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

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

Detailed Description
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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.

Official Title
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The Effect of Perioperative LevosIMendan Administration on Postoperative N-terminal pRo Brain Natriuretic Peptide Concentration in Patients With Increased cardiOVascular Risk Factors Undergoing Noncardiac surgEry - A Double-blinded Randomized Clinical Trial

Conditions
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Cardiovascular Risk Factor

Intervention / Treatment
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* Drug: Levosimendan
* Drug: Placebo


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

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Levosimendan<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative maximum troponin T concentration | Levosimendan improves myocardial perfusion and might therefore reduce the postoperative maximum rise in TnT | First five postoperative days | 
| Incidence of MINS (myocardial injury in non cardiac surgery) | 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. | First three postoperative days | 
| Myocardial Infarction | 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. | 30 days and 1 year after surgery | 
| Disability | 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. | 30 days and 1 year after surgery | 
| NT-proBNP Mortality | 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. | 30 days and 1 year after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levosimendan, NT-proBNP, MINS, Cardiovascular Disease