Heart failure (HF) affects more than 23 million people around the world,1 it represents one of the main causes of cardiovascular morbidity and mortality, its prevalence increasing with age.2 The latest clinical practice guidelines3 classify HF into three groups according to left ventricular ejection fraction (LVEF): HF with reduced LVEF (< 40%), mid-range LVEF (40–49%), and preserved LVEF (≥ 50%), resulting in different repercussions on therapeutic patient management.

Heart failure and reduced ejection fraction (HFrEF) treatment comprises neurohormonal antagonists, including angiotensin converting enzyme inhibitors or angiotensinogen receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, which have been shown to improve prognosis. Recently, sacubitril/valsartan (SV) has joined this therapeutic arsenal. This drug combines a neprilysin inhibitor and angiotensin II receptor antagonist, resulting in an increase in natriuretic peptide levels, while inhibiting the effects of angiotensin II. SV has been shown to be superior to enalapril in reducing the risk of death and hospitalization for HF.4 The combination with the best efficacy on patient prognosis has proven to be angiotensin II receptor antagonist+beta-blockers+mineralocorticoid receptor antagonists.5

The SV efficacy has been demonstrated in several randomized clinical trials that compared this combination to enalapril. The results of the PARADIGM-HF,4 an international double-blind clinical trial in patients with chronic HF that were previously treated using angiotensin-converting enzyme inhibitors and beta-blockers,4 have revealed that SV significantly improves the prognosis of HFrEF patients in New York Heart Association (NYHA) class II–IV, as compared to enalapril. In addition, SV was demonstrated to reduce long-term mortality, both overall and of cardiovascular origin, and the need of hospital readmission due to worsening HF. On the other hand, data from the PIONEER-HF clinical trial6 showed that, in patients admitted for acute HF, SV similarly reduces N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and readmission rates compared to enalapril.

Data from the PROVE-HF clinical trial7 have shown that there was a correlation between the reduction in NT-proBNP levels after SV therapy in HFrEF patients and several signs of reverse cardiac remodeling at one-year follow-up. Recently a subanalysis of the PROVE-HF have shown that among a cohort of patients with HFrEF who met primary prevention implantable cardioverter defibrillator (ICD) eligibility criteria at baseline, 32% improved their ejection fraction to >35% by 6 months and 62% to >35% by 12 months after initiation of SV therapy, with relevant clinical implications.8

Based on the drug's prescribing information,9 SV administration is allowed if systolic blood pressure≥100mmHg, potassium level<5.4mmol/L, and estimated glomerular filtration rate>60mL/min/1.73m2. Caution is warranted in the event of estimated glomerular filtration rate of 30–60mL/min/1.73m2, whereas SV is definitely discouraged in patients with end-stage renal disease. These criteria are in line with those of the main trial proving the drug's efficacy and safety.5 A few evidences have been reported in the literature supporting its use outside of these criteria.10

The use of an ICD to avoid sudden cardiac death is indicated in patients with symptomatic HF (NYHA Class II/III) and LVEF≤35% after ≥3 months of optimal medical therapy. SV treatment in patients with LVEF≤35% has been associated with LVEF recovery and improvement in functional class.4,6,7 This implies that a few patients that, prior to SV therapy, displayed an indication for an ICD based on the current guidelines3 would no longer require such an ICD intervention. This paradigm opens an entirely new approach to preventn sudden death in HFrEF patients.

This study sought to analyze SV effectiveness and safety in HFrEF patients in real-world clinical practice and evaluate its impact on other outcome measures, including the indication for ICD.

We performed a prospective study in real-world SV-treated patients with HFrEF. The study was carried out in one single center between 2017 and 2019 (Hospital Universitario Juan Ramón Jiménez, a tertiary hospital). This center's HF unit comprises three cardiologists and two nurses specialized in HF care HF unit is considered the reference unit for a population of 550000 people, with around 800 patients admitted year.

Ethical approval for the study was obtained from the hospital's Clinical Investigation Ethics Committee (Fundación Andaluza Beturia para la Investigación en Salud) and informed consent was obtained from the patients in writing.

Patients

All consecutive HFrEF patients attending the Heart Failure Unit of the Juan Ramon Jimenez University Hospital who started SV treatment between October 2017 and December 2018 were included (N=204), regardless of whether they were in or outpatients. Fig. 1 shows patients enrolment into the study. HF definition of HF was consistent with that of the European Society of Cardiology guidelines,3 including presentation of typical HF symptoms that may be accompanied by HF signs caused by a structural of functional cardiac abnormalities. HFrEF is defined by the presence of HF symptoms in a NYHA Class II, III, or IV patient, with LVEF<40%. The inclusion criteria for the study were: (a) adult patients (18 years old and over) that fulfilled the HF diagnosis; (b) LVEF<40% confirmed by echocardiography. The exclusion criteria were: (a) patients with LVEF≥40%; (b) concomitant dementia or other conditions with a life-expectancy of < 1 year; (c) potential follow-up difficulties.

