Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2

LCZ696, a molecular complex of the angiotensin receptor blocker (ARB) valsartan with an inhibitor of neprilysin (NEP, neutral endopeptidase-24.11) sacubitril improved mortality compared to enalapril in patients with heart failure (HF), reduced ejection fraction (EF), and increased brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) in the PARADIGM-HF trial.1 The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF.2 LCZ696 has been underutilized in heart failure, in part due to concerns about hypotension. NEP degrades several vasodilator peptides including bradykinin, substance P and brain-type natriuretic peptide. Decreased degradation of endogenous bradykinin could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis. Inhibition of the bradykinin B2 receptor using icatibant would be expected to prevent this effect. Objectives The main objectives of this mechanistic randomized, double-blind, crossover-design study are: * The primary objective is to test the hypothesis that endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis at initiation. * The secondary objective is to test the hypothesis endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis after up-titration. Eighty (80) subjects with stable heart failure who meet all inclusion/exclusion criteria will be enrolled. Subjects who qualify will collect their urine for 24 hours before each study day for measurement of volume, sodium and potassium. At the start of the study, they will stop their regular angiotensin-converting enzyme (ACE) inhibitor or ARB. After a 48-hour washout, they will undergo a study day in which they are given a single dose of 50 mg LCZ696. They will also receive either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order (double-blind). After a 96-hour washout, they will repeat the study day and receive a single dose of 50 mg LCZ696 and the opposite study drug (icatibant or placebo). After completion of the two acute study days, subjects will take LCZ696 50 mg bid for two weeks, followed by LCZ696 100 mg bid for three weeks, and then LCZ696 200 mg bid, following the conservative up-titration protocol from the TITRATION study.3 Criteria for continuing up-titration appear in the full study protocol. On the 7th and 10th day of the 200 mg bid or highest tolerated dose, subjects will again undergo two more study days three days apart in which they are randomized to receive either icatibant or vehicle.

Inclusion Criteria: 1. Black and white men and women 2. Stable patients with a reduced ejection fraction (EF) 1. EF ≤40%, and 2. history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF) 3. stable clinical symptoms including no hospitalizations for the last six months 4. who are not already taking LCZ696 3. treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks 4. for patients with NYHA Class II or III HF, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or serum potassium. 5. For female subjects, the following conditions must be met: 1. postmenopausal status for at least one year, or 2. status post-surgical sterilization 3. or if of childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β- human chorionic gonadotropin (HCG) testing on every study day Exclusion Criteria: 1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs 2. History of angioedema 3. History of decompensated HF within the last three months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) 4. History of heart transplant or on a transplant list or with left ventricular assistance device 5. Symptomatic hypotension and/or a systolic blood pressure (SBP)\5.4 mmol/L during the study 7. Impaired renal function (eGFR of \9% 17. In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696 18. Hematocrit \3.0 x upper limit of normal range\] 27. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs 28. Treatment with chronic systemic glucocorticoid therapy within the last year 29. Treatment with lithium salts 30. History of alcohol or drug abuse 31. Treatment with any investigational drug in the one month preceding the study 32. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study 33. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study