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

Phase 4

Terminated

Conditions: Diastolic Dysfunction
Left Ventricular Hypertrophy

Interventions: Drug: placebo drug
Drug: levosimendan

Registration Number: NCT01188369

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 20

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	placebo drug	Identical placebo
levosimendan	levosimendan	infusion 0,1ug/kg/min for duration of ca. 4 hours prior to operation and until the end of operation

Primary Outcome Measures

Name	Time	Method
E/E'(Unitless)	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

Name	Time	Method
Isovolumetric Relaxation Time (IVRT) (s)	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.
Ejection Fraction (Per Cent)	End of operation until approx. 4 hours after operation	Transeosophageal echocardiography: Measure of systolic function
Cardiac Index (l/Min/m2)	4 hours after operation until 21 hours after operation	Invasive measurement measuring the cardiac output divided by calculated body surface area (DuBois formula)
Central Venous Pressure (mmHg)	4 hours after operation until 21 hours after operation	Invasive measurement of pressure in the vena cava
Pulmonary Artery Pressures (mmHg)	4 hours after operation until 21 hours after operation	Invasive measurement of mean pressure in the pulmonary artery
Systemic Arterial Pressure (mmHg)	4 hours after operation until 21 hours after operation	Invasive measurements of arterial mean pressure
N-terminal Pro Brain Natriuretic Peptide (NT proBNP)(pg/ml)	21 hours after operation until 96 hours after operation	blood sample reflecting stretch of the atrium/ventricle
Troponin T (ug/l)	21 hours after operation until 96 hours after operation	Blood sample expressing damage to the myocytes
Lactate (mmol/l)	4 hours after operation until 21 hours after operation	Arterial sampling of blood lactate
Mixed Venous Oxygenation (Per Cent)	4 hours after operation until 21 hours after operation	Oxygen content (per cent of hemoglobin saturated) of venous blood in pulmonary artery
E/A Ratio (Unitless)	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
Regional Longitudinal Strain (Unitless)	96 hours after operation until 6 months after operation	Index of systolic function derived from single transthoracic echocardiographic (TTE) projection
Need for Conventional Inotropical Agents	From start of operation until 5 days after operation	Conventional inotropics are comprised of all inotropics acting primarily through alfa- or beta- stimulation.
Intravenous Fluid Requirement (l)	Within 24 hours from start of operation	Total volume of intravenous fluid required including blood products.
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)	From intubation until extubation, approximately 6 hours	Total time intubated including time of operation and in the intensive care ward
Postoperative Admission Time at Intensive Care Unit (Hours)	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
No. of Patients With Adverse Events	-4 hours until + 96 hours with respect to start of operation	Development of Ventricular tachycardia
No. of Patients With Adverse Event	4 hours before operation until approximately 1 hour before operation	Occurence of headache
No. of Patients With Adverse Event.	4 hours before operation until 1 hour before operation	Occurence of nausea
Peak Systolic Velocity (m/s)	96 hours after operation until 6 months after operation	Tissue Doppler measure of systolic function
Tricuspid Annular Plane Systolic Excursion (TAPSE) (mm)	96 hours after operation until 6 months after operation	Transthoracic echocardiographic measure of systolic function
E/A-ratio (Unitless)	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.
E'/A'-Ratio (Unitless)	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.
Left Ventricular Rotation (Degrees)	96 hour after operation until 6 months after operation	TTE: Index of both systolic and diastolic function
Inflammatory Parameters	21 hours after operation until 96 hours after operation	Blood sample values of pro- and antiinflammatory mediators
Urine Clearance	from start of operation until 24 hours after operation	Urine analysis. Measure of kidney function.
E/A-ratio (Transoesophageal)	from end of operation until approximately 4 hours after operation	Transoesophageal echocardiographic measure of diastolic heart function