Fig. 1.

Flowchart of patients included in the study. HF, heart failure; LVEF, left ventricle ejection fraction; RVF, right ventricular function.

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To our knowledge, this is one of the most comprehensive studies on SV in HFrEF patients carried out to date. The study included outpatients and inpatients, in addition to involving different efficacy and safety outcomes, some of which have not yet been studied in previously conducted clinical trials According to the results obtained, SV treatment for 12 months exerts the following effects: a) clear reduction in ICD indication; b) increase in LVEF, decrease in NT-proBNP and readmission; rates; c) combined efficacy endpoint achieved in 81.3% of patients. In addition, SV has proven to be safe without resulting in creatinine concentration, potassium level, or systolic blood pressure value changes, and with only a low discontinuation rate (6%).

Despite the observation that clinical trials are the first-choice tool for evaluating the efficacy of drugs, we should not forget that patients included in clinical trials are highly selected; generally, they do not represent real-life settings.10 This underlines the relevance of conducting real-life studies like the one reported herein in order to be enable us to assess their effectiveness in real-life patients across the entire disease spectrum. Indeed, our population also included older patients with more advanced heart disease and worse kidney function than previous SV clinical trials have done.4,6,7

Different observational studies have been carried out on the SV use under real-life conditions. Regarding efficacy endpoints, this drug has been shown to be effective in improving LVEF11–14 and functional outcome by improving NYHA class,12,13,15,16 while reducing hospital admissions for worsening HF.13,15–17 Also, a recent study focused on changes in ICD indications following SV treatment.8Table 6 provides a summary of the most relevant studies under real-life conditions.14-19

The study's efficacy results showed that 81% of SV-treated patients attained the combined efficacy endpoint (defined by at least one of the following criteria: improvement in LVEF, better functional class, or fewer hospital readmissions. It must be stressed that although various studies have published efficacy results based on different parameters, none of them have used a combined measurement as in our case, which can be considered an estimate of overall drug efficacy.

Advances made in HF management have enabled us to reduce sudden death in HFrEF patients, through implementing optimal medical therapy18 and using various devices.19 Despite these major advances made, more than one-third of all-cause mortality in contemporary clinical trials is still to be accounted for by sudden cardiac death.20 ICD implantation has proven its long-term efficacy in preventing patients from sudden cardiac death,21 but approach has a high economic cost, and it is not devoid of serious harm.22,23 The cost-effectiveness of ICD implantation for primary prevention in patients with a LVEF<40% and ischemic or non-ischemic heart disease has been previously analyzed.22 These data have revealed that the mean lifetime cost of ICD was shown to be much higher. Accordingly, the cost of a ‘no ICD strategy’ was € 50685±€ 4604 vs € 86759±€ 3343 for an ‘ICD strategy’, although the ICD implantation strategy was cost-effective. Regarding complications, van der Heijden et al.23 showed that the 12-year ICD complication rate, with or without cardiac resynchronization therapy, was 20% (95% confidence interval [95%CI], 18–22%) for inappropriate shock, 6% (95%CI, 5–8%) for device-related infection, and 17% (95%CI, 14–21%) for lead failure. These study results underline that a decrease in ICD indications likely achieves significant cost saving and an improvement in HF patients’ quality of life.

The reduction in ICD indications achieved in our study (79.9% prior to 49.5% at 12 months; P<.00001) proves to be very interesting information. In an article published by El Battrawy et al.,24 SV failed to decrease ventricular arrhythmias after 12-month follow-up, whereas in a recent article by Rohde et al.,25 it is concluded that the benefit of such a reduction is greater in ICD users and non-ischemic cardiomyopathy patients. Nevertheless, no direct comparison between ICD use and SV addition has been published so far. Yet, in some studies, SV has been shown to effectively reduce ventricular tachycardia and ventricular fibrillation rates, while decreasing the number of ICD-delivered shocks.26,27 Consequently, SV treatment may definitely turn out to be cost-effective versus ICD implantation.28

On the other hand, our data show a reverse remodeling with improvement in LVEF (from 29.8 to 33.7%; P<.0001); these results are similar to those published by Martens et al.29 The mean value of NT-proBNP was reduced (3928 to 2903pg/mL; P=.012), together with a marked improvement in functional class (40% remained asymptomatic after using SV), as described by Lau et al.30

As for the drug's safety in our sample, neither worsening of creatinine or potassium values nor changes in systolic blood pressure were observed. Not surprisingly, the drug discontinuation rate was only 6%.

The results of this real-life study prove that SV treatment attains effectiveness in 88.3% of patients without any associated safety concerns. In addition, the improvement in left ventricle remodeling and reduction in ICD indications observed are likely to significantly impact patients’ prognosis and quality of life, all of which at a lower cost.

This work was not funded.

All the authors have participated in the writing of the article and have accepted the conditions for its publication.

None.