PIONEER-HF: a new frontier in the role of neprilysin inhibition in the management of heart failure with reduced ejection fraction

The addition of a neprilysin inhibitor to a renin–angiotensin system (RAS) antagonist, using the combination of sacubitril and valsartan, was shown to reduce morbidity and mortality in outpatients with chronic heart failure and reduced ejection fraction (HFrEF).1 In PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial), sacubitril/valsartan reduced the risk of cardiovascular death or heart failure (HF) hospitalization by 20%, compared with a RAS blocker alone [the gold-standard angiotensin-converting enzyme (ACE)-inhibitor enalapril]. Consequently, international guidelines have recommended adding a neprilysin inhibitor in patients with HFrEF who remain symptomatic despite treatment with a RAS antagonist, beta-blocker, and mineralocorticoid receptor antagonist [by switching from existing ACE-inhibitor or angiotensin II receptor blocker (ARB) to sacubitril/valsartan].2 However, there remained a series of unanswered questions as to the role of sacubitril/valsartan in particular subgroups of patients: PARADIGM-HF did not recruit hospitalized patients; it required patients to be tolerant of maximal doses of both enalapril and sacubitril/valsartan during sequential single-blinded run-in periods prior to randomization; and it did not include patients who were ACE-inhibitor or ARB naïve. PIONEER-HF (Comparison of Sacubitril–Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode trial) was therefore designed to assess the efficacy and safety of sacubitril/valsartan compared to enalapril in patients who were hospitalized for acute decompensated HF.3,4 The trial recruited haemodynamically stable patients after at least 24 h and up to 10 days after their initial presentation with a left ventricular ejection fraction of ≤40%, an N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) level of ≥1600pg/mL, and signs and symptoms of fluid overload. Prior treatment with an ACE-inhibitor or ARB was not required. Patients were randomized to either double-blind sacubitril/valsartan at an initial dose of 24/26 mg or 49/51 mg bid, or enalapril 2.5 mg or 5 mg bid with the choice of dose determined by systolic blood pressure at randomization according to a pre-specified algorithm. There was no initial run-in period as in PARADIGM-HF. Patients were followed up for 8 weeks, with the dose increased to a target of sacubitril/valsartan 97/103 mg bid or enalapril 10 mg bid as tolerated. The primary endpoint was the time-averaged proportional change in NT-proBNP concentration from baseline through 4 and 8 weeks following randomization, with key safety outcomes of the incidence of worsening renal function, hyperkalaemia, symptomatic hypotension, and angioedema. Secondary biomarker outcomes included time-averaged proportional changes in high-sensitivity troponin T (hsTnT) and B-type natriuretic peptide concentrations. A composite of exploratory clinical outcomes was also pre-specified. Eight hundred and eighty-one patients (72.1% male) with a mean age of 61 ± 14 years were randomized at a median of 68 h after initial presentation to hospital. Approximately one-third of patients had presented with de novo HF, and around half of those randomized were not receiving treatment with a RAS antagonist at baseline. At 8 weeks, 55.2% and 60.8% of patients received the targets doses of sacubitril/valsartan and enalapril, respectively. A significantly greater reduction in NT-proBNP was observed with sacubitril/valsartan as compared to enalapril; the ratio of the geometric means of NT-proBNP concentration at Weeks 4 and 8 to the baseline values was 0.53 with sacubitril/valsartan as compared to 0.75 with enalapril [percent change −46.7% vs. −25.3%; ratio of change 0.71; 95% confidence interval (CI) 0.63–0.81; P < 0.001]. This finding was evident as early as 1 week following randomization (ratio of change 0.76, 95% CI 0.69–0.85). A similar reduction in favour of sacubitril/valsartan was observed in levels of hsTnT (ratio of change 0.85, 95% CI 0.77–0.94). Furthermore, the incidence of safety outcomes did not differ significantly between the treatment groups. The exploratory clinical endpoint of investigator reported rehospitalization for HF was significantly reduced with a hazard ratio (HR) for sacubitril/valsartan compared to enalapril of 0.56 (95% CI 0.37–0.84). In a post hoc analysis, using clinical event committee adjudicated endpoints, sacubitril/valsartan, compared with enalapril, significantly reduced the risk of cardiovascular death or