Substance and Substrate
2020; Lippincott Williams & Wilkins; Volume: 141; Issue: 5 Linguagem: Inglês
10.1161/circulationaha.120.045008
ISSN1524-4539
AutoresBiykem Bozkurt, Justin A. Ezekowitz,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 141, No. 5Substance and Substrate Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSubstance and SubstrateLVEF and Sex Subgroup Analyses of PARAGON-HF and PARADIGM-HF Trials Biykem Bozkurt, MD, PhD and Justin Ezekowitz, MBBCh, MSc Biykem BozkurtBiykem Bozkurt Biykem Bozkurt, MD, PhD, MEDVAMC, 2002 Holcombe Blvd, Houston, TX 77030. Email E-mail Address: [email protected] Baylor College of Medicine, DeBakey VA Medical Center, Winters Center for Heart Failure Research, Cardiovascular Research Institute, Houston, TX (B.B.). Search for more papers by this author and Justin EzekowitzJustin Ezekowitz Department of Medicine, Division of Cardiology, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Canada (J.E.). Search for more papers by this author Originally published3 Feb 2020https://doi.org/10.1161/CIRCULATIONAHA.120.045008Circulation. 2020;141:362–366This article is a commentary on the followingSacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart FailureEffects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection FractionArticles, see p 90 and 352Paragon derives from the old Italian word paragone, which means “touchstone,” a stone on which metal was rubbed to judge the purity of gold or silver. In modern English, paragon has come to signify a standard against which something should be judged. In the modern era of heart failure (HF), the use of left ventricular ejection fraction (LVEF) has almost become a paragon of phenotyping and may be misleading.Chotomies of Scale: Dichotomy and TrichotomyAs clinicians are aware, management should not depend on a single numeric LVEF value, but rather on the patient as a whole with emphasis on pathogenesis, expected benefits, and potential risks. The dichotomization of LVEF of above or below, for example, 40% was a boon to developing and applying new therapies that may work in the sickest of patients with a clear(er) phenotype, but further classification into HF with reduced EF (HFrEF), mid-range EF (HFmEF), and preserved EF (HFpEF) has now come full circle and challenge our ability to develop treatments specific for causes. HFmEF (LVEF of 40%–49%) poses further challenges because of its ambiguity and dynamic trajectory. Its characteristics overlap with HFrEF and HFpEF, straddling either phenotype, sometimes one more than the other depending on the clinical circumstances or patients studied. In population-based studies, usually without exclusions of specific causes of HF, HFmEF comprises 10% to 20% of the HF population and resembles the HFrEF group, with similar or better survival than HFrEF patients.1,2 Although at face value they may appear to do so, the differentiation of these phenotypes does not depend solely on LVEF, or a single numeric LVEF at 1 time point. In many patients, HFmEF reflects a transitional trajectory for a dynamic temporal change, either to improvement or recovery from HFREF or to deterioration to HFREF.3,4 Persistent HFmEF can be seen in some, including heterogeneous causes such as those with infiltrative, restrictive, or hypertrophic cardiomyopathies.3,4 Therefore, a lower than normal LVEF does not necessarily represent 1 phenotype and does not always entail the maladaptive deleterious mechanisms seen in patients with HFrEF. Furthermore, patients with restrictive, infiltrative and hypertrophic cardiomyopathies, who may have HFmEF, have traditionally been excluded from clinical trials, emphasizing the necessity to focus on pathogenesis rather than LVEF. The prevalence of true HFmEF, without overlap of other phenotypes, has posed a major challenge for recruitment in trials, resulting in termination owing to enrollment futility.5 Furthermore, meta-analyses report diverse findings with neurohormonal antagonism in patients with HFmEF, specifying benefit in certain subgroups, underlining the heterogeneity of this phenotype.6,7Benefit of Sacubitril-Valsartan Across Different LVEF CategoriesIn this issue of Circulation, in a pooled analysis of combined data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)8 and PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction)9 trials, Solomon and colleagues10 report that the association of beneficial effects of sacubitril-valsartan varied by LVEF, were greatest among patients with lower LVEF, and by continuous LVEF and cubic spline analysis, the benefits appeared to extend to patients with HFmEF. At