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

This study has been terminated.
(Terminated prematurely due to high incidence of postoperative atrial fibrillation. The study has not been unblinded.)
Sponsor:
Information provided by (Responsible Party):
University of Aarhus
ClinicalTrials.gov Identifier:
NCT01188369
First received: August 10, 2010
Last updated: August 3, 2012
Last verified: August 2012
  Purpose

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.


Condition Intervention Phase
Diastolic Dysfunction
Left Ventricular Hypertrophy
Drug: levosimendan
Drug: placebo drug
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Levosimendan on Systolic Deformation and Diastolic Function in Patients Eligible for Aortic Valve Replacement With Left Ventricular Hypertrophy

Resource links provided by NLM:


Further study details as provided by University of Aarhus:

Primary Outcome Measures:
  • E/E'(unitless) [ Time Frame: 4 hours before operation until 21 hour after operation ] [ Designated as safety issue: No ]
    Ration between early transmitral flow (E) and mitral annular tissue velocity(E'). This ratio is an echocardiographic index of diastolic function


Secondary Outcome Measures:
  • Ejection fraction (per cent) [ Time Frame: 4 hours before until 1 hour before start of operation ] [ Designated as safety issue: No ]
    TTE: Index of systolic function

  • Peak systolic velocity (m/s) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Tissue Doppler measure of systolic function

  • Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic measure of systolic function

  • E/A-ratio (unitless) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  • E'/A'-ratio (unitless) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  • Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 4 hours before surgery until 1 hour before operation ] [ Designated as safety issue: No ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  • Ejection fraction (per cent) [ Time Frame: At start of operation until end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Transeosophageal echocardiography: Measure of systolic function

  • Cardiac index (l/min/m2) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  • Central venous pressure (mmHg) [ Time Frame: 4 hours before operation until 1 hours before operation ] [ Designated as safety issue: No ]
    Invasive measurement of pressure in the vena cava

  • Pulmonary artery pressures (mmHg) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Invasive measurement of mean pressure in the pulmonary artery

  • Systemic arterial pressure (mmHg) [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: No ]
    Invasive measurements of arterial mean pressure

  • N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 4 hours before operation until 4 hours after operation ] [ Designated as safety issue: No ]
    blood sample reflecting stretch of the atrium/ventricle

  • Troponin T (ug/l) [ Time Frame: 4 hours before operation until 4 hours after operation ] [ Designated as safety issue: No ]
    Blood sample expressing damage to the myocytes

  • lactate (mmol/l) [ Time Frame: 4 hours before operation until 4 hour after operation ] [ Designated as safety issue: No ]
    Arterial sampling of blood lactate

  • Mixed venous oxygenation (per cent) [ Time Frame: 4 hours before operation until 4 hour after operation ] [ Designated as safety issue: No ]
    Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery

  • E/A ratio (unitless) [ Time Frame: At the start of operation until the end of operationon, approximately 3 hours ] [ Designated as safety issue: No ]
    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

  • Regional longitudinal strain (unitless) [ Time Frame: At the start of operation until the end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.

  • Need for conventional inotropical agents [ Time Frame: From start of operation until 5 days after operation ] [ Designated as safety issue: No ]
    Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation.

  • Intravenous fluid requirement (l) [ Time Frame: Within 24 hours from start of operation ] [ Designated as safety issue: No ]
    Total volume of intravenous fluid required including blood products.

  • Operation time (minutes) [ Time Frame: From "knife start" until "knife end", approximately 3 hours ] [ Designated as safety issue: No ]
  • Time on heart-lung machine (minutes) [ Time Frame: From time of cardioplegia until selfsufficient cardiac action, approximately 1 hour ] [ Designated as safety issue: No ]
  • Intubation time (minutes) [ Time Frame: From intubation until extubation, approximately 6 hours ] [ Designated as safety issue: No ]
    Total time intubated including time of operation and in the intensive care ward

  • Postoperative admission time at intensive care unit (hours) [ Time Frame: From admission to the intensive care unit until discharge from intensive care unit, approximately 24 hours ] [ Designated as safety issue: No ]
    Total admission time in the intensive care after operation

