Differential Vascular and Endocrine Effects of Valsartan/Sacubitril in Heart Failure With Reduced Ejection Fraction

Valsartan/sacubitril (Entresto®; LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that has recently been approved for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). The drug consists of a 1:1 complex of the angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. In a recent randomized controlled trial in patients with heart failure and reduced ejection fraction (PARADIGM-HF), valsartan/sacubitril significantly reduced all-cause and cardiovascular mortality as well as hospitalizations for heart failure compared to enalapril. The precise reason why combined angiotensin receptor and neprilysin blockade is superior to ACE blockade is still unclear and knowledge of the mechanisms involved would provide further insight which patients with symptomatic heart failure will particularly benefit from valsartan/sacubitril. On the one hand, many of the peptides affected by neprilysin blockade act on vascular endothelial cells. On the other, neprilysin inhibition may induce significant endocrine changes with a shift to more favorable hormonal profile in HFrEF patients. Detailed studies on the vascular and endocrine effects of valsartan/sacubitril in humans are lacking so far. The investigators hypothesize that valsartan/sacubitril results in an incremental improvement of endothelial dysfunction and endocrine imbalance over valsartan in patients with heart failure with reduced ejection fraction.

Inclusion criteria

• Patients ≥ 18 years of age, male or female, with a diagnosis of symptomatic heart failure (NYHA class II-IV) per ESC heart failure guidelines
• LVEF ≤ 40%
• Established guideline-recommended therapy with an ACEI, ARB and a beta-blocker, as clinically indicated and tolerated, at stable doses for at least 3 weeks prior to inclusion.

Exclusion criteria

• History of hypersensitivity or allergy to any of the study drugs
• History of angioedema.
• Sitting systolic blood pressure <90 mmHg at Visit 1 (screening) or Visit 2 (randomization)
• Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
• Estimated GFR < 20 mL/min/1.73m2
• Serum potassium > 5.5 mmol/L at Visit 1 (screening) or Visit 2 (randomization).
• Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1.
• Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after Visit 1.
• Implantation of a cardiac resynchronization therapy device (CRTD) within 2 months prior Visit 1 or intent to implant a CRTD within next 3 months.
• History of heart transplant, on a transplant list or with ventricular assistance device (VAD).
• Presence of significant endocrine diseases.
• Presence of active acute infectious diseases.
• Known narrow-angle glaucoma
• Known epilepsy
• Cimino-shunt operation on both arms
• Pregnancy, intention thereof during study; lack of sufficient contraception; breastfeeding