ORIGINAL RESEARCH published: 18 February 2021 doi: 10.3389/fphys.2021.642117 A Simple Score to Identify Edited by: Super-Responders to Rui Plácido, University of Lisbon, Portugal Sacubitril/Valsartan in Ambulatory Reviewed by: Massimo Volpe, Patients With Heart Failure Sapienza University of Rome, Italy Juan Badimon, Carles Moliner-Abós 1 , Diana Mojón Álvarez 2 , Mercedes Rivas-Lasarte 1* † , Icahn School of Medicine at Mount Laia Carla Belarte 2† , Julia Pamies Besora 1 , Eduard Solé-González 2† , Sinai, United States Paula Fluvià-Brugues 1 , Isabel Zegrí-Reiriz 1† , Laura López López 1† , Vicens Brossa 1† , *Correspondence: Maria José Pirla 1 , Nuria Mesado 1 , Sonia Mirabet 1 , Eulàlia Roig 1 and Mercedes Rivas-Lasarte Jesús Álvarez-García 1,3† rivaslasarte@gmail.com 1 Cardiology Department, Hospital de la Santa Creu i Sant Pau, IIB-SantPau, CIBERCV, Universidad Autónoma † ORCID: de Barcelona, Barcelona, Spain, 2 Cardiology Department, Hospital del Mar, Barcelona, Spain, 3 The Zena and Michael A. Mercedes Rivas-Lasarte Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States orcid.org/0000-0002-8704-3104 Laia Carla Belarte orcid.org/0000-0003-2774-1290 Introduction: Sacubitril/valsartan (SV) promotes cardiac remodeling and improves Eduard Solé-González orcid.org/0000-0002-5727-9925 prognosis in patients with heart failure (HF). However, the response to the drug may Isabel Zegrí-Reiriz vary between patients and its implementation in daily clinical practice has been slower orcid.org/0000-0001-9742-8537 than expected. Our objective was to develop a score predicting the super-response to Laura López López orcid.org/0000-0002-8653-6206 SV in HF outpatients. Vicens Brossa orcid.org/0000-0003-0403-6425 Methods: This is a retrospective analysis of 185 consecutive patients prescribed Jesús Álvarez-García SV from two tertiary hospitals between September 2016 and February 2018. Super- orcid.org/0000-0002-2015-6446 responder was defined as a patient taking the drug and (i) without HF admissions, Specialty section: death, or heart transplant, and (ii) with a ≥50% reduction in NT-proBNP levels and/or an This article was submitted to increase of ≥10 points in LVEF in a 12-month follow-up period after starting SV. Clinical, Clinical and Translational Physiology, a section of the journal echocardiographic, ECG, and biochemical variables were used in a logistic regression Frontiers in Physiology analysis to construct a score for super-response to SV which was internally validated Received: 15 December 2020 using bootstrap method. Accepted: 26 January 2021 Published: 18 February 2021 Results: Out of 185 patients, 65 (35%) fulfilled the super-responder criteria. Predictors Citation: for super-response to SV were absence of both previous aldosterone antagonist and Moliner-Abós C, Mojón Álvarez D, diuretic treatment, NYHA I-II class, female gender, previous 1-year HF admission, and Rivas-Lasarte M, Belarte LC, Pamies Besora J, Solé-González E, sinus rhythm. An integrating score distinguished a low- (<25%), intermediate- (∼46%), Fluvià-Brugues P, Zegrí-Reiriz I, and high-probability (>80%) for 1-year super-response to SV. The AUC for the model López López L, Brossa V, Pirla MJ, was 0.72 (95%CI: 0.64–0.80), remaining consistent after internal validation. Mesado N, Mirabet S, Roig E and Álvarez-García J (2021) A Simple Conclusion: One-third of our patients presented a super-response to SV. We propose Score to Identify Super-Responders to Sacubitril/Valsartan in Ambulatory an easy-to-calculate score to predict super-response to SV after 1-year initiation based Patients With Heart Failure. on variables that are currently assessed in clinical practice. Front. Physiol. 