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Abstract Aims This study aims to investigate the eligibility of the Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor (ARNI) with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study to a real-world heart failure population. Methods and results Medical records of all heart failure patients living within the catchment area of Umeå University Hospital were reviewed. This district consists of around 150 000 people. Out of 2029 patients with a diagnosis of heart failure, 1924 (95%) had at least one echocardiography performed, and 401 patients had an ejection fraction of ≤35% at their latest examination. The major PARADIGM-HF criteria were applied, and 95 patients fulfilled all enrolment criteria and thus were eligible for sacubitril–valsartan. This corresponds to 5% of the overall heart failure population and 24% of the population with ejection fraction ≤ 35%. The eligible patients were significantly older (73.2 ± 10.3 vs. 63.8 ± 11.5 years), had higher blood pressure (128 ± 17 vs. 122 ± 15 mmHg), had higher heart rate (77 ± 17 vs. 72 ± 12 b.p.m.), and had more atrial fibrillation (51.6% vs. 36.2%) than did the PARADIGM-HF population. Conclusions Only 24% of our real-world heart failure and reduced ejection fraction population was eligible for sacubitril–valsartan, and the real-world heart failure and reduced ejection fraction patients were significantly older than the PARADIGM-HF population. The lack of data on a majority of the patients that we see in clinical practice is a real problem, and we are limited to extrapolation of results on a slightly different population. This is difficult to address, but perhaps registry-based randomized clinical trials will help to solve this issue.

Federal regulatory agencies such as the United States Food and Drug Administration review pharmacological evidence to ensure the safety and efficacy of new and repurposed pharmaceuticals prior to market approval. The discussions, disagreements and procedural decisions contained within such reviews offer unique insight into a pharmaceutical's strengths, weaknesses and opportunities, yet are often overlooked as a significant source of pharmacological information for research and development. To highlight the value of such resources, we present a case study on Entresto, a first‐in‐class angiotensin receptor‐neprilysin inhibitor for the treatment of heart failure with reduced ejection fraction, and explore the regulatory rationale underlying its market approval. Using information extracted from Entresto's online approval package at Drugs@FDA, we explore some of the procedural complexities underlying market approval of new pharmaceuticals, discuss the broad pharmacological implications contained within regulatory agency grey literature, and highlight opportunities for future therapeutic development. Federal regulatory agencies such as the United States Food and Drug Administration review pharmacological evidence to ensure the safety and efficacy of new and repurposed pharmaceuticals prior to market approval. The discussions, disagreements and procedural decisions contained within such reviews offer unique insight into a pharmaceutical’s strengths, weaknesses and opportunities, yet are often overlooked as a significant source of pharmacological information for research and development.

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk for HF progression and death. Sacubitril/valsartan (previously known as LCZ696) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor (sacubitril) and an angiotensin II (Ang-II) receptor blocker (valsartan). NEP is an endopeptidase that metabolizes different vasoactive peptides including natriuretic peptides, bradykinin and Ang-II. In consequence, its inhibition increases mainly the levels of both, natriuretic peptides (promoting diuresis, natriuresis and vasodilatation) and Ang-II whose effects are blocked by the angiotensin receptor blocker, valsartan (reducing vasoconstriction and aldosterone release). Results from the 8442 patient PARADIGM-HF study showed in patients with New York Heart Association (NYHA) class II–IV and reduced ejection fraction treated with LCZ696 (versus enalapril), the following benefits: reduction of the risk of death from cardiovascular causes by 20%; reduction of HF hospitalizations by 21%; reduction of the risk of all-cause mortality by 16%. Overall there was a 20% risk reduction on the primary endpoint, composite measure of cardiovascular (CV) death or time to first HF hospitalization. PARADIGM-HF was stopped early after a median follow up of 27 months. Post hoc analyses of PARADIGM-HF as well as the place in therapy of sacubitril/valsartan, including future directions, are included in the present review.

