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Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 23-29

Evidence of superiority of sacubitril/valsartan versus angiotensin-converting enzyme inhibitors or angiotensin ii receptor blockers in the heart failure with reduced ejection fraction patient's journey

Department of Cardiovascular, Papa Giovanni XXIII Hospital, Bergamo, Italy

Date of Submission16-Jan-2021
Date of Acceptance18-Feb-2021
Date of Web Publication30-Mar-2021

Correspondence Address:
Michele Senni
Department of Cardiovascular, Papa Giovanni XXIII Hospital, Bergamo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2470-7511.312591

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Sacubitril/valsartan (S/V) is a new drug which has been recently recommended by the international guidelines for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF). Compared to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), S/V is associated with a better cardiovascular outcome, and to a greater beneficial effect on myocardial reverse remodeling. Recent evidence has shown that S/V is not only recommended in chronic patients but it is also approved in the acute setting; moreover, its safety and tolerability have been demonstrated also in the pediatric population. This review summarizes data on the effectiveness and tolerability of S/V in HFrEF patients and offers practical insights to manage this drug in every setting, providing an overview from randomized clinical trials' data to real-world evidence.

Keywords: Heart failure; Real-world evidence; Reverse remodeling; Sacubitril-valsartan

How to cite this article:
Gori M, D'Elia E, Senni M. Evidence of superiority of sacubitril/valsartan versus angiotensin-converting enzyme inhibitors or angiotensin ii receptor blockers in the heart failure with reduced ejection fraction patient's journey. Cardiol Plus 2021;6:23-9

How to cite this URL:
Gori M, D'Elia E, Senni M. Evidence of superiority of sacubitril/valsartan versus angiotensin-converting enzyme inhibitors or angiotensin ii receptor blockers in the heart failure with reduced ejection fraction patient's journey. Cardiol Plus [serial online] 2021 [cited 2021 Oct 16];6:23-9. Available from:

  Introduction Top

Heart failure (HF) is a highly prevalent disease in the community and it portends an adverse prognosis.[1] According to the international current guidelines, neurohormonal antagonists (β-blocker, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonist [MRA]) reduce morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF) and are recommended as class IA indications (unless contraindicated or not tolerated).[2] Recently, an Expert Consensus Decision Pathway has been resealed providing guidance and recommendations on including the upfront use of sacubitril/valsartan (S/V) without angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) pretreatment,[3] in light of the amount of data concerning the efficacy and superiority of S/V compared to ACEi/ARBs.[4],[5] Despite these data, according to the CHAMP-HF outpatient registry, S/V was prescribed in only 13% of eligible patients and at a target dose in only 30% of these.[6] In order to behave in a proper manner for the individual HFrEF patient, an impelling need is to offer the best drug and optimal dose, when the target dose cannot be tolerated, trying to implement S/V to the maximum, and consequently to achieve an advantage in the management, prognosis and left ventricular reverse remodeling.

In this review, we will provide an overview of the randomized clinical trials (RCTs) regarding patient's journey for S/V in HFrEF [Figure 1] and [Table 1], and we will take a look into new data on the real-world evidence (RWE) base for S/V in the same population.
Figure 1: Patient's journey for S/V in HFrEF.
S/V: Sacubitril/Valsartan; CV: Cardiovascular, HF: Heart failure, HFrEF: Heart failure with reduced ejection fraction, LVESVI: Left ventricle end-systolic volume index, LVEDVI: Left ventricle end-diastolic volume index, LAVI: Left atrial volume index, NT-proBNP: N-terminal pro-B-type Natriuretic Peptide, BNP: B-type Natriuretic Peptide

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Table 1: Summary of the clinical trial of sacubitril-valsartan in heart failure reduced ejection fraction

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  Sacubitril/valsartan in the Outpatient Setting: The PARADIGM-Heart Failure Trial and the TITRATION Study Top

PARADIGM-heart failure trial

PARADIGM-HF trial was a multicenter, prospective, randomized clinical trial of S/V compared with enalapril in patients with left ventricle ejection fraction (LVEF) ≤40%.[4]