12:642117. doi: 10.3389/fphys.2021.642117 Keywords: sacubitril/valsartan, heart failure, super-response, score, cardiac remodeling Frontiers in Physiology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan INTRODUCTION research committee and with the Helsinki declaration. Due to the retrospective nature of the study, it was considered that informed Sacubitril/valsartan (SV) is the first agent of the angiotensin consent was not required. receptor–neprilysin inhibitor (ARNI) drug class (Singh et al., 2017). In the PARADIGM−HF trial, ARNI compared to Study Variables enalapril reduced the risk of cardiovascular death or heart Data were collected using the electronic health record of both failure (HF) hospitalization by 20%. Moreover, the risks of hospitals. The following clinical variables were gathered at study all−cause, cardiovascular, and sudden cardiac death were also inclusion and during the follow-up period: demographic and significantly reduced by SV (McMurray et al., 2014). Therefore, previous clinical history, NYHA functional class, systolic blood both American and European guidelines on HF recommend pressure, laboratory blood tests including NT-proBNP within the SV for symptomatic HF patients with reduced ejection fraction previous 30 days before SV initiation, ECG, echocardiography (HFrEF) (Ponikowski et al., 2016; Yancy et al., 2017). within the previous 6 months, and pharmacological and non- Although the benefit of SV was consistent across the clinical pharmacological treatment. spectrum of HF (McMurray et al., 2014), the response to the drug may vary between patients from real life and those from clinical Super-Response to SV and Follow-Up trial. In fact, the study population of the trial represented a subset After initiation of SV, the frequency of the follow-up visits was of a larger cohort eligible for the initial run-in period ensuring performed at the discretion of the attending cardiologist. Most of tolerability of target doses of both enalapril and ARNI before the patients were visited every 2–4 weeks at the HF clinic of each randomization (Desai et al., 2016). Previous studies (Pellicori center, with renal function, potassium, and clinical status check. et al., 2017; Martens et al., 2018), and more recently, the Once the drug was up-titrated until maximum tolerated dose, a Prospective Study of Biomarkers, Symptom Improvement, and new determination of NT-proBNP and echocardiography were Ventricular Remodeling During SV Therapy for Heart Failure usually done. The incident HF follow-up duration was calculated (PROVE-HF) study (Januzzi et al., 2019) have showed that as the time from starting SV until the time of censoring: death, SV promotes reverse myocardial remodeling. Moreover, a sub- heart transplantation, or a 12-month complete period. Over analysis of this study showed that patients with a higher decrease a similar follow-up duration, the number of HF admissions in NT-proBNP levels or in left ventricular end diastolic diameter before the initiation of SV was calculated. Super-responder to during the first 6 months after SV initiation had a lower rate of SV was defined as a patient taking the drug and (i) without HF hospitalizations or death in the following months (Januzzi HF admissions, death, or heart transplant and (ii) with a ≥50% et al., 2020). However, the identification of such predictors of reduction in NT-proBNP levels (Zile et al., 2016) and/or an super-response to ARNI is insufficient so far (Martens et al., 2018; increase of ≥10 points in LVEF (Januzzi et al., 2019) in a Nakou et al., 2018; Moliner-Abós et al., 2019; Vicent et al., 2019; 12-month follow-up period after starting the SV. The primary Chang et al., 2020; Díez-Villanueva et al., 2020). In addition, objective was to determine the prevalence and predictors of since its approval in late 2015 the implementation of SV in daily super-response to SV. clinical practice has been poor, partially due to high cost (Di Tano and Bettari, 2017; DeVore et al., 2018; Sangaralingham et al., Statistical Analysis 2018; Kahn et al., 2020). So, the development of tools aimed to Continuous variables were expressed as the mean ± standard recognize patients with a very favorable response to specific drugs deviation (SD) or as median (interquartile range) and were could improve the efficiency in a setting where