Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Enrollment
- 51
- Locations
- 2
- Primary Endpoint
- Central hemodynamics
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 50 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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)
Arms & Interventions
Entresto
Combination of valsartan and sacubitril titrated to 103+97 mg B.I.D. for 26 weeks
Intervention: Entresto Pill (Drug)
Placebo
Matching placebo B.I.D. for 26 weeks
Intervention: Entresto Pill (Drug)
Outcomes
Primary Outcomes
Central hemodynamics
Time Frame: 26 weeks
The primary endpoint will be the ratio of mean PCWP at peak exercise divided by cardiac index at peak exercise.
Secondary Outcomes
- cardiac MRI(26 weeks)
- Biomarker 1(26 weeks)
- Biomarker 2(26 weeks)
- Biomarker 3(26 weeks)
- Echocardiographic 1(26 weeks)
- Echocardiographic 2(26 weeks)
Investigators
Jacob Moller
Professor
Odense University Hospital