postoperative day.
Myocardial Infarction	30 days and 1 year after surgery	Levosimendan reduces the event rates of myocardial infarction and death during 30 days and 1 year after surgery as compared to placebo. Myocardial infarction is defined as a rise of TnT at least one value is above the 99th percentile URL and with at least one of the following: (i) symptoms of acute myocardial ischaemia; (ii) new ischaemic ECG changes; (iii) development of pathological Q waves; (iiii) imaging evidence of new loss of viable myocardium; (v) new regional wall motion abnormality in a pattern consistent with an ischemic ethiology; (vi) identification of a coronary thrombus by angiography including intracoronary imaging or autopsy.
NT-proBNP Mortality	30 days and 1 year after surgery	Perioperative NT-proBNP elevations are associated with postoperative mortality, cardiac mortality, mortality and nonfatal MI, and cardiac failure at both 30 days and 180 days or more after surgery.; NT-proBNP values have been stratified to the previous published thresholds to predict mortality or MI after surgery.
Disability	30 days and 1 year after surgery	We evaluate the WHODAS 2.0 score before surgery on the day of consent, 30 days after surgery, and 1 year after surgery per phone call. For analyzing we use simply scoring. Each score is assigned to each of the following items - "none" (0), "mild" (1), "moderate" (2), "severe" (3), and "extreme (4).; We will simply add up the scores from the items without recoding or collapsing of response categories, thus, there is no weighting of the individual items. As a result, the simple sum of the scores of the items across all domains constitutes a statistic that is sufficient to describe the degree of functional limitations.

Trial Locations

Locations (1)

Medical University of Vienna; 🇦🇹 Vienna, Austria