  • No. of patients with adverse events [ Time Frame: -4 hours until + 96 hours with respect to start of operation ] [ Designated as safety issue: Yes ]
    Development of Ventricular tachycardia

  • No. of patients with adverse event [ Time Frame: -4 hours until + 96 hours with respect to start of operation ] [ Designated as safety issue: Yes ]
    Development of atrial flutter/fibrillation

  • No. of patients with adverse event [ Time Frame: 4 hours before operaton until 1 hour before operaton ] [ Designated as safety issue: Yes ]
    Need for norepinephrine as an antagonist to the vasodilatatory effect of levosimendan

  • No. of patients with adverse event. [ Time Frame: 4 hours before operation until 1 hour before operation ] [ Designated as safety issue: Yes ]
    Occurence of nausea

  • No. of patients with adverse event [ Time Frame: 4 hours before operation until approximately 1 hour before operation ] [ Designated as safety issue: Yes ]
    Occurence of headache

  • Regional longitudinal strain (unitless) [ Time Frame: 4 hours before until 1 hour before start of operation ] [ Designated as safety issue: No ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  • Ejection fraction (per cent) [ Time Frame: 1 hour before until 21 hour after start of operation ] [ Designated as safety issue: No ]
    TTE: Index of systolic function

  • Ejection fraction (per cent) [ Time Frame: 21 hours after operation until 96 hours after start of operation ] [ Designated as safety issue: No ]
    TTE: Index of systolic function

  • Ejection fraction (per cent) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    TTE: Index of systolic function

  • Regional longitudinal strain (unitless) [ Time Frame: Froml the end of operation until approx 4 hours after operation ] [ Designated as safety issue: No ]
    Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.

  • E/A ratio (unitless) [ Time Frame: At the end of operationon until approx 4 hours after operation ] [ Designated as safety issue: No ]
    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

  • Left ventricular rotation (degrees) [ Time Frame: 96 hour after operation until 6 months after operation ] [ Designated as safety issue: No ]
    TTE: Index of both systolic and diastolic function

  • Mixed venous oxygenation (per cent) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery

  • lactate (mmol/l) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Arterial sampling of blood lactate

  • Troponin T (ug/l) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Blood sample expressing damage to the myocytes

  • Troponin T (ug/l) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Blood sample expressing damage to the myocytes

  • N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    blood sample reflecting stretch of the atrium/ventricle

  • N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    blood sample reflecting stretch of the atrium/ventricle

  • Systemic arterial pressure (mmHg) [ Time Frame: 1 hour before operation until start of operation ] [ Designated as safety issue: No ]
    Invasive measurements of arterial mean pressure

  • Systemic arterial pressure (mmHg) [ Time Frame: Start of operation until the end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Invasive measurements of arterial mean pressure

  • Systemic arterial pressure (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurements of arterial mean pressure

  • Systemic arterial pressure (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurements of arterial mean pressure

  • Pulmonary artery pressures (mmHg) [ Time Frame: 1 hour before operation until start of operation ] [ Designated as safety issue: No ]
    Invasive measurement of mean pressure in the pulmonary artery

  • Pulmonary artery pressures (mmHg) [ Time Frame: Start of operation until end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Invasive measurement of mean pressure in the pulmonary artery

  • Pulmonary artery pressures (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement of mean pressure in the pulmonary artery

  • Pulmonary artery pressures (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement of mean pressure in the pulmonary artery

  • Regional longitudinal strain (unitless) [ Time Frame: 1 hour before start of operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  • Regional longitudinal strain (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  • Regional longitudinal strain (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  • Central venous pressure (mmHg) [ Time Frame: 1 hour before operation until start of operation ] [ Designated as safety issue: No ]
    Invasive measurement of pressure in the vena cava

  • Central venous pressure (mmHg) [ Time Frame: Start of operation until end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Invasive measurement of pressure in the vena cava

  • Central venous pressure (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement of pressure in the vena cava