pharmacological compared with the Student’s t-test, log-rank test. Categorical treatment is increasingly complex and expensive. variables were expressed as percentages and compared with the Hence, we conducted a study aimed to determine the χ 2 or Fisher’s exact tests. prevalence and clinical predictors of super-response to SV. Variable selection was performed using logistic regression models, with super-response to SV as a dichotomous dependent variable. In order to find the best predictive model with the MATERIALS AND METHODS highest area under the receiving operating characteristic (ROC) curve (AUC), exploratory analyses were performed including Study Population clinical meaningful variables showing a significant level in the This study includes a cohort of all consecutive patients univariate analysis (p-value < 0.2) and prioritizing parsimony. attended at the HF clinics from two tertiary referral centers The internal validity of the final predictive model was tested in Barcelona (Spain) since September 2016 to February 2018 for 15 bootstrap re-samples, using the “CVAUROC” package in which SV was introduced. The clinical criteria for initiating for Stata (Luque-Fernandez et al., 2019). The calibration of the drug were (i) symptomatic HF defined as New York Heart model was assessed by the Hosmer–Lemeshow test for goodness Association (NYHA) class II–IV, (ii) left ventricular ejection of fit and plotting the observed frequencies against the expected fraction (LVEF) ≤ 40% measured by echocardiography, and probabilities. Finally, a score of super-response was proposed as (iii) pretreatment according to the current European Society of the addition of the β coefficients of each predictor multiplied Cardiology (ESC) guidelines (Ponikowski et al., 2016) (including by 10 and rounded to the nearest integer number. Mean ACEI or ARB). All procedures performed in the study were crossvalidated sensitivity and specificity for each category of the in accordance with the ethical standards of the institutional score were presented. A two-sided p-value < 0.05 was considered Frontiers in Physiology | www.frontiersin.org 2 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan TABLE 1 | Clinical characteristics of the study population. Super-responders Standard responders P-value Study population (N = 65) (N = 120) (N = 185) Age, years 65 (13) 67 (12) 0.354 67 (12) Sex, female 20 (31) 26 (22) 0.171 46 (25) Ischemic etiology 30 (46) 59 (49) 0.695 89 (48) NYHA class 0.090 I 2 (3) 2 (2) 4 (2) II 47 (72) 67 (56) 114 (61) III 16 (25) 49 (40) 65 (35) IV 0 (0) 2 (2) 2 (1) LVEF, % 31 (6) 31 (7) 0.708 31 (6) LVEDD, mm 60 (9) 63 (9) 0.077 62 (9) ECG rhythm 0.027 Sinusal 47 (72) 66 (55) 113 (61) Atrial fibrillation 18 (28) 46 (39) 64 (35) Pacemaker 0 (0) 7 (6) 7 (4) SBP, mmHg 124 (15) 121 (20) 0.242 122 (18) NT-proBNP, ng/L 1694 (888–4103) 1817 (898–3917) 0.982 1844 (891–4104) Creatinine, mg/dL 1.1 (0.4) 1.1 (0.3) 0.651 1.1 (0.3) GFR, mL/min/1.73 m2 70 (20) 68 (17) 0.637 69 (18) GFR < 60 mL/min/1.73 m2 22 (35) 48 (40) 0.475 70 (38) Potassium, mEq/L 4.4 (0.5) 4.5 (0.5) 0.340 4.5 (0.5) ICD 16 (25) 45 (38) 0.075 61 (33) CRT 8 (12) 20 (17) 0.417 28 (15) Mitraclip 2 (3) 4 (3) 0.925 6 (3) Levosimendan 10 (15) 15 (13) 0.584 25 (14) ACEi/ARB 58 (89) 110 (92) 0.584 168 (91) Beta-blockers 63 (97) 111 (93) 0.225 174 (94) MRA 39 (60) 96 (80) 0.003 135 (73) Ivabradine 10 (16) 21 (18) 0.728 31 (17) Diuretics 44 (68) 99 (83) 0.022 143 (73) Initial dose ARNI, mg 0.517 24/26 41 (63) 85 (71) 126 (68) 49/51 22 (34) 33 (28) 55 (30) 97/103 2 (3) 2 (2) 4 (2) HF admission in last year 38 (59) 53 (44) 0.063 91 (49) After 1 year follow-up NYHA class <0.001 I 22 (34) 16 (16) 38(23) II 39 (60) 54 (53) 93 (56) III 4 (6) 29 (28) 33 (20) IV 0 (0) 3 (3) 3 (1) LVEF,% 42 (12) 33 (9) <0.001 36 (11) ≥10 points LVEF 36 (56) 10 (10) <0.001 46 (29) NT-proBNP, ng/L 696 (259–1802) 1766 (850–3120) <0.001 1324 (574–2513) ≥50% of change in NT-proBNP 39 (66) 18 (16) <0.001 57 (33) Creatinine, mg/dL 1.2 (0.4) 1.3 (0.7) 0.104 1.3 (0.6) GFR, mL/min/1.73 