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

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ClinicalTrials.gov Identifier: NCT01188369
Recruitment Status : Terminated (Terminated prematurely due to high incidence of postoperative atrial fibrillation. The study has not been unblinded.)
First Posted : August 25, 2010
Last Update Posted : August 6, 2012
Sponsor:
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:
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 or disease Intervention/treatment Phase
Diastolic Dysfunction Left Ventricular Hypertrophy Drug: levosimendan Drug: placebo drug Phase 4

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  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : September 2010
Estimated Primary Completion Date : December 2012
Estimated Study Completion Date : March 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. E/E'(unitless) [ Time Frame: 4 hours before operation until 21 hour after operation ]
    Ration between early transmitral flow (E) and mitral annular tissue velocity(E'). This ratio is an echocardiographic index of diastolic function


Secondary Outcome Measures :
  1. Ejection fraction (per cent) [ Time Frame: 4 hours before until 1 hour before start of operation ]
    TTE: Index of systolic function

  2. Peak systolic velocity (m/s) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Tissue Doppler measure of systolic function

  3. Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Transthoracic echocardiographic measure of systolic function

  4. E/A-ratio (unitless) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  5. E'/A'-ratio (unitless) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  6. Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 4 hours before surgery until 1 hour before operation ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  7. Ejection fraction (per cent) [ Time Frame: At start of operation until end of operation, approximately 3 hours ]
    Transeosophageal echocardiography: Measure of systolic function

  8. Cardiac index (l/min/m2) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  9. Central venous pressure (mmHg) [ Time Frame: 4 hours before operation until 1 hours before operation ]
    Invasive measurement of pressure in the vena cava

  10. Pulmonary artery pressures (mmHg) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Invasive measurement of mean pressure in the pulmonary artery

  11. Systemic arterial pressure (mmHg) [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Invasive measurements of arterial mean pressure

  12. N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 4 hours before operation until 4 hours after operation ]
    blood sample reflecting stretch of the atrium/ventricle

  13. Troponin T (ug/l) [ Time Frame: 4 hours before operation until 4 hours after operation ]
    Blood sample expressing damage to the myocytes

  14. lactate (mmol/l) [ Time Frame: 4 hours before operation until 4 hour after operation ]
    Arterial sampling of blood lactate

  15. Mixed venous oxygenation (per cent) [ Time Frame: 4 hours before operation until 4 hour after operation ]
    Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery

  16. E/A ratio (unitless) [ Time Frame: At the start of operation until the end of operationon, approximately 3 hours ]
    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

  17. Regional longitudinal strain (unitless) [ Time Frame: At the start of operation until the end of operation, approximately 3 hours ]
    Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.

  18. Need for conventional inotropical agents [ Time Frame: From start of operation until 5 days after operation ]
    Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation.

  19. Intravenous fluid requirement (l) [ Time Frame: Within 24 hours from start of operation ]
    Total volume of intravenous fluid required including blood products.

  20. Operation time (minutes) [ Time Frame: From "knife start" until "knife end", approximately 3 hours ]
  21. Time on heart-lung machine (minutes) [ Time Frame: From time of cardioplegia until selfsufficient cardiac action, approximately 1 hour ]
  22. Intubation time (minutes) [ Time Frame: From intubation until extubation, approximately 6 hours ]
    Total time intubated including time of operation and in the intensive care ward

  23. 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 ]
    Total admission time in the intensive care after operation

  24. No. of patients with adverse events [ Time Frame: -4 hours until + 96 hours with respect to start of operation ]
    Development of Ventricular tachycardia

  25. No. of patients with adverse event [ Time Frame: -4 hours until + 96 hours with respect to start of operation ]
    Development of atrial flutter/fibrillation

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

  27. No. of patients with adverse event. [ Time Frame: 4 hours before operation until 1 hour before operation ]
    Occurence of nausea

  28. No. of patients with adverse event [ Time Frame: 4 hours before operation until approximately 1 hour before operation ]
    Occurence of headache

  29. Regional longitudinal strain (unitless) [ Time Frame: 4 hours before until 1 hour before start of operation ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  30. Ejection fraction (per cent) [ Time Frame: 1 hour before until 21 hour after start of operation ]
    TTE: Index of systolic function

  31. Ejection fraction (per cent) [ Time Frame: 21 hours after operation until 96 hours after start of operation ]
    TTE: Index of systolic function

  32. Ejection fraction (per cent) [ Time Frame: 96 hours after operation until 6 months after operation ]
    TTE: Index of systolic function

  33. Regional longitudinal strain (unitless) [ Time Frame: Froml the end of operation until approx 4 hours after operation ]
    Transoesophageal echocardiographic (TEE) measure of systolic function. At this time not validated properly against acknowledged indices of systolic function.