  • Central venous pressure (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement of pressure in the vena cava

  • Peak systolic velocity (m/s) [ Time Frame: 1 hour before operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Tissue Doppler measure of systolic function

  • Peak systolic velocity (m/s) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Tissue Doppler measure of systolic function

  • Peak systolic velocity (m/s) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Tissue Doppler measure of systolic function

  • Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 1 hour before operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic measure of systolic function

  • Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic measure of systolic function

  • Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic measure of systolic function

  • E/A-ratio (unitless) [ Time Frame: 1 hour before operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  • E/A-ratio (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  • E/A-ratio (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  • E'/A'-ratio (unitless) [ Time Frame: 1 hour before operation until 21 hours after roperation ] [ Designated as safety issue: No ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  • E'/A'-ratio (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  • E'/A'-ratio (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  • Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 1 hour before operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  • Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  • Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 96 hours after operation until 6 months after operation ] [ Designated as safety issue: No ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  • Ejection fraction (per cent) [ Time Frame: End of operation until approx. 4 hours after operation ] [ Designated as safety issue: No ]
    Transeosophageal echocardiography: Measure of systolic function

  • Isovolumetric relaxation time (IVRT) (s) [ Time Frame: End of operation until approx. 4 hours after operation ] [ Designated as safety issue: No ]
    Transeosophageal echocardiography: Time from closure of aortic valve to opening of mitral valve. Measure of diastolic function.

  • Cardiac index (l/min/m2) [ Time Frame: 1 hour before operation until start of operation ] [ Designated as safety issue: No ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  • Cardiac index (l/min/m2) [ Time Frame: Start of operation until end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  • Cardiac index (l/min/m2) [ Time Frame: End of operation operation until approx. 4 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  • Cardiac index (l/min/m2) [ Time Frame: 4 hours after operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  • Inflammatory parameters [ Time Frame: 4 hours before operation until 21 hours after operation ] [ Designated as safety issue: No ]
    Blood sample values of pro- and antiinflammatory mediators

  • Inflammatory parameters [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Blood sample values of pro- and antiinflammatory mediators

  • E/A-ratio (transoesophageal) [ Time Frame: from start of operation until end of operation, approximately 3 hours ] [ Designated as safety issue: No ]
    Transoesophageal echocardiographic measure of diastolic heart function

  • E/A-ratio (transoesophageal) [ Time Frame: from end of operation until approximately 4 hours after operation ] [ Designated as safety issue: No ]
    Transoesophageal echocardiographic measure of diastolic heart function

  • urine clearance [ Time Frame: from start of operation until 24 hours after operation ] [ Designated as safety issue: No ]
    Urine analysis. Measure of kidney function.

  • E/E' (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ] [ Designated as safety issue: No ]
    Echocardiographic index of diastolic function.


Enrollment: 20
Study Start Date: September 2010
Estimated Study Completion Date: March 2013
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Simdax
Placebo Comparator: Placebo
Identical placebo
Drug: placebo drug
Intravenous infusion, colour identical to levosimendan
Other Name: Placebo

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.

  Eligibility

Ages Eligible for Study:   30 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01188369

Locations
Denmark
Department of Anaesthesiology
Århus N, Region Midtjylland, Denmark, 8200
Sponsors and Collaborators
University of Aarhus
Investigators
Principal Investigator: Peter Juhl-Olsen, M.D. Department of Anaesthesiology
  More Information

No publications provided

Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT01188369     History of Changes
Other Study ID Numbers: 1616
Study First Received: August 10, 2010
Last Updated: August 3, 2012
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by University of Aarhus:
levosimendan
heart failure
inotropics
diastolic dysfunction
left ventricular hypertrophy
aortic valve stenosis

Additional relevant MeSH terms:
Hypertrophy
Hypertrophy, Left Ventricular
Cardiomegaly
Cardiovascular Diseases
Heart Diseases
Pathological Conditions, Anatomical
Simendan
Anti-Arrhythmia Agents
Cardiotonic Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase Inhibitors
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 29, 2014