Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI

Study Overview
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Brief Summary
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This study examines the effect of Entresto on central hemodynamic parameters during exercise in patients with diastolic dysfunction following acute myocardial infarction. Half of the patients will receive Entresto and the other half will receive placebo.

Detailed Description
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In patients with acute myocardial infraction (AMI) only 25-33% have entirely normal left ventricular (LV) systolic and diastolic function. Studies have show that echocardiographic signs of increased LV filling pressure (diastolic dysfunction) are associated with poor outcome after AMI. The optimal management of this group of patients is currently not known. LCZ696 is a novel combination drug consisting of two antihypertensives, sacubitril and valsartan. LCZ696 have demonstrated to reduce mortality in patients with systolic heart failure. In patients with heart failure with preserved ejection fraction a positive effect has been demonstrated on natriuretic peptides and left atrial remodelling when treated with LCZ696, further, experimental data suggest inhibition of cardiac fibrosis. Hypothesis: LCZ696 compared with placebo will improve central hemodynamics (reduce pulmonary capillary wedge pressure (PCWP)), and increase cardiac index (CI) during exercise in patients with diastolic dysfunction following AMI. A beneficial effect that is attributed to improved cardiac remodelling (attenuation of cardiac fibrosis). Primary objective To asses the effect of 6 months treatment with LCZ696 compared with placebo on ratio of PCWP/CI during exercise in patients with a recent AMI and Doppler echocardiographic signs of diastolic dysfunction and preserved systolic function.

Official Title
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Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI

Conditions
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Myocardial Infarction, Diastolic Dysfunction

Intervention / Treatment
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* Drug: Valsartan+ sacubitril
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented ST segment elevation or non ST- myocardial infarction according to current guidelines Complete revascularization Age ≥50 years LVEF ≥45% on echocardiography performed within 72 hours of the MI. Diastolic dysfunction defined as: Ratio of early diastolic peak mitral inflow velocity (E) to early mitral annulus diastolic velocity (e') ratio > 8 and at least moderate LA dilatation (LA volume index>34 mL/m2). Signed informed consent Exclusion Criteria: Intolerance towards study medication Permanent atrial fibrillation, Known history of cardiomyopathy, More than mild valvular heart disease, Severe obstructive or restrictive pulmonary disease, Inability to perform exercise testing, Inadequate acoustic windows on echocardiography, Ongoing treatment with an angiotensin converting enzyme inhibitor at randomization. Class I indication for an angiotensin converting enzyme inhibitor Symptomatic hypotension, a systolic blood pressure of less than 100 mm Hg at screening An estimated glomerular filtration rate (eGFR) below 30 ml per minute per 1.73 m2 of body-surface area at any time, A serum potassium level of more than 5.2 mmol per liter at screening, A history of hereditary or idiopathic angioedema or unacceptable side effects during receipt of angiotensin converting enzyme inhibitor or angiotensin receptor blocker Inability to provide informed consent Concomitant use of drugs containing aliskiren in patients with diabetes mellitus. Severe reduced liver function, biliary cirrhosis or cholestasis (Child-Pugh class C) Pregnant or nursing(lactating) women(see section 8.2.1 for details) Fertile women unless they are using a highly effective method of contraception(see section 8.2.2 for details)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Entresto<br>Combination of valsartan and sacubitril titrated to 103+97 mg B.I.D. for 26 weeks | Drug: Valsartan+ sacubitril<br>* Treatment with Entresto(valsartan+sacubitril)<br>* Other names: Entresto;|
| Placebo Comparator: Placebo<br>Matching placebo B.I.D. for 26 weeks | Drug: Placebo Oral Tablet<br>* Matching placebo treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central hemodynamics | The primary endpoint will be the ratio of mean PCWP at peak exercise divided by cardiac index at peak exercise. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cardiac MRI | Amount of hyperenhancement on cardiac MRI using a semiquantitative assessment of late gadolinium hyperenhancement in a 17 segment model of the LV. | 26 weeks | 
| Biomarker | ST2 concentration at rest. | 26 weeks | 
| Biomarker | MR-proANP at rest. | 26 weeks | 
| Biomarker | NT-proBNP at rest. | 26 weeks | 
| Echocardiographic | Left atrial volume by echocardiography and left atrial emptying fraction by echocardiography at rest. | 26 weeks | 
| Echocardiographic | Proportion of patients with moderate or severe diastolic dysfunction at rest.echocardiography at rest. | 26 weeks |