The Effectiveness and Safety of Levosimendan in Patients With Severe Aortic Stenosis and Heart Failure Undergoing Transcatheter Aortic Valve Replacement

A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effectiveness and Safety of Levosimendan in Patients With Severe Aortic Stenosis and Heart Failure Undergoing Transcatheter Aortic Valve Replacement

A study to evaluate the effectiveness and safety of levosimendan compared with placebo in subjects with severe aortic stenosis and heart failure undergoing transcatheter aortic valve replacement

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Aortic Valve Stenosis; Transcatheter Aortic Valve Replacement; Cardiac Event; Safety Issues; Effect of Drug; Inotropic Agents
• Intervention / Treatment: Drug: Levosimendan; Other: Placebo

Detailed Description

The number of subjects undergoing transcatheter aortic valve replacement to treat aortic stenosis have been increasing in recent decades. Levosimendan, an innovative inotrope, is powerfully evidenced to have the function to improve cardiac output and hemodynamic parameters. However, there is no specified study concentrated on the role of Levosimendan in surgical procedure such as transcathter aortic intervention. This double-blind, randomized, placebo-controlled study is aimed to investigate the effectiveness and safety of Levosimendan in adults having severe aortic stenosis combined with heart failure undergoing transcatheter aortic valve replacement. Therefore, the purpose of this trial is to explore whether the improvement of cardiac and renal performance can be rendered by intra-operative Levosimendan infusion.

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jianhui Wang, MD; Phone Number: 010-88398082; Email: stewenwang@sina.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100037
      • Recruiting
      • Jianhui Wang
      • Contact: Jianhui Wang, MD; Phone Number: 010-88398082; Email: stewenwang@sina.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed (by the subjects or their legally acceptable representatives) informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study

2. Severe aortic stenosis

   1. Mean transaortic gradient ≥ 40 mmHg(at rest or stress)
   2. Aortic peak velocity ≥ 4m/s;
   3. Arotic valve area <0.8 cm2 and/or aortic valve area index< 0.5cm2/m2

3. Cardiac dysfunction

   1. LVEF≤50% (estimated by Simpson)
   2. NT-proBNP≥1500ng/L；
   3. Symptoms of dyspnea and fatigue when at rest or after slight exertion (New York Heart Association ≥ Ⅲ -Ⅳ)
   4. Intermittant fluid retention and/or symptoms induced by low cardiac output at rest, but lack of hemodynamic instability

Exclusion Criteria:

1. Decompensated acute cardiac failure due to hemodynamic instability
2. A historty of torsade de points ventricular tachycardia
3. Known allergic reaction or sensitivity to Levosimendan or excipients
4. Received levosimendan within 1 week prior to the planned clinical trial
5. Serum potassium < 3.5 mmol/L and > 5.5 mmol/L before the drug study
6. Systolic blood pressure < 90mmHg at baseline
7. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2.
8. Unable to participate in study for being critically ill asssed by clinicians
9. Other concomitant severe morbidities leading to poor prognosis and decreased mortality, such as malignant tumor and disease involving other vital organs; life expectancy less than 1 year.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan; Levosimendan 0.1µg/kg/min will last for 24h after the valve is released.	Drug: Levosimendan; On the basis of routine care given by corresponding clinicians, 0.1µg/kg/min levosimendan is given for 24 hours.
Placebo Comparator: Placebo; 5% glucose 0.1µg/kg/min administration will continue for 24h after the valve is released.	Other: Placebo; On the basis of routine care given by corresponding clinicians, 0.1µg/kg/min 5% glucose infusion is given for 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The change of NT-proBNP level	day 1, day 3, day 5, month 1 and month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change of CK-MB		day 1, day 3, day 5, month 1 and month 3
The change of c-TnI		day 1, day 3, day 5, month 1 and month 3
The change of left ventricular ejection fraction	It is evaluated by echcardiography.	day 1, day 3, day 5, month 1 and month 3
The change of left ventricular end-diastolic diameter	It is evaluated by echcardiography.	day 1, day 3, day 5, month 1 and month 3
The number of patients in need of secondary intra-operative vasoactive-inotropic substances	Vasoactive-inotropic substances include dobutamine, milrinone, epinephrine, dopamine and vasopressors.	Peri-operation
The incidence of postoperative kidney injury	The kidney injury will be assessed by the change of serum creatinine, urea nitrogen and cystatin C.	day 1, day 3, day 5, month 1 and month 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of adverse events	Adverse events include hypotension and arrythmia.	Peri-operation
The incidence of atrial fibrillation		Peri-operation
The change of electrolyte	The change of electrolyte is evaluated by potassium, calcium and lactic acid level.	Peri-operation
The number of patients having liver dysfunction	Liver dysfunction is assessed by the change of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).	Peri-operation
The length of intensive care unit stay		From date of surgery until intensive care unit discharge (assessed up to 1 month)
In-hospital medical expense		From baseline until hospital discharge (assessed up to 1 month)

Collaborators and Investigators

• Sponsor: China National Center for Cardiovascular Diseases
• Collaborators: China International Medical Foundation

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): December 30, 2022

Study Registration Dates

• First Submitted: September 15, 2020
• First Submitted That Met QC Criteria: September 27, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: September 27, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Heart failure; Effectiveness; Transcatheter Aortic Valve Replacement; Aortic valve stenosis; Levosimendan; NT-proBNP
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Heart Failure; Aortic Valve Stenosis; Constriction, Pathologic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: 2020-1357

Drug and device information, study documents

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