m2 65 (21) 61 (20) 0.221 63 (20) Final dose ARNI, mg <0.001 24/26 11 (17) 24 (20) 35(19) 49/51 14 (22) 18 (15) 32 (17) 97/103 40 (62) 41 (34) 81 (44) Discontinuing 0 (0) 37 (31) 37 (20) 1-year HF admission 0 (0) 50 (42) <0.001 50 (27) 1-year heart transplant 0 (0) 8 (7) <0.001 8 (4) 1-year mortality 0 (0) 24 (20) <0.001 24 (13) Results are expressed in number (%), mean (SD), or median (IQR). List of abbreviations: NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end diastolic diameter; SBP, systolic blood pressure; NT-proBNP, NT amino terminal propeptide brain natriuretic peptide; GFR, glomerular filtration rate; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronize therapy; ACEi, angiotensin cardioverter enzyme inhibitor; ARB, aldosterone receptor antagonist; MRA, mineraloid receptor antagonist; ARNI, aldosterone receptor neprilysin inhibitor; HF, heart failure. Frontiers in Physiology | www.frontiersin.org 3 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan FIGURE 1 | Probability of super-response to sacubitril/valsartan according to the AWARD-Class score categories. TABLE 2 | The AWARD-Class score. in the super-responder group. After a 1-year follow-up, super- responders presented a better NYHA class, higher LVEF, lower β Points OR (95% P-value coefficient confidence plasma levels of NT-proBNP, and similar renal function with interval) higher doses of SV compared to those with a standard response. Table 1 summarizes the clinical characteristics of the Antialdosteronic naive 0.836 8 2.3 (1.1–4.8) 0.024 study population. Woman 0.536 5 1.7 (0.8–3.6) 0.161 HF Admission in last year 0.601 6 1.8 (0.9–3.6) 0.088 Sinus Rhythm 0.692 7 2.0 (1.0–4.0) 0.052 Predictors for Super-Response: The Diuretics naive 0.743 7 2.1 (1.0–4.5) 0.059 AWARD-Class Score I-II NYHA Class 0.835 8 2.3 (1.1–4.8) 0.025 After a multivariate logistic analysis, the absence of previous List of abbreviations: OR, odds ratio; HF, heart failure; NYHA, New York aldosterone antagonist treatment (OR 2.3, 95% CI: 1.1–4.8) Heart Association. and NYHA I-II class (OR 2.3, 95% CI: 1.1–4.8) were the only independent predictors of super-response to SV. Along statistically significant. All the analyses were performed using with these two factors, the model which predicted best STATA software (v. 13.1). the super-response to SV included gender, presence of HF admission over the past year, ECG rhythm, and presence of diuretics (AUC 0.720; 95% CI: 0.644–0.797). In order RESULTS to build a score able to predict the probability of super- response for a given patient, we assigned a scale of 41 points Prevalence of Super-Responders to based on the β-coefficient of each variable (Table 2). This score—the AWARD-Class score—allowed the estimation of the Sacubitril/Valsartan chance of super-response to SV, as illustrated in Figure 1. Out of 185 patients, 65 (35.1%) fulfilled the super-responder Indeed, this score distinguished a low- (24% event rate), criteria. Of them, 29 patients presented an NT-proBNP reduction intermediate- (47% event rate), and high-probability groups (83% of 50% or more, 26 improved LVEF at least 10 points, and, event rate) for 1-year follow-up after SV initiation. Table 3 finally, 10 patients accomplished both conditions. Overall, super- resumes the prognostic performance of the AWARD-Class score responders were more frequent in sinus rhythm and without in each category. aldosterone antagonists or diuretics at the time of SV initiation than standard responders. Although non-significant statistically, clinical characteristics such as women, NYHA I-II class, less Internal Validation and Calibration of the dilated left ventricle, and without implantable cardioverter Model defibrillator were more frequent among super-responders. Lastly, After the bootstrap sampling, the AUC for this model was previous HF admission rate during the past year was higher 0.738 (95% CI 0.616–0.792), which was non-statistically different Frontiers in Physiology | www.frontiersin.org 4 