Effects of Levosimendan in Patients Eligible for Aortic Valve Replacement With Left Ventricular Hypertrophy

Effects of Levosimendan on Systolic Deformation and Diastolic Function in Patients Eligible for Aortic Valve Replacement With Left Ventricular Hypertrophy

This is a clinical, randomised, double-blinded study in which patients eligible for aortic valve replacement are enrolled. Patients receive infusion of either levosimendan or placebo 4 hours prior to surgery and until the end of surgery.

Study Overview

• Status: Terminated
• Conditions: Diastolic Dysfunction; Left Ventricular Hypertrophy
• Intervention / Treatment: Drug: levosimendan; Drug: placebo drug

Detailed Description

Levosimendan or placebo will be infusion for approximately 4 hours prior to aortic valve replacement in patients with severe hypertrophy of the left ventricle and echocardiographic signs of diastolic dysfunction. Outcome measures will be obtained at some of the following:

• Approximately 4 hours prior to surgery. Baseline. Start of levosimendan/placebo infusion
• Immediately before surgery
• After induction of anaesthesia and before "knife time" = start of surgery.
• At the end of surgery: Levosimendan infusion will stop.
• Approximately 4 hours after surgery immediately before extubation.
• Approximately 21 hours after surgery
• Approximately 96 hours after surgery (day 4)
• 6 months after surgery

Outcome measures are comprised of invasive measurements, blood samples, transthoracic echocardiography and transoesophageal echocardiography focusing on measures of systolic and diastolic function of the heart.

Interim analysis will be conducted after 30 included patients.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Region Midtjylland
    • Århus N, Region Midtjylland, Denmark, 8200
      • Department of Anaesthesiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eligible for aortic valve replacement
• EF > 45%
• Left ventricular posterior wall > 12mm
• Sinus rhythm

Exclusion Criteria:

• Concomitant bypass operation
• Severe mitral insufficiency
• Active endocarditis
• Insufficient ultrasound opportunity
• Systolic blood pressure < 100 mmHg
• moderate-severe renal failure
• allergy to levosimendan
• lack of patient consent Pregnancy or status of lactating
• Fertile women who do not use relevant anticonception