rehospitalization for HF at 8 weeks (HR 0.58, 95% CI 0.39–0.87; P = 0.007).5 When examined separately, adjudicated rehospitalization for HF was reduced at 8 weeks by 39% (95% CI 7–60%), with this benefit evident as early as 30 days following randomization (HR 0.72, 95% CI 0.42–1.25). In summary, PIONEER-HF provides evidence that addition of a neprilysin inhibitor to conventional therapy, including a RAS blocker, in hospitalized HF patients stabilized after an episode of decompensation was safe and effective when compared with conventional therapy alone. This seemed to be the case in patients with a first presentation of HFrEF and in those who were ACE-inhibitor or ARB naïve (i.e. in patients who were not included in PARADIGM-HF) and without any run-in period. This trial supports the use of sacubitril/valsartan at an earlier stage in patients with HFrEF (at first presentation and not necessarily after prior use of a RAS blocker) and in hospital as opposed to just in the outpatient setting. The latter is especially important because it is recognized that recently hospitalized patients are at particularly high risk of death and readmission. Initiation of therapy before discharge may be an important opportunity to try and reduce this risk. It is of interest to review why neprilysin inhibition is beneficial in HFrEF. The effects of this treatment are thought, in part, to result from inhibition of the breakdown of natriuretic peptides. Augmentation of natriuretic peptide levels in turn lead to arterial and venous vasodilation, along with natriuresis and diuresis. Activation of the guanylyl cyclase-A receptor by natriuretic peptides increases intracellular cyclic guanosine 3′5′ monophosphate (cGMP) which may have anti-fibrotic and anti-apoptotic actions. In a pre-specified analysis of PIONEER-HF, in patients randomized to sacubitril/valsartan activation of these target pathways was evidenced by a significant increase in urinary cGMP concentrations as early as 1 week following randomization.6 A rapid decline in biomarkers of both haemodynamic stress [NT-proBNP and soluble ST2 (sST2)] and myocardial injury (hsTnT) was also observed in patients randomized to sacubitril/valsartan compared with enalapril; these differences were evident from 1 week for NT-proBNP and sST2 and 4 weeks for hsTnT. This favourable biomarker profile may also result from augmentation of other vasoactive peptides degraded by neprilysin including bradykinin, adrenomedullin calcitonin-gene related peptide, substance-P, and vasoactive intestinal polypeptide (Table 1).7 Potential physiological effects of neprilysin inhibition on its substrates ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; SNS, sympathetic nervous system. Potential physiological effects of neprilysin inhibition on its substrates ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; SNS, sympathetic nervous system. The results of PIONEER-HF add to those from PARADIGM-HF in demonstrating an association between favourable changes in biomarkers and better outcomes, although a direct cause and effect relationship cannot be concluded.8,9 Questions still remain as to the direct cardiac effects of neprilysin inhibition such as any potential beneficial effect on cardiac remodelling and the role of other substrates for neprilysin in mediating such effects, e.g. apelin (Table).10 In combination with data from PARADIGM-HF reporting that longer-term treatment with sacubitril/valsartan reduced levels of biomarkers of extracellular matrix remodelling, a series of pre-clinical models have reported a variety of beneficial cardioprotective effects of neprilysin inhibition.11 In murine models of myocardial infarction, combined neprilysin inhibition and angiotensin receptor blockade resulted in a greater inhibition of cardiac fibrosis and hypertrophy with an attenuation of adverse remodelling and improvements in cardiac function compared to either monotherapy alone.12,13 The greater reduction in fibrosis observed has been suggested to be due to a more effective attenuation of angiotensin II mediated fibrosis, secondary to increased natriuretic peptide levels, with a possible contributory inhibitory effect of neprilysin inhibition on the expression of tissue growth factor-β mRNA also reported.14 Similar renal anti-fibrotic effects have also been reported, providing a potential mechanistic explanation behind the observation that sacubitril/valsartan was more effective than enalapril at attenuating the decline in renal function over time in patients with HFrEF.15,16 Cardioprotective properties of neprilysin inhibition