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan TABLE 3 | Prognostic performance of the AWARD-Class score categories. Sensitivity Specificity PPV NPV Low score (0–20 points) 88% 32% 29% 89% Intermediate score (21–30 points) 37% 90% 77% 62% High score (≥31 points) 0% 100% 100% 17% List of abbreviations: PPV, positive predictive value; NPV, negative predictive value. FIGURE 3 | Calibration plot of the AWARD-Class score for super-response to sacubitril/valsartan. Predictors of Super-Response to Sacubitril/Valsartan Only a few studies have indicated possible predictors for a FIGURE 2 | Comparison of the ROC curves of the derivation (curve containing favorable response to SV in ambulatory patients with HF dots) and internal validation models. List of abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; P, p-value; NS, (Martens et al., 2018; Nakou et al., 2018; Vicent et al., 2019; non-significance. Chang et al., 2020; Díez-Villanueva et al., 2020) (Table 4). These are observational cohort studies, most reflecting single-center experiences, and with a follow-up of less than 1 year after the compared to the AUC of the derivation cohort (Figure 2). start of the drug. The favorable response to SV was defined Calibration of the score was fairly good as shown by the as the evidence of a positive cardiac remodeling assessed by non-significant Hosmer–Lemeshow test (P = 0.820) and the echocardiography or a significant improvement in the functional calibration plot (Figure 3). capacity of patients. Two studies agreed that higher doses of SV were more likely to observe a favorable response (Martens et al., 2018; Chang et al., 2020). Other predictors proposed were female sex (Vicent et al., 2019), the absence of an ICD (Díez- DISCUSSION Villanueva et al., 2020), the non-ischemic etiology of HF (Chang et al., 2020), the smaller diameter of the LV (Chang et al., 2020), Main Findings and the plasmatic levels of troponin (Nakou et al., 2018). In Up to 35% of patients from two different tertiary hospitals this regard, our study coincides in that women were significantly fulfilled the super-responder criteria to SV. This study proposes more frequent “super-responders” than men. This fact has been a simple score that predicts super-response to SV after 1-year equally observed in both the PARAGON-HF trial (McMurray initiation. Moreover, the score allows discrimination between et al., 2020) and in a pooled analysis with the results of the low-, intermediate-, and high-probability of super-response PARADIGM trial (Solomon et al., 2020), where SV seemed to based on variables that are currently assessed in clinical practice. reduce the risk of HF hospitalization more in women than in men TABLE 4 | Predictors for a favorable response to SV in previous studies. References N Design FU Response Predictors Martens et al., 2018 141 Single-center ∼3 m Cardiac remodeling by echo High dose of SV Nakou et al., 2018 48 Single-center 6m Functional capacity by CPET Troponin-I Díez-Villanueva et al., 2020 249 Multi-center ∼7 m Cardiac remodeling by echo Non-ICD Vicent et al., 2019 427 Multi-center ∼7 m Functional capacity by NYHA Females Chang et al., 2020 437 Single-center 12 m Cardiac remodeling by echo Non-ischemic, ↓LVEDD, high dose of SV List of abbreviations: SV, sacubitril/valsartan; FU, follow-up; m, months; CPET, cardio-pulmonary exercise testing; ICD, implantable cardioverter defibrillator; LVEDD, left ventricular end diastolic diameter. Frontiers in Physiology | www.frontiersin.org 5 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan in higher values of LVEF, and also with other therapeutic options range of relevant variables of HF, we did not collect specific for patients with low LVEF such as CRT (Costanzo, 2017). information about other comorbidities or psychosocial factors. Smaller LV end diastolic diameter and the absence of previous Both hospitals comprised patients from the same geographic ICD were also more prevalent in our super-responder population; area and mostly Caucasians; thus our model