Short summary

In patients with acute moycardial infarction(AMI) left ventricular systolic or diastolic dyfunction is common, with only 25-33% of the patientes having an entirely normal LV function. Both systolic an diastolic dysfunction is well established independt risk factors for mortality and morbidity after AMI. In patients with diastolic dysfunction but normal systolic function optimal medical treatment is incompletly understood.

Rationale

Diastolic dysfunction after AMI:

Left ventricular (LV) systolic or diastolic dysfunction following acute myocardial infarction (AMI) is common with only 25-33% of the patients having an entirely normal LV function. Based on echocardiographic examinations an estimated 25% of all patients will present with apparently normal systolic function based on LV ejection fraction but diastolic dysfunction based on Doppler echocardiographic criteria.

Direct or indirect measurements of increased LV filling pressure is well-established independent risk factor for mortality and morbidity after AMI. Several recent studies have demonstrated that Doppler echocardiographic indices suggestive of increased LV filling pressure and increased pulmonary arterial pressure are associated with excess mortality and morbidity after AMI. The causal mechanism behind the increased mortality and morbidity due to diastolic dysfunction in patients with preserved systolic function is however poorly understood. Recent data from our group have demonstrated that the underlying pathophysiological response to physical stress in these patients is characterized by a disproportionate increase in LV filling pressure to maintain adequate perfusion (cardiac output) thus suggestive of an upward shift of the pressure volume relationship with increased LV chamber stiffness possibly due to increased myocardial fibrosis. Furthermore, this condition is also characterized by an impaired natriuretic and renal endocrine response to acute volume expansion. Thus the pathophysiological characteristics of this condition closely resamples that of heart failure with preserved ejection fraction. The optimal management of this group of post-AMI patients is however incompletely understood.

LCZ696 is a combination drug consisting of two antihypertensives, valsartan and sacubitril. Valsartan acts by blocking the angiotensin II receptor type 1 and thereby causes vasodilation and increases excretion of sodium and water via the kidneys by attenuating aldosterone production. Sacubitril is a prodrug that is activated to an active metabolite (LBQ657) that acts by inhibiting the enzyme neprilysin. Neprilysin is responsible for the degradation of natriuretic peptides released from the LV and left atrium in response to increased wall stress and myocyte stretch and act by attenuating the deleterious effects of volume and pressure overload on the heart, a protective mechanism that have been suggested to be deficient in early stage of heart failure with preserved LVEF. Augmentation of these mechanisms likely at least partly explain the beneficial effect on outcome of ARNi in heart failure with reduced LVEF that recently was found in the PARADIGM-HF trial, where angiotensin receptor - neprilysin inhibition (ARNi) compared with enalapril treatment was associated with a risk reduction of 20% of composite primary endpoint death and hospitalization for heart failure. In patients with heart failure and preserved ejection fraction ARNi has been demonstrated to have a beneficial effects on natriuretic peptides and left atrial remodeling in a clinical Phase II trial. Furthermore, recent experimental data also suggest ARNi attenuated cardiac remodeling and dysfunction after experimental AMI in rodents and importantly inhibit cardiac fibrosis in experimental AMI, as well as in vitro beyond that achieved by stand-alone angiotensin receptor blockade. Thus in theory LCZ696 may possess several beneficial properties that may improve hemodynamics and cardiac remodeling in patients with diastolic dysfunction after AMI.

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 after AMI. A beneficial effect that is attributed to improved cardiac remodeling (attenuation of cardiac fibrosis).

Description of the cohort

Key inclusion criteria

1. Documented ST segment elevation or non ST- myocardial infarction according to current guidelines.

2. Complete revascularization.

3. Age ≥50 years

4. LVEF ≥45% on echocardiography performed within 72 hours of the MI.

5. Diastolic dysfunction defined as: Ratio of early diastolic peak mitral inflow velocity (E) to early mitral annulus diastolic velocity (e') ratio > 8 and LA dilatation (LA volume index>34 mL/m2).

6. Signed informed consent

Key exclusion criteria

1. Intolerance towards study medication

2. Permanent atrial fibrillation,

3. Known history of cardiomyopathy,

4. More than mild valvular heart disease,

5. Severe obstructive or restrictive pulmonary disease,

6. Inability to perform exercise testing,

7. Inadequate acoustic windows on echocardiography,

8. Ongoing treatment with an angiotensin converting enzyme inhibitor at randomization.

9. Class I indication for an angiotensin converting enzyme inhibitor

10. Symptomatic hypotension, a systolic blood pressure of less than 100 mm Hg at screening

11. An estimated glomerular filtration rate (eGFR) below 30 ml per minute per 1.73 m2 of body-surface area at any time,

12. A serum potassium level of more than 5.2 mmol per liter at screening,

13. A history of hereditary or idiopathic angioedema or unacceptable side effects during receipt of angiotensin converting enzyme inhibitor or angiotensin receptor blocker

14. Inability to provide informed consent

15. Concomitant use of drugs containing aliskiren in patients with diabetes mellitus.

16. Severe reduced liver function, biliary cirrhosis or cholestasis (Child-Pugh class C)

17. Pregnant or nursing(lactacing) women

18. Fertile women unless they are using a highly effective method of contraception

Data and biological material

Meassurements from right heart catheterization, echocardiography and cardiac MRI. Bloodsamples from initial visit, visit 2 and visit 3(end of study)

Collaborating researchers and departments

Department of Cardiology, Odense University Hospital

• Professor Jacob Eifer Møller, MD, DMSc, PhD.

Department of Cardiology, Rigshospitalet

• Professor Finn Gustafsson, MD, DMSc, PhD.

Department of Cardiology, Aarhus University Hospital

• Consultant Mads Andersen, MD, PhD