have also been reported in experimental models of hypertension and diabetes with a reduction in genetic markers of activation of inflammatory, profibrotic and apoptotic signalling pathways providing further insight into the potential mechanisms of action of neprilysin inhibitors.17,18 Ongoing trials such as PARADISE-MI (ClinicalTrials.gov identifier: NCT02924727), PROVE-HF (NCT02887183), and a multi-parametric cardiac magnetic resonance imaging based study in patients with asymptomatic left ventricular systolic dysfunction and a prior myocardial infarction (NCT03552575), will add to the growing body of information as to the mechanism of action behind the benefits of neprilysin inhibition in patients with HFrEF. Conflict of interest: Professor McMurray's employer, Glasgow University, has been paid by Novartis (who manufacture sacubitril/valsartan) for his time spent as committee member for the trials listed (using sacubitril/valsartan), meetings related to these trials and other activities related to sacubitril/valsartan e.g. lectures, advisory boards and other meetings. Novartis has also paid his travel and accommodation for some of these meetings. These payments were made through a Consultancy with Glasgow University and he has not received personal payments in relation to these trials/this drug. The trials include - PARADIGM-HF: co-PI; PARAGON-HF: co-PI; PERSPECTIVE, PARADISE-MI and UK HARP III Trial: executive/steering committees. Professsor McMurray and Dr Docherty are conducting an investigator originated study funded by the British Heart Foundation (Project Grant no. PG/17/23/32850) using sacubitril/valsartan supplied by Novartis. Biography: John J.V. McMurray is a Professor of Medical Cardiology and Deputy Director (Clinical) of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow and Honorary Consultant Cardiologist at the Queen Elizabeth University Hospital, Glasgow. Professor McMurray received his MB ChB (Hons) and postgraduate MD degree (by thesis) from the University of Manchester. His primary research interests include heart failure, atrial fibrillation, and the cardiovascular consequences of diabetes and chronic kidney disease, with a focus on clinical trials. He has chaired and participated in numerous clinical trial executive/steering and data-monitoring committees and currently chairs the event adjudication group at Glasgow University, which has served as the endpoint committee for many trials. Professor McMurray was the lead author of the World Health Organization and first Scottish Intercollegiate Guidelines Network Guidelines on the Management of Heart Failure. In addition, he was a member of the 2008 European Society of Cardiology Heart Failure Guidelines Task Force, Chair of the 2012 Task Force, a member of the 2013 American College of Cardiology/American Heart Association Heart Failure Guidelines Committee, and a member of the 2014 National Institute for Health and Care Excellence (NICE) Acute Heart Failure Guideline Committee. He is a member of NICE Appraisal Committee A. He is also a member of the editorial board of the New England Journal of Medicine and sits on the editorial boards of several leading cardiovascular journals, including the European Heart Journal—where he is an Associate Editor—Circulation and Diabetes Care. He has published over 1000 original papers, reviews, and book chapters and has an H-index of 181(see https://scholar.google.co.uk/citations?user=n0ZdRMoAAAAJ&hl=en). Professor McMurray and Professor Salim Yusuf were jointly awarded the 8th Arrigo Recordati International Prize for Scientific Research in June 2015. Professor McMurray was awarded the MacKenzie medal of the British Cardiovascular Society and the Louis and Artur Lucian Award for Research in Circulatory Diseases in June 2017. In 2019, he was awarded an OBE by Her Majesty The Queen, in recognition of his services to cardiovascular research. Professor McMurray was included in the 2015, 2016, 2017, and 2018 listing of Highly Cited Researchers by Thomson-Reuters (see http://hcr.stateofinnovation.com/). Biography: Kieran F. Docherty is a Cardiology Specialist Registrar in the West of Scotland Deanery and a Clinical Research Fellow at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow. He graduated MB ChB (Hons) from the University of Glasgow. He is currently undertaking a PhD under the supervision of Professor John McMurray and Professor Mark Petrie examining the effects of neprilysin inhibition on left ventricular remodelling. His research interests include the epidemiology and prevention of heart failure, and clinical trials.