would need further however, these factors were not part of the best equation to validation in different populations. In addition, we recognize that predict the super-response to SV. Instead, the AWARD-Class the “super-responder” concept has been defined arbitrarily, but score proposes that aldosterone antagonist-naive patients and we have chosen the conditions based on the results of the two those with a previous HF-admission during last year—probably largest studies evaluating NT-proBNP change (Zile et al., 2016) reflecting subjects with a shorter history of HF—along with better and cardiac remodeling (Januzzi et al., 2019). Finally, further NYHA class and the absence of diuretics—translating a less studies are warranted to test the performance of this score at advanced HF stage—are the best predictors for a super-response longer follow-ups and in different clinical scenarios such as to SV in our study population. Supporting the concept of early acute HF hospitalization or with the addition of new drugs to initiation of SV, recent randomized clinical trials have shown the HFrEF armamentarium (McMurray et al., 2019; Ryan and that SV initiation during or early after an HF hospitalization— Maron, 2020; Santos-Gallego et al., 2020; Teerlink et al., 2020). even in de novo HF—conferred a better prognosis compared to previous standard treatment (Velazquez et al., 2019; Wachter et al., 2019b; Senni et al., 2020). Moreover, our model has been CONCLUSION developed integrating populations from two different hospitals and establishing as a mandatory criterion for super-response The prevalence of super-responders to SV was of 35% in our the absence of hard clinical events such as HF readmission, study population. A simple score based on precise variables heart transplantation, or death over the next year, in addition that are currently assessed in clinical practice to predict super- to positive cardiac remodeling and/or a significant reduction of response to SV after 1-year initiation is proposed and should be NT-proBNP levels. Importantly, this simple score is based on validated in different populations. variables routinely collected in the daily clinical practice and allows stratifying into three groups according to the probability DATA AVAILABILITY STATEMENT of super-response. Indeed, if a patient scores more than 30 points, the probability of not suffering any clinical event and recovering The raw data supporting the conclusions of this article will be at least 10 points of LVEF and/or halve at least their previous made available by the authors, without undue reservation. levels of natriuretic peptides after 1 year would be sky high, given that this group shows a specificity and a positive predictive value of 100% after internal validation (Table 3). ETHICS STATEMENT Clinical Implications The studies involving human participants were reviewed and In the outpatient environment, this score should provide the approved by Hospital del Mar, Barcelona. Written informed opportunity to identify those patients who would most benefit consent for participation was not required for this study in from SV. We consider that its use could imply several clinical accordance with the national legislation and the institutional benefits, especially in three scenarios. First, it would help its requirements. implementation in daily clinical practice, which until now has been slower than expected in different countries (DeVore et al., 2018; Wachter et al., 2019a; de Frutos et al., 2020). Selecting AUTHOR CONTRIBUTIONS patients with a super-response could be particularly helpful in MR-L, JÁ-G, LB, ES-G, SM, and ER conceptualized or designed health systems where resources are limited (Krittayaphong and the work. CM-A, DM, JP, PF-B, IZ-R, LL, VB, MP, and NM Permsuwan, 2018; Kahn et al., 2020). Second, the identification contributed to data acquisition. CM-A, MR-L, JÁ-G, LB, and of a subgroup of patients with an excellent 1-year prognosis ES-G analyzed or interpreted the data. CM-A, MR-L, and JÁ-G (without