One of the defining features of heart failure (HF) is neurohormonal activation. The renin-angiotensin-aldosterone-system (RAAS) and sympathetic nervous system (SNS) cause vasoconstriction and fluid retention and, in response, the secretion of natriuretic peptides (NPs) from volume and pressure-overloaded myocardium promotes vasodilation and diuresis. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been the cornerstone of medical treatment for HF with a reduced ejection fraction (HFrEF) but, until recently, it was unclear how the beneficial effects of NPs may be augmented in patients with HF. Neprilysin, a metalloproteinase widely distributed throughout the body, plays a role in degrading the gross excess of circulating NPs in patients with HF. Early studies of neprilysin inhibition suggested possible physiological benefits. In 2014, the PARADIGM-HF trial found that sacubitril-valsartan, a combination of the ARB valsartan, and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with HFrEF, reducing the relative risk of cardiovascular (CV) death or first hospitalisation with HF by 20%. Almost half of the patients with HF symptoms have a “preserved” ejection fraction (HFpEF); however, the PARAGON-HF study found that sacubitril-valsartan in patients with LVEF ≥ 45% had no effect on CV death or first and recurrent hospitalisations with HF compared to valsartan. Guidelines across the world have changed to include sacubitril-valsartan for patients with HFrEF yet, nearly 6 years after PARADIGM-HF, there is still uncertainty as to when and in whom sacubitril-valsartan should be started. Furthermore, there may yet be subsets of patients with HFpEF who might benefit from treatment with sacubitril-valsartan. This review will describe the mechanisms behind the outcome benefit of sacubitril-valsartan in patients with HFrEF and to consider its future role in the management of patients with HF.

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.

PurposePARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril in patients with heart failure and reduced ejection fraction (HF-REF). How widely applicable sacubitril/valsartan treatment is in unselected patients with HF-REF is not known. We examined eligibility of patients with HF-REF for treatment with sacubitril/valsartan, according to the criteria used in PARADIGM-HF, in the Swedish Heart Failure Registry (SwedeHF).MethodsPatients were considered potentially eligible if they were not hospitalized, had symptoms (NYHA class II–IV) and a reduced LVEF (≤ 40%), and were prescribed an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a dose equivalent to enalapril ≥ 10 mg daily. In these patients, we evaluated further eligibility according to the main additional PARADIGM-HF inclusion criteria.ResultsOf 12,866 outpatients in NYHA functional class II–IV with an LVEF ≤ 40%, 9577 were prescribed at least 10 mg of enalapril (or equivalent) daily. Complete additional data were available for 3099 of these patients (32.4%) and of them 75.5% were potentially eligible for treatment with sacubitril/valsartan. The most common reason for ineligibility was a low natriuretic peptide level (n = 462, 14.9%). Only a small proportion of patients were ineligible due to low eGFR or serum potassium level. Because only 78% of patients were taking ≥ 10 mg enalapril or equivalent daily, only 58.9% of all patients (75.5% of 78%) were eligible for sacubitril/valsartan.ConclusionsBetween 34 and 76% of symptomatic patients with HF-REF in a ‘real world’ population are eligible for treatment with sacubitril/valsartan, depending on background ACEI/ARB dose. The most common reason for ineligibility is a low natriuretic peptide level.

Cardiovascular (CV) disease is a major cause of morbidity and mortality in the developing and the developed world. Mortality from CV disease had plateaued in the recent years raising concerning alarms about the sustained efficacy of available preventive and treatment options. Heart failure (HF) is among the major contributors to the CV-related health care burden, a persisting concern despite the use of clinically proven guideline-directed therapies. A requirement for more efficient medical therapies coupled with recent advances in bio-innovation led to the creation of sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), which demonstrated substantial CV benefit when compared with the standard of care, enalapril, in patients with HF and reduced ejection fraction. Further investigations of this novel combination ARNI at the tissue level shed light into the anti-remodeling and cardioprotective effects of sacubitril/valsartan, while clinical studies in the phenotypes of HF with preserved ejection fraction, hypertension and subsets, coronary outcomes, postmyocardial infarction, and renal disease suggested that this combination could be beneficial across a wide spectrum of CV disease. Sacubitril/valsartan is a much-needed therapeutic advance in the avenue of CV disease.

Purpose of review Compared to enalapril, use of angiotensin-receptor blocker and neprilysin inhibitor sacubitril/valsartan to treat patients with heart failure and reduced ejection fraction (HFrEF) is associated with substantial reductions in both cardiovascular mortality and heart failure progression. The purpose of this review is to discuss the real-world experience of sacubitril/valsartan. Recent findings In the years following the publication of the landmark PARADIGM-HF trial in 2014 and its subsequent FDA approval, a growing evidence base supports the safety and efficacy of sacubitril/valsartan in a broad spectrum of patients with HFrEF. Updated clinical practice guidelines have embraced the use of sacubitril/valsartan in preference to ACE inhibitors or ARBs in selected patients. Summary In this review, we highlight the clinical trials that led to these key updates to clinical guidelines, offer practical strategies for patient selection and utilization in clinical practice, and identify important areas of uncertainty that require future research.