baseline, patients with a higher LVEF were older, had higher blood pressure and body mass index, and a higher prevalence of female sex, history of hypertension, diabetes mellitus, and worse renal function. Conversely, the levels of NT-proBNP (N-terminal pro–B-type natriuretic peptide) were lower and patients were less symptomatic by New York Heart Association Class. As expected, event rates for cardiovascular mortality and HF hospitalizations (HFH) decreased with increasing LVEF, but noncardiovascular mortality rates were similar across LVEF subgroups. Compared with renin-angiotensin system inhibition, sacubitril-valsartan resulted in lower cardiovascular death and HFH rates, but the treatment benefit waned with increasing LVEF and the benefit by continuous ejection fraction analysis in midrange LVEF was driven primarily by a reduction in HFH rates.10Given the positive findings of the PARADIGM-HF trial, demonstrating reductions in cardiovascular death and HFH rates with sacubitril-valsartan in HFrEF,8 this pooled analysis combining PARADIGM-HF and PARAGON-HF trials showing larger treatment effects with sacubitril-valsartan in lower LVEF patients is not surprising.10 In the same pooled analysis, the treatment effect of sacubitril-valsartan was significant up to an LVEF of 42.5% by decile LVEF analyses, and the upper threshold for benefit was proposed to be even higher, close to normal LVEF by restricted cubic spline analyses, especially for women.10 This was unforeseen, as sacubitril-valsartan did not reduce the primary outcome of cardiovascular death and HFH in HFpEF with LVEF ≥ 45% in the PARAGON-HF trial.9 Furthermore, when usual LVEF categories were studied (LVEF≤40%, >40%–50%, and >50%), clinical events were significantly reduced only in patients with LVEF≤40%, but not in patients with HFmEF (LVEF>40%–50%) or HFpEF (LVEF>50%; Figure).10 However, statistical power in the LVEF>40% to 50% group was low, and trends towards the reduction in HFH were seen in this LVEF range.Download figureDownload PowerPointFigure. Summary of major clinical end points in trials with angiotensin receptor neprilysin inhibitor (ARNi) sacubitril-valsartan compared against renin-angiotensin system (RAS) inhibitor across different phenotypes of heart failure (HF): HF with reduced ejection fraction (HFrEF), HF with midrange ejection fraction (HFmEF), and HF with preserved ejection fraction (HFpEF). Blue dashed line represents left ventricular ejection fraction (LVEF) cut-off for eligibility in the PARADIGM-HF trial (LVEF 40% to 50%, and LVEF>50%.10 The red dashed line represents extension of LVEF cut-off for benefit from sacubitril-valsartan, primarily for HF hospitalizations, when pooled data are analyzed for LVEF as a continuous variable or ranges of LVEF by deciles. The solid red line represents the extension of LVEF cut-off for clinical benefit in women, primarily for heart failure hospitalizations when restricted cubic spline analyses are performed on the pooled data. *P 50%, and recurrent HFH to >60%, with a similar degree of benefit in HFmEF as in HFrEF.2 Neither of these post hoc analyses was compelling enough for further studies or guideline updates, in part because of the consistent lack of benefit on cardiovascular death, underscoring limitations of post hoc analyses in these clinical trials.Benefit in Women: A Biological Effect on Disease or A Statistical Anomaly?In the pooled analysis, Solomon and colleagues suggest that the therapeutic benefits of sacubitril-valsartan appeared to extend to a higher LVEF range in women compared with men.10 In a companion publication, McMurray et al report differences in clinical outcomes with sacubitril-valsartan according to sex in the PARAGON-HF trial.13 Women constituted 52% of the PARAGON-HF population, and, compared with men, were older, had more obesity, less often coronary artery disease, a higher baseline LVEF, worse symptoms of HF, lower estimated glomerular filtration rate, and lower NT-proBNP levels. Overall, women had higher event rates of HFH and lower rates of cardiovascular death compared to men. With sacubitril-valsartan treatment, risk for HFH, but not cardiovascular death, was reduced for women, but not in men.13 The reduction in HFH rates was not associated with improvements in functional status or quality of life in women.The improvement in renal function and reduction in blood pressure with sacubitril-valsartan were similar in women and men, whereas the improvement in the Kansas City Cardiomyopathy Questionnaire scores was even less in women compared with men. Women had a higher risk of new-onset atrial fibrillation