events and positive cardiac remodeling) would allow in drafted the work. All the authors substantially contributed in the turn to differ the potential indication of expensive and invasive critical revision of the manuscript, ensured the accuracy, and complex therapies, such as CRT or ICD (Zacà, 2018), especially approved the final version. in patients with non-ischemic cardiomyopathy (Jilek et al., 2020). And third, the AWARD-Class score fuels the debate on the timing that SV should be started within the treatment algorithm FUNDING of patients with HF and reduced LVEF (Ambrosy et al., 2019; Escobar et al., 2019). This work was supported by the CIBERCV and the Red de Investigación Cardiovascular (RD12/0042/0002) of the Spanish Study Limitations Instituto de Salud Carlos III and by the Fondo Europeo de Several limitations of this study have to be stated. This was a Desarollo Regional (FEDER). MR-L has a personal Rio Hortega retrospective observational study with a relatively small number grant (CM17/00028) from Instituto de Salud Carlos III. JÁ-G has of patients. Although the AWARD-Class score includes a wide a personal grant from Private Foundation Daniel Bravo. Frontiers in Physiology | www.frontiersin.org 6 February 2021 | Volume 12 | Article 642117 Moliner-Abós et al. Super-Responders to Sacubitril/Valsartan REFERENCES McMurray, J. J. V., Jackson, A. M., Lam, C. S. P., Redfield, M. M., Anand, I. S., Ge, J., et al. (2020). Effects of sacubitril-valsartan versus valsartan in women Ambrosy, A. P., Fudim, M., and Chioncel, O. (2019). Should providers compared with men with heart failure and preserved ejection fraction: insights prescribe sacubitril/valsartan based on trial eligibility, approval indication, from PARAGON-HF. Circulation 141, 338–351. doi: 10.1161/circulationaha. or guideline recommendations? Eur. J. Heart Fail. 21, 1398–1401. 119.044491 doi: 10.1002/ejhf.1555 McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, Chang, H. Y., Chen, K. C., Fong, M. C., Feng, A. N., Fu, H. N., Huang, K. C., M. 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MR-L and haemodynamically stabilised heart failure patients in hospital or early after PF-B have received an educational grant from Novartis. discharge: primary results of the randomised TRANSITION study. Eur. J. Heart Fail. 21, 998–1007. The remaining authors declare that the research was conducted in the absence of Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Colvin, M. M., any commercial or financial relationships that could be construed as a potential et al. (2017). 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA conflict of interest. guideline for the management of heart failure. J. Am. Coll. Cardiol. 70, 776–803. doi: 10.1016/j.jacc.2017.04.025 Copyright © 2021 Moliner-Abós, Mojón Álvarez, Rivas-Lasarte, Belarte, Pamies Zacà, V. (2018). Sacubitril/valsartan or an implantable cardioverter-defibrillator Besora, Solé-González, Fluvià-Brugues, Zegrí-Reiriz, López López, Brossa, Pirla, in heart failure with reduced ejection fraction patients: a cost-effectiveness Mesado, Mirabet, Roig and Álvarez-García. This is an open-access article distributed analysis. J. Cardiovasc. Med. 19, 597–605. doi: 10.2459/jcm.0000000000000708 under the terms of the Creative Commons Attribution License (CC BY). The use, Zile, M. R., Claggett, B. L., Prescott, M. F., McMurray, J. J. V., Packer, M., Rouleau, distribution or reproduction in other forums is permitted, provided the original J. L., et al. (2016). Prognostic implications of changes in N-terminal pro-B- author(s) and the copyright owner(s) are credited and that the original publication type natriuretic peptide in patients with heart failure. J. Am. Coll. Cardiol. 68, in this journal is cited, in accordance with accepted academic practice. No use, 2425–2436. doi: 10.1016/j.jacc.2016.09.931 distribution or reproduction is permitted which does not comply with these terms. Frontiers in Physiology | www.frontiersin.org 8 February 2021 | Volume 12 | Article 642117