The trial involved 8442 patients with symptomatic HFrEF (New York Heart Association [NYHA] functional Class II–IV), and elevated B-type natriuretic peptide levels or hospitalization for HF within the previous 12 months. After a median follow-up of 27 months, the trial was stopped early for the net clinical benefit of S/V in reducing the risks of the primary outcome of cardiovascular death and HF hospitalization. These findings were highly significant and consistent across all prespecified subgroups. Although S/V was associated with symptomatic hypotension more frequently than enalapril, more participants assigned to enalapril discontinued study medication due to adverse effects. The magnitude of S/V's advantages over angiotensin-converting enzyme (ACE) inhibition was highly significant. Furthermore, S/V's benefit was documented also in patients who were already receiving optimal doses of beta-blockers and MRA, and it was also confirmed in all the prespecified subgroups analyzes such as sex, age, regions, and race characteristics. According to the PARADIGM-HF trial results, S/V has been approved for use in patients with symptomatic HFrEF despite guideline-directed medical therapy (GDMT). Of note, in a post hoc analysis of PARADIGM-HF, S/V dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of S/V relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs.[5]

Modality of TITRATION: The TITRATION study

The TITRATION study tested the tolerability of S/V in a population similar to the RWE, thus including patients not previously on treatment, or with variable pretreatment with ACEi/ARBs, following a “condensed” (3 weeks) or “conservative” (6 weeks) of uptitration of S/V from 50 mg bid to 200 mg bid random regimen.[7] S/V was similarly well tolerated in both arms. Treatment success was achieved by 77.8% of the patients in the uptitration “condensed” arm, and in 84.3% of the “conservative” arm (P = 0.078). In patients initially intolerant to the S/V dose, a downtitration could be useful, allowing, eventually, to reach the target dose. This study suggested a practical approach to reach the optimal S/V dose indicated in the PARADIGM-HF trial.

  The Acute Phase: PIONEER and TRANSITION Trials Top


The PIONEER study was designed to assess whether the superiority of S/V versus enalapril was confirmed also in the acute setting.[8] The enrollment of this trial was started as soon as the patients were stable during an inpatient HF admission. Hemodynamic stabilization was defined as a systolic blood pressure of 100 mmHg or greater and no need for intensification of intravenous diuretics or use of intravenous vasodilators in a 6-h window before they could be randomized. Finally, 440 patients were randomized to S/V and 441 to enalapril. Dosing was started with the lowest dose using a systolic blood pressure titration algorithm, and based on blood pressure thresholds that changed through the trial, it was allowed to uptitrate the dose to the target one, which was 97/103 mg bid for S/V versus 10 mg bid for enalapril. Using the titration algorithm, 60% of the population got to the target dose of enalapril by 8 weeks, as well as about 55% got to the S/V target dose.

The primary endpoint of the study was N-terminal pro-B-type natriuretic peptide (NT-proBNP) change, while safety was a secondary endpoint. In the 8-week period from baseline to the mean of weeks 4 and 8, S/V was associated with a 47% reduction in NT-proBNP, while enalapril was associated with a 25% reduction. There was a 29% relative risk reduction of NT-proBNP lowering in favor of S/V, which was highly statistically significant. In regard to the safety endpoints, there were no statistically significant differences between the two study arms, even in renal function. In addition, regarding the exploratory clinical outcome of serious clinical composite, there was a significantly relative risk reduction of 46% in favor of S/V. The composite was driven by a 44% reduction in HF hospitalizations.


TRANSITION was a study aiming to evaluate S/V safety and efficacy in patients stabilized after hospitalization for acute HF, regardless of whether they received it in-hospital or after discharge.[9] The primary endpoint was the proportion of patients achieving the target dose of S/V 200 mg twice daily at 10 weeks after randomization. Secondary endpoints included discontinuation due to drug-related adverse events and tolerability of different S/V doses. The primary endpoint was not significantly different between the two groups, 45% of the predischarge group achieved the target dose of S/V and 50.4% of the postdischarge group. Study drug discontinuation only occurred in approximately 4% in both groups. Rates of adverse events, serious adverse events, and death did not significantly differ between the groups. Importantly, PIONEER-HF and TRANSITION trials have also established the safety and tolerability of S/V in the patients with new-onset HF. Thus, early intervention with S/V should be considered to delay disease progression in patients with de novo HFrEF.

