Review Angiotensin receptor–neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs Mauro Gori a , Maurizio Volterrani b , Massimo Piepoli c , Michele Senni a, ⁎ a Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy b Cardiology Department, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy c Heart Failure Unit, Cardiology Dept., Guglielmo da Saliceto Hospital, Piacenza, Italy abstract article info Article history: Received 10 June 2016 Accepted 21 June 2016 Available online xxxx Sacubritil * valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor–neprilysin inhibitor (ARNi). This combination drug has been successfully studied in patients with heart failure with both preserved (HFpEF) and reduced ejection fraction (HFrEF). In this review, the evidences in patients with HFpEF and HFrEF are summarized, including the results of more recent studies. © 2016 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiotensin receptor–neprilysin inhibitor ARNi Heart failure LCZ696 1. LCZ696 in heart failure with preserved ejection fraction LCZ696 has been tested in a phase 2 trial in HFpEF, the PARAMOUNT (Prospective Comparison of ARNi with ARB on Management of Heart Failure with Preserved Ejection Fraction) trial [1]. In PARAMOUNT, LCZ696 200 mg twice daily was compared with valsartan 160 mg twice daily, which is the bioequivalent amount of valsartan in that dose of LCZ696. PARAMOUNT was a double-blind randomized study in 301 patients with signs and symptoms of HF, aged 40 years or older, with NT-proBNP N 400 pg/ml, and a left ventricular ejection frac- tion (LVEF) ≥ 45%, while on active diuretic therapy. The main exclusion criteria included eGFR b 30 ml/min/1.73 m 2 , non-cardiac dyspnea, and significant valvular heart disease. The primary endpoint, the decline in NT-proBNP at 12 weeks after initiation of the treatment, was greater in the LCZ696 group (26% reduction) than in the valsartan group (Fig. 1). Furthermore, after 36 weeks of treatment both left atrial dimen- sion and volume, which has been proposed as a marker of diastolic dis- ease burden [2], also declined more with LCZ696. Of note, left atrial volume reduction associated with LCZ696 varied according to baseline level of plasma biomarkers reflecting profibrotic processes; patients with values less than the observed median showed left atrial reverse re- modeling, while those above median did not [3]. In addition, patients in the LCZ696 arm had greater improvements in New York Heart Associa- tion (NYHA) class. As compared to valsartan, LCZ696 reduced to a great- er extent blood pressure (BP). Nevertheless, subsequent analyses have shown that the LCZ696 effects on reduction in NT-proBNP and improve- ments in left atrial size and NYHA class were independent of the BP- lowering effect [4]. Interestingly, despite the substantial reduction in BP in the LCZ696 arm, LCZ696 better preserved renal function compared to valsartan after 36 weeks of therapy, as shown by lower levels of serum creatinine and higher estimated glomerular filtration rate (eGFR) [5]. These results suggested that LCZ696 may attenuate decline in renal function in patients with HFpEF. Another post-hoc analysis of the PARAMOUNT trial has recently shown that LCZ696 may reduce a measure of myocardial injury, such as high-sensitivity troponin T [6]. Given PARAMOUNT's favorable results, the PARAGON (Prospective Comparison of LCZ696 with ARB Global Outcome in HF with Preserved Ejection Fraction) trial (NCT01920711) has begun to determine wheth- er LCZ696 can reduce cardiovascular death or total HF hospitalizations in patients with HFpEF. The enrollment of 4300 patients with LVEF ≥ 45% is planned with the following key inclusion criteria: current symp- tomatic HF (NYHA functional classes II–IV), elevated natriuretic pep- tides or history of HF hospitalization within 9 months, and evidence of structural heart disease, demonstrated by left ventricular hypertrophy or left atrial enlargement. While the results of this trial are awaited in 2019, the greater benefit of LCZ696 over enalapril in the higher spec- trum of LVEF in PARADIGM-HF seems to suggest that the novel drug will be successful also in the setting of HFpEF [7]. International Journal of Cardiology xxx (2016) xxx–xxx ⁎ Corresponding author at: Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Piazza OMS, 1, 24127 Bergamo, Italy. E-mail address: msenni@hpg23.it (M. Senni). IJCA-22711; No of Pages 5 http://dx.doi.org/10.1016/j.ijcard.2016.06.083 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Please cite this article as: M. Gori, et al., Angiotensin receptor–neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.06.083