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Identical placebo	Drug: placebo drug; Intravenous infusion, colour identical to levosimendan; Other Names: Placebo
Experimental: levosimendan; infusion 0,1ug/kg/min for duration of ca. 4 hours prior to operation and until the end of operation	Drug: levosimendan; Intravenous infusion, 0,1ug/kg/min, duration 4 hours prior to operation and until the end of operation.; Other Names: Simdax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
E/E'(Unitless)	Ration between early transmitral flow (E) and mitral annular tissue velocity(E'). This ratio is an echocardiographic index of diastolic function	4 hours before operation until 21 hour after operation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Isovolumetric Relaxation Time (IVRT) (s)	Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function	4 hours before surgery until 1 hour before operation
Ejection Fraction (Per Cent)	Transeosophageal echocardiography: Measure of systolic function	At start of operation until end of operation, approximately 3 hours
Cardiac Index (l/Min/m2)	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)	4 hours before operation until 1 hour before operation
Central Venous Pressure (mmHg)	Invasive measurement of pressure in the vena cava	4 hours before operation until 1 hours before operation
Pulmonary Artery Pressures (mmHg)	Invasive measurement of mean pressure in the pulmonary artery	4 hours before operation until 1 hour before operation
Systemic Arterial Pressure (mmHg)	Invasive measurements of arterial mean pressure	4 hours before operation until 1 hour before operation
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)	blood sample reflecting stretch of the atrium/ventricle	4 hours before operation until 4 hours after operation
Troponin T (ug/l)	Blood sample expressing damage to the myocytes	4 hours before operation until 4 hours after operation
Lactate (mmol/l)	Arterial sampling of blood lactate	4 hours before operation until 4 hour after operation
Mixed Venous Oxygenation (Per Cent)	Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery	4 hours before operation until 4 hour after operation
E/A Ratio (Unitless)	TEE ratio between early (E) transmitral flow and late (A) transmitral flow. An index of diastolic function althought not validated properly yet when measured from the oesophagus	At the start of operation until the end of operationon, approximately 3 hours
Regional Longitudinal Strain (Unitless)	Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.	At the start of operation until the end of operation, approximately 3 hours
Need for Conventional Inotropical Agents	Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation.	From start of operation until 5 days after operation
Intravenous Fluid Requirement (l)	Total volume of intravenous fluid required including blood products.	Within 24 hours from start of operation
Operation Time (Minutes)		From "knife start" until "knife end", approximately 3 hours
Time on Heart-lung Machine (Minutes)		From time of cardioplegia until selfsufficient cardiac action, approximately 1 hour
Intubation Time (Minutes)	Total time intubated including time of operation and in the intensive care ward	From intubation until extubation, approximately 6 hours
Postoperative Admission Time at Intensive Care Unit (Hours)	Total admission time in the intensive care after operation	From admission to the intensive care unit until discharge from intensive care unit, approximately 24 hours
No. of Patients With Adverse Events	Development of Ventricular tachycardia	-4 hours until + 96 hours with respect to start of operation
No. of Patients With Adverse Event	Development of atrial flutter/fibrillation	-4 hours until + 96 hours with respect to start of operation
No. of Patients With Adverse Event	Need for norepinephrine as an antagonist to the vasodilatatory effect of levosimendan	4 hours before operaton until 1 hour before operaton
No. of Patients With Adverse Event.	Occurence of nausea	4 hours before operation until 1 hour before operation
No. of Patients With Adverse Event	Occurence of headache	4 hours before operation until approximately 1 hour before operation
Regional Longitudinal Strain (Unitless)	Index of systolic function derived from single transthoracic echocardiographic (TTE) projection	4 hours before until 1 hour before start of operation
Ejection Fraction (Per Cent)	TTE: Index of systolic function	1 hour before until 21 hour after start of operation
Ejection Fraction (Per Cent)	TTE: Index of systolic function	21 hours after operation until 96 hours after start of operation
Ejection Fraction (Per Cent)	TTE: Index of systolic function	96 hours after operation until 6 months after operation
Regional Longitudinal Strain (Unitless)	Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.	Froml the end of operation until approx 4 hours after operation
E/A Ratio (Unitless)	TEE ratio between early (E) transmitral flow and late (A) transmitral flow. An index of diastolic function althought not validated properly yet when measured from the oesophagus	At the end of operationon until approx 4 hours after operation
Left Ventricular Rotation (Degrees)	TTE: Index of both systolic and diastolic function	96 hour after operation until 6 months after operation
Mixed Venous Oxygenation (Per Cent)	Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery	4 hours after operation until 21 hours after operation
Lactate (mmol/l)	Arterial sampling of blood lactate	4 hours after operation until 21 hours after operation
Troponin T (ug/l)	Blood sample expressing damage to the myocytes	4 hours after operation until 21 hours after operation
Troponin T (ug/l)	Blood sample expressing damage to the myocytes	21 hours after operation until 96 hours after operation
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)	blood sample reflecting stretch of the atrium/ventricle	4 hours after operation until 21 hours after operation
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)	blood sample reflecting stretch of the atrium/ventricle	21 hours after operation until 96 hours after operation
Systemic Arterial Pressure (mmHg)	Invasive measurements of arterial mean pressure	1 hour before operation until start of operation
Systemic Arterial Pressure (mmHg)	Invasive measurements of arterial mean pressure	Start of operation until the end of operation, approximately 3 hours