  Reverse Remodeling Data: The PRIME, PROVE-Heart Failure, and EVALUATE-Heart Failure Studies Top

PRIME study

In the PRIME study, 118 patients with HFrEF and chronic functional mitral regurgitation secondary to left ventricular dysfunction on standard medical therapy were enrolled.[12] Patients were assigned to valsartan alone or S/V and were assessed by echocardiography. The primary outcome was the change in effective regurgitant orifice area of functional mitral regurgitation at 12 months. Compared with the valsartan group, the S/V group had a greater decrease in effective regurgitant orifice area (−0.058 cm2 vs. −0.018 cm2; P = 0.032) and in regurgitant volume (mean difference, −7.3 mL; 95% confidence interval, −12.6 to − 1.9). Decrease in the left ventricle end-diastolic volume index was greater in the S/V group, while there were no significant differences in other left ventricle parameters, in incomplete mitral leaflet closure area, and in changes in blood pressure. S/V, thus, could be considered as a way to optimize medical therapy of stable patients with HFrEF and functional mitral regurgitation.

PROVE-heart failure study

In the PARADIGM-HF trial, reduction in NT-proBNP concentrations was tightly associated with improved outcomes of patients treated with S/V. As NT-proBNP reduction during GDMT has previously been linked to reversal of cardiac remodeling,[10] the PROVE-HF sought to further examine this question. PROVE-HF was an open-label study of 794 patients with chronic HFrEF assigned to S/V evaluated with an echocardiogram before treatment, at 6 months, and 12 months. NT-proBNP concentrations were measured at each study visit. Following study completion, echocardiograms were transmitted to a core laboratory where they were interpreted following completion of all study procedures in a temporally and clinically blinded fashion. The study demonstrated a significant 37% reduction in NT-proBNP after initiation of S/V; reduction in NT-proBNP was strongly associated with reverse cardiac remodeling. For example, from a baseline LVEF of 28%, by 12 months LVEF increased an average of 9.4% many patients demonstrated even more dramatic improvement.[11] In a similar fashion, there were decreases in the indexed left ventricle and LA volumes, left ventricle mass index, and improvement in diastolic function as reflected in the reduction of E/e' ratio. Results were consistent among prespecified subgroup patients: those with new-onset HF and/or those not taking an ACEi or ARBs at enrollment, or those not achieving the target sacubitril-valsartan dose.

EVALUATE-heart failure study

In EVALUATE-HF, the researchers assessed whether a change in aortic characteristic impedance might pathophysiologically contribute to the superiority of S/V compared with enalapril in patients with HFrEF. They randomly assigned 464 patients with HF and LVEF 40% or less to S/V or enalapril.[13] At 12 weeks, the S/V group had a decrease in aortic characteristic impedance (primary outcome) and the enalapril group had an increase in this parameter, but the difference was not statistically significant. However, the S/V group had significantly greater reductions in NT-proBNP, and greater reduction of several echocardiographic parameters, such as left ventricular end-diastolic or systolic volume index, left atrial volume index, and mitral E/e' ratio compared with the enalapril group (secondary endpoints). In addition, the investigators demonstrated a significant improvement in the overall summary score of the 12-item Kansas City Cardiomyopathy Questionnaire, an exploratory secondary endpoint. These data suggest a clear remodeling benefit even after 3 months of treatment with S/V compared with standard of care.

  Pediatric Population: PANORAMA-Heart Failure Trial Top

PANORAMA-HF study is the largest prospective ongoing HF trial conducted to assess whether S/V is superior to enalapril for treatment of HF pediatric patients with reduced systemic left ventricular systolic function.[14] PANORAMA-HF is a two-part study. Part 1 is an open-label dose determination study. Part 2 is a randomized, double-blind, 52-week study comparing S/V to enalapril in patients aged 1 month to <18 years old with HF (NYHA Class II–IV) and LVEF <40%.

