Angiotensin receptor/neprilysin inhibitor-a breakthrough in chronic heart failure therapy: summary of subanalysis on PARADIGM-HF trial findings

Abstract

It is over 4 years since the Prospective Comparison of angiotensin receptor/neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was published in New England Journal of Medicine. The PARADIGM-HF trial was the one that contributed to the official approval to use ARNI simultaneously with cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD) in patients who receive optimal medical treatment and still presented NYHA II-IV class symptoms according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. The aim of this article is to summarise current knowledge on the activity of ARNI in a selected group of patients with heart failure with reduced ejection fraction (HFrEF) based on a recent PARADIGM-HF subanalysis in the field of renal function in patients with and without chronic kidney disease, glycaemia control in patients with diabetes, ventricular arrhythmias and sudden cardiac death and health-related quality of life. This article includes also recently announced findings on the TRANSITION study which revealed that HFrEF therapy with ARNI might be safely initiated after an acute decompensated heart failure episode, including patients with heart failure de novo and ACEI/ARB naïve, both hospitalised or shortly after discharge, in contrary to the PARADIGM-HF trial, where patients had to be administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg a day for at least 4 weeks before the screening.

Keywords: Angiotensin receptor/neprilysin inhibitor; Angiotensin-converting enzyme; Chronic heart failure; Chronic kidney disease; Diabetes; PARADIGM-HF; Quality of life; Sudden cardiac death; TRANSITION.

Fig. 1

Pathways of activation renin-angiotensin-aldosterone and natriuretic peptide systems and points of interest for ACEI, ARB, and ARNI (“+” for activation and “–” for inhibition); adapted from: Jhund PS, McMurray JJV. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart. 2016 Sep 1;102(17):1342-7 [9]. ANP—A-type natriuretic peptide; ACEI—angiotensin-converting enzyme inhibitor; ARB—angiotensin receptor blocker; ARNI—angiotensin receptor/neprilysin inhibitor; BNP—B-type natriuretic peptide; CNP—C-type natriuretic peptide; RAAS—renin-angiotensin-aldosterone system

Fig. 2

Concentration of glycated haemoglobin at screening and over 3 years of follow-ups in patients with diagnosed diabetes and non-diabetic patients and HbA1c concentration ≥ 6.5% at screening randomised to enalapril or sacubitril/valsartan arm [21]. ACEI—angiotensin-converting enzyme inhibitor; ARNI—angiotensin receptor/neprilysin inhibitor; HbA1c—glycated haemoglobin

Fig. 3

Mechanism of better glycaemia control when the use of sacubitril/valsartan underlies inter alia an increased concentration of peptides which cannot be degraded by actually blocked neprilysin (“–” for inhibition, “↑” for increase). ARNI—angiotensin receptor/neprilysin inhibitor; BNP—B-type natriuretic peptide; DPP-4—dipeptidyl peptidase-4; GLP-1—glucagon-like peptide-1

Fig. 4

Change score differences of KCCQ physical and social activities between enalapril and sacubitril/valsartan group at 8-month and at 36-month follow-up [37, 38]. KCCQ—Kansas City Cardiomyopathy Questionnaire; mo—months