Systemic Arterial Pressure (mmHg)	Invasive measurements of arterial mean pressure	End of operation until approx 4 hours after operation
Systemic Arterial Pressure (mmHg)	Invasive measurements of arterial mean pressure	4 hours after operation until 21 hours after operation
Pulmonary Artery Pressures (mmHg)	Invasive measurement of mean pressure in the pulmonary artery	1 hour before operation until start of operation
Pulmonary Artery Pressures (mmHg)	Invasive measurement of mean pressure in the pulmonary artery	Start of operation until end of operation, approximately 3 hours
Pulmonary Artery Pressures (mmHg)	Invasive measurement of mean pressure in the pulmonary artery	End of operation until approx 4 hours after operation
Pulmonary Artery Pressures (mmHg)	Invasive measurement of mean pressure in the pulmonary artery	4 hours after operation until 21 hours after operation
Regional Longitudinal Strain (Unitless)	Index of systolic function derived from single transthoracic echocardiographic (TTE) projection	1 hour before start of operation until 21 hours after operation
Regional Longitudinal Strain (Unitless)	Index of systolic function derived from single transthoracic echocardiographic (TTE) projection	21 hours after operation until 96 hours after operation
Regional Longitudinal Strain (Unitless)	Index of systolic function derived from single transthoracic echocardiographic (TTE) projection	96 hours after operation until 6 months after operation
Central Venous Pressure (mmHg)	Invasive measurement of pressure in the vena cava	1 hour before operation until start of operation
Central Venous Pressure (mmHg)	Invasive measurement of pressure in the vena cava	Start of operation until end of operation, approximately 3 hours
Central Venous Pressure (mmHg)	Invasive measurement of pressure in the vena cava	End of operation until approx 4 hours after operation
Central Venous Pressure (mmHg)	Invasive measurement of pressure in the vena cava	4 hours after operation until 21 hours after operation
Peak Systolic Velocity (m/s)	Tissue Doppler measure of systolic function	1 hour before operation until 21 hours after operation
Peak Systolic Velocity (m/s)	Tissue Doppler measure of systolic function	21 hours after operation until 96 hours after operation
Peak Systolic Velocity (m/s)	Tissue Doppler measure of systolic function	96 hours after operation until 6 months after operation
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)	Transthoracic echocardiographic measure of systolic function	1 hour before operation until 21 hours after operation
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)	Transthoracic echocardiographic measure of systolic function	21 hours after operation until 96 hours after operation
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)	Transthoracic echocardiographic measure of systolic function	96 hours after operation until 6 months after operation
E/A-ratio (Unitless)	Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.	1 hour before operation until 21 hours after operation
E/A-ratio (Unitless)	Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.	21 hours after operation until 96 hours after operation
E/A-ratio (Unitless)	Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.	96 hours after operation until 6 months after operation
E'/A'-Ratio (Unitless)	Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.	1 hour before operation until 21 hours after roperation
E'/A'-Ratio (Unitless)	Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.	21 hours after operation until 96 hours after operation
E'/A'-Ratio (Unitless)	Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.	96 hours after operation until 6 months after operation
Isovolumetric Relaxation Time (IVRT) (s)	Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function	1 hour before operation until 21 hours after operation
Isovolumetric Relaxation Time (IVRT) (s)	Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function	21 hours after operation until 96 hours after operation
Isovolumetric Relaxation Time (IVRT) (s)	Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function	96 hours after operation until 6 months after operation
Ejection Fraction (Per Cent)	Transeosophageal echocardiography: Measure of systolic function	End of operation until approx. 4 hours after operation
Isovolumetric Relaxation Time (IVRT) (s)	Transeosophageal echocardiography: Time from closure of aortic valve to opening of mitral valve. Measure of diastolic function.	End of operation until approx. 4 hours after operation
Cardiac Index (l/Min/m2)	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)	1 hour before operation until start of operation
Cardiac Index (l/Min/m2)	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)	Start of operation until end of operation, approximately 3 hours
Cardiac Index (l/Min/m2)	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)	End of operation operation until approx. 4 hours after operation
Cardiac Index (l/Min/m2)	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)	4 hours after operation until 21 hours after operation
Inflammatory Parameters	Blood sample values of pro- and antiinflammatory mediators	4 hours before operation until 21 hours after operation
Inflammatory Parameters	Blood sample values of pro- and antiinflammatory mediators	21 hours after operation until 96 hours after operation
E/A-ratio (Transoesophageal)	Transoesophageal echocardiographic measure of diastolic heart function	from start of operation until end of operation, approximately 3 hours
E/A-ratio (Transoesophageal)	Transoesophageal echocardiographic measure of diastolic heart function	from end of operation until approximately 4 hours after operation
Urine Clearance	Urine analysis. Measure of kidney function.	from start of operation until 24 hours after operation

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Peter Juhl-Olsen, M.D., Department of Anaesthesiology

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: August 10, 2010
• First Submitted That Met QC Criteria: August 24, 2010
• First Posted (Estimate): August 25, 2010

Study Record Updates

• Last Update Posted (Actual): December 3, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: heart failure; diastolic dysfunction; levosimendan; aortic valve stenosis; left ventricular hypertrophy; inotropics
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Cardiomegaly; Hypertrophy; Hypertrophy, Left Ventricular; 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: 1616