In October 2019, the U. S. Food and Drug Administration has approved S/V in patients aged 1 year and older. The approval was based on an analysis at 12 weeks from the PANORAMA-HF trial which demonstrated reductions NT-proBNP. Considering the similar results observed in the PARADIGM-HF trial, an improvement in cardiovascular outcomes is also expected in the pediatric population on S/V. The reductions from baseline in NT-proBNP for S/V (44%) and enalapril (33%) were similar to those observed in adults. Moreover, the safety and tolerability of S/V in the pediatric population were in line with that observed in adult patients.

  Real-World Evidence of Sacubitril/Valsartan Top

RCTs are essential in assessing the efficacy and safety of any novel drug, but patients enrolled in clinical trials may differ in demographical and clinical characteristics compared with patients in clinical practice. RWE allows longer follow-up and offers practical observations in a less controlled environment, thus it is considered a great tool to understand the real-world outcomes with new therapies. Consequently, RWE is playing an increasing role in comprehensive evidence-based decision-making by clinicians, payers, and health technology assessment agencies.

According to a systematic review of RWE base for S/V recently published including 68 observational studies comparing before/after use of S/V or comparing S/V with ACEi/ARBs and covering 316.712 patients, the safety and tolerability profile of S/V appeared to be consistent and broadly in line with that observed in PARADIGM-HF and local labels.[15] In these studies, improvements in HF hospitalizations, all-cause hospitalizations, all-cause mortality, and cardiovascular mortality were reported. Benefits were also seen on NT-proBNP and NYHA classes.

The main limitation to uptitration was discontinuation due to hypotension and worsening renal function. Despite that, the median value for dropouts or discontinuations from real-world studies was 10.3% (range: 2%-35.7%), compared with 17.8% in PARADIGM-HF.

  Clinical Perspectives Top

Based on the clinical trials and the RWE summarized in this review, strong evidence of superiority of S/V compared to ACEi/ARBs in the outpatient setting has been underlined, and the benefit of S/V confirmed regardless of background therapy. In the acute phase, moreover, initiation of S/V during the hospitalization might allow better titration and easier treatment of side effects.

The typical HFrEF phenotype is characterized by the presence of advanced age, and several comorbidities, such as renal failure, hypotension, and hyperkalemia that can represent a serious obstacle to the implementation of GDMT. Nonetheless, initiation and titration of S/V is needed not only to improve symptoms but also to promote reverse cardiac remodeling. To this regard, patients' education is crucial: an explanation about how the S/V has to be started and titrated has to be made in advance.

In particular, in a chronic setting, the recommended starting dose of S/V is one 24/26 mg tablet twice a day. For those patients taking a high dose of the loop diuretic, in the absence of congestion, clinicians may decide to lower the diuretic dose in order to reduce the risk for hypotension. Even in the acute phase, indications, cautions, and warnings for S/V are similar. In addition, RWE confirmed the safety and tolerability profile of S/V demonstrated in the clinical trials above mentioned.

Recently, the benefit of S/V has also been stressed in a comparative analysis of three randomized controlled studies performed to estimate lifetime gains in event-free survival and overall survival with comprehensive pharmacological therapy (S/V, β blocker, MRA, and SGLT2-sodium/glucose cotransporter 2-inhibitor) versus conventional therapy.[16] Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2.7 additional years (for an 80-year-old) to 8.3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for HF, and 1.4 additional years (for an 80-year-old) to 6.3 additional years (for a 55-year-old) of survival compared with conventional therapy.

In the end, not only the use of S/V is highly recommended but also the combination use of S/V, β blocker, MRA, and SGLT2 inhibitors have been elected as the new therapeutic standard “poker” for HFrEF.

  Conclusions Top

S/V improves survival in a broad range of patients with HFrEF compared to ACE inhibitor (ACE-i)/ARBs, including those aged ≥75 years, and/or with comorbidities, as demonstrated also in RWE. More reverse remodeling has been documented in HFrEF patients assigned to S/V compared to ACE-i/ARBs. As a result, S/V has been recommended as a preferred alternative to an ACE-i or ARB in patients already treated with these compounds and in a chronic ambulatory setting, and may also be considered for new-onset HF to improve the outcomes and to simplify management by avoiding the need to titrate ACE-i first and then switch to S/V.

Financial support and sponsorship


Conflicts of interest

Dr. Senni has received consulting income from Novartis Pharmaceuticals.

All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

  References Top

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  [Figure 1]

  [Table 1]


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