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Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI (ARNiAMI)

Primary Purpose

Myocardial Infarction, Diastolic Dysfunction

Status

Unknown status

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Valsartan+ sacubitril

Placebo Oral Tablet

About this trial

This is an interventional treatment trial for Myocardial Infarction

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Department of Cardiology, Rigshospitalet
Department of Cardiology, Odense UniversityhospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Entresto

Placebo

Arm Description

Combination of valsartan and sacubitril titrated to 103+97 mg B.I.D. for 26 weeks

Matching placebo B.I.D. for 26 weeks

Outcomes

Primary Outcome Measures

Central hemodynamics

The primary endpoint will be the ratio of mean PCWP at peak exercise divided by cardiac index at peak exercise.

Secondary Outcome Measures

cardiac MRI

Amount of hyperenhancement on cardiac MRI using a semiquantitative assessment of late gadolinium hyperenhancement in a 17 segment model of the LV.

Biomarker

ST2 concentration at rest.

Biomarker

MR-proANP at rest.

Biomarker

NT-proBNP at rest.

Echocardiographic

Left atrial volume by echocardiography and left atrial emptying fraction by echocardiography at rest.

Echocardiographic

Proportion of patients with moderate or severe diastolic dysfunction at rest.echocardiography at rest.

Full Information

NCT ID

NCT04149990

First Posted

October 31, 2019

Last Updated

October 6, 2021

Sponsor

Jacob Moller

Collaborators

Danish Heart Foundation, Odense University Hospital, Rigshospitalet, Denmark

1. Study Identification

Unique Protocol Identification Number

NCT04149990

Brief Title

Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI

Acronym

ARNiAMI

Official Title

Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Unknown status

Study Start Date

October 12, 2018 (Actual)

Primary Completion Date

October 2022 (Anticipated)

Study Completion Date

May 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jacob Moller

Collaborators

Danish Heart Foundation, Odense University Hospital, Rigshospitalet, Denmark

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myocardial Infarction, Diastolic Dysfunction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Entresto

Arm Type

Active Comparator

Arm Description

Combination of valsartan and sacubitril titrated to 103+97 mg B.I.D. for 26 weeks

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Matching placebo B.I.D. for 26 weeks

Intervention Type

Drug

Intervention Name(s)

Valsartan+ sacubitril

Other Intervention Name(s)

Entresto

Intervention Description

Treatment with Entresto(valsartan+sacubitril)

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Intervention Description

Matching placebo treatment

Primary Outcome Measure Information:

Title

Central hemodynamics

Description

The primary endpoint will be the ratio of mean PCWP at peak exercise divided by cardiac index at peak exercise.

Time Frame

26 weeks

Secondary Outcome Measure Information:

Title

cardiac MRI

Description

Amount of hyperenhancement on cardiac MRI using a semiquantitative assessment of late gadolinium hyperenhancement in a 17 segment model of the LV.

Time Frame

26 weeks

Title

Biomarker

Description

ST2 concentration at rest.

Time Frame

26 weeks

Title

Biomarker

Description

MR-proANP at rest.

Time Frame

26 weeks

Title

Biomarker

Description

NT-proBNP at rest.

Time Frame

26 weeks

Title

Echocardiographic

Description

Left atrial volume by echocardiography and left atrial emptying fraction by echocardiography at rest.

Time Frame

26 weeks

Title

Echocardiographic

Description

Proportion of patients with moderate or severe diastolic dysfunction at rest.echocardiography at rest.

Time Frame

26 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Facility Information:

Facility Name

Department of Cardiology, Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Finn Gustafsson

Finn Gustafsson <Finn.Gustafsson@regionh.dk>

Facility Name

Department of Cardiology, Odense Universityhospital

City

Odense

ZIP/Postal Code

5000

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Peter Frederiksen, MD

Phone

+4524672970

peter.hartmund.frederiksen@rsyd.dk

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Angiotensin-Neprilysin Inhibition in Diastolic Dysfunction After AMI

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