  34. E/A ratio (unitless) [ Time Frame: At the end of operationon until approx 4 hours after operation ]
    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

  35. Left ventricular rotation (degrees) [ Time Frame: 96 hour after operation until 6 months after operation ]
    TTE: Index of both systolic and diastolic function

  36. Mixed venous oxygenation (per cent) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery

  37. lactate (mmol/l) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Arterial sampling of blood lactate

  38. Troponin T (ug/l) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Blood sample expressing damage to the myocytes

  39. Troponin T (ug/l) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Blood sample expressing damage to the myocytes

  40. N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    blood sample reflecting stretch of the atrium/ventricle

  41. N-terminal pro Brain natriuretic peptide (NT proBNP)(pg/ml) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    blood sample reflecting stretch of the atrium/ventricle

  42. Systemic arterial pressure (mmHg) [ Time Frame: 1 hour before operation until start of operation ]
    Invasive measurements of arterial mean pressure

  43. Systemic arterial pressure (mmHg) [ Time Frame: Start of operation until the end of operation, approximately 3 hours ]
    Invasive measurements of arterial mean pressure

  44. Systemic arterial pressure (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ]
    Invasive measurements of arterial mean pressure

  45. Systemic arterial pressure (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Invasive measurements of arterial mean pressure

  46. Pulmonary artery pressures (mmHg) [ Time Frame: 1 hour before operation until start of operation ]
    Invasive measurement of mean pressure in the pulmonary artery

  47. Pulmonary artery pressures (mmHg) [ Time Frame: Start of operation until end of operation, approximately 3 hours ]
    Invasive measurement of mean pressure in the pulmonary artery

  48. Pulmonary artery pressures (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ]
    Invasive measurement of mean pressure in the pulmonary artery

  49. Pulmonary artery pressures (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Invasive measurement of mean pressure in the pulmonary artery

  50. Regional longitudinal strain (unitless) [ Time Frame: 1 hour before start of operation until 21 hours after operation ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  51. Regional longitudinal strain (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  52. Regional longitudinal strain (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Index of systolic function derived from single transthoracic echocardiographic (TTE) projection

  53. Central venous pressure (mmHg) [ Time Frame: 1 hour before operation until start of operation ]
    Invasive measurement of pressure in the vena cava

  54. Central venous pressure (mmHg) [ Time Frame: Start of operation until end of operation, approximately 3 hours ]
    Invasive measurement of pressure in the vena cava

  55. Central venous pressure (mmHg) [ Time Frame: End of operation until approx 4 hours after operation ]
    Invasive measurement of pressure in the vena cava

  56. Central venous pressure (mmHg) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Invasive measurement of pressure in the vena cava

  57. Peak systolic velocity (m/s) [ Time Frame: 1 hour before operation until 21 hours after operation ]
    Tissue Doppler measure of systolic function

  58. Peak systolic velocity (m/s) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Tissue Doppler measure of systolic function

  59. Peak systolic velocity (m/s) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Tissue Doppler measure of systolic function

  60. Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 1 hour before operation until 21 hours after operation ]
    Transthoracic echocardiographic measure of systolic function

  61. Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Transthoracic echocardiographic measure of systolic function

  62. Tricuspid annular plane systolic excursion (TAPSE) (mm) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Transthoracic echocardiographic measure of systolic function

  63. E/A-ratio (unitless) [ Time Frame: 1 hour before operation until 21 hours after operation ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  64. E/A-ratio (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  65. E/A-ratio (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Transthoracic echocardiographic ratio between early (E) and late (A) transmitral blood velocities. Index of diastolic function.

  66. E'/A'-ratio (unitless) [ Time Frame: 1 hour before operation until 21 hours after roperation ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  67. E'/A'-ratio (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  68. E'/A'-ratio (unitless) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Tissue Doppler transthoracic echocardiography: Ratio between tissue velocities at the mitral plan during early (E) diastole and late (A) diastole. Index of diastolic function.

  69. Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 1 hour before operation until 21 hours after operation ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  70. Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  71. Isovolumetric relaxation time (IVRT) (s) [ Time Frame: 96 hours after operation until 6 months after operation ]
    Transthoracic measure of the time from aortic valve closure until mitral valve opening. A measure of diastolic function

  72. Ejection fraction (per cent) [ Time Frame: End of operation until approx. 4 hours after operation ]
    Transeosophageal echocardiography: Measure of systolic function

  73. Isovolumetric relaxation time (IVRT) (s) [ Time Frame: End of operation until approx. 4 hours after operation ]
    Transeosophageal echocardiography: Time from closure of aortic valve to opening of mitral valve. Measure of diastolic function.

  74. Cardiac index (l/min/m2) [ Time Frame: 1 hour before operation until start of operation ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  75. Cardiac index (l/min/m2) [ Time Frame: Start of operation until end of operation, approximately 3 hours ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  76. Cardiac index (l/min/m2) [ Time Frame: End of operation operation until approx. 4 hours after operation ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  77. Cardiac index (l/min/m2) [ Time Frame: 4 hours after operation until 21 hours after operation ]
    Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)

  78. Inflammatory parameters [ Time Frame: 4 hours before operation until 21 hours after operation ]
    Blood sample values of pro- and antiinflammatory mediators

  79. Inflammatory parameters [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Blood sample values of pro- and antiinflammatory mediators

  80. E/A-ratio (transoesophageal) [ Time Frame: from start of operation until end of operation, approximately 3 hours ]
    Transoesophageal echocardiographic measure of diastolic heart function

  81. E/A-ratio (transoesophageal) [ Time Frame: from end of operation until approximately 4 hours after operation ]
    Transoesophageal echocardiographic measure of diastolic heart function

  82. urine clearance [ Time Frame: from start of operation until 24 hours after operation ]
    Urine analysis. Measure of kidney function.

  83. E/E' (unitless) [ Time Frame: 21 hours after operation until 96 hours after operation ]
    Echocardiographic index of diastolic function.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   30 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT01188369     History of Changes
Other Study ID Numbers: 1616
First Posted: August 25, 2010    Key Record Dates
Last Update Posted: August 6, 2012
Last Verified: August 2012

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
Pathological Conditions, Anatomical
Cardiomegaly
Heart Diseases
Cardiovascular Diseases
Simendan
Anti-Arrhythmia Agents
Cardiotonic Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Protective Agents
Physiological Effects of Drugs