with sacubitril-valsartan compared with valsartan, whereas men had a lower risk.13 Lower NT-proBNP levels in women (despite worse HF symptoms) were attributed to higher LVEF levels. A potential question is whether sacubitril-valsartan could be more effective among those patients with HF with paradoxically lower baseline NT-proBNP levels despite advanced symptoms. Interestingly, however, changes in NT-proBNP levels and increases in urinary cGMP/creatinine ratios were similar in women and men, thus arguing against a biological sex difference in pharmacokinetics or response to neprilysin inhibition. Still, a biological difference cannot be ruled out as there are unmeasured peptides that are potential substrates for neprilysin such as adrenomedullin, bradykinin, or substance P, which may be affected by estrogen. Estrogen has also been reported to upregulate expression of neprilysin,14 and inhibit adrenal angiotensin-receptor binding. Thus, estrogen could enhance the efficacy of sacubitril and reduce the efficacy of valsartan.15 Conversely, estrogen deficiency may contribute to low levels of neprilysin, overactivity of the renin-angiotensin system, and increased efficacy of valsartan in postmenopausal women.16 However, in PARADIGM-HF, and a community-based general population, neprilysin levels had no relationship with female sex, age, body mass index, renal function, or NT-proBNP levels, arguing against sex differences with neprilysin in the normal population.17 Similarly, in real-world patients with HFrEF, no significant sex differences were observed in treatment response to angiotensin receptor neprilysin inhibitor.18 It is also important to note that there were also no sex and treatment interactions with valsartan in the VALIANT (The Valsartan in Acute Myocardial Infarction)19 or VaL-HeFT (The Valsartan Heart Failure Trial) trials,20 arguing against potential reduced efficacy of valsartan in women or a higher efficacy of valsartan in men.In the pooled analysis of PARAGON-HF and PARADIGM-HF trials, the effect modification by LVEF on the efficacy of sacubitril-valsartan was similar in men and women.10 There was more benefit from sacubitril-valsartan at a lower LVEF for both genders, but interestingly the upper threshold of loss of benefit was higher, almost at 60% in women, versus 45% to 50% in men.10 Likewise, in the TOPCAT trial, although the overall hazard ratios were similar between men and women, women appeared to benefit across the whole LVEF spectrum, but men benefited only in the lower LVEF range.11 because the efficacy does not appear to differ by sex in the lower end of the LVEF spectrum, the hypothesized sex-based differences, in response to angiotensin receptor neprilysin inhibitor or spironolactone only at a higher LVEF, remain unsettled, and raise the possibility of the findings being attributable to chance alone or to the possibility of presence of contractile dysfunction extending to higher LVEF measurements in women.11,13 Still, these findings may also imply the differences in pathophysiology or pathogenesis of HF between men and women.ConclusionManagement of HF should not depend on a single numeric ejection fraction value, but rather on the patient as a whole with emphasis on the underlying etiology. Similarly, post hoc analyses are inadequate to be the paragon to define thresholds and subsets of patients who may benefit from therapies. Future randomized clinical trials in women and HFmEF may help answer questions about the efficacy of angiotensin receptor neprilysin inhibition in these populations.DisclosuresDr Bozkurt discloses consultation for Bayer and scPharmaceuticals, is on the Clinical Events Committee for Guide-HF Trial by Abbott Pharmaceuticals, and Data Safety Monitoring Board for Anthem Trial by Liva Nova Pharmaceuticals. J. Ezekowitz reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circBiykem Bozkurt, MD, PhD, MEDVAMC, 2002 Holcombe Blvd, Houston, TX 77030. Email [email protected]eduReferences1. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.Eur J Heart Fail. 2017; 19:1574–1585. doi: 10.1002/ejhf.813CrossrefMedlineGoogle Scholar2. Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, Swedberg K, Yusuf S, Granger CB, Pfeffer MA, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.Eur J Heart Fail. 2018; 20:1230–1239. doi: 10.1002/ejhf.1149CrossrefMedlineGoogle Scholar3. Rastogi A, Novak E, Platts AE, Mann DL. Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.Eur J Heart Fail. 2017; 19:1597–1605. doi: 10.1002/ejhf.879CrossrefMedlineGoogle Scholar4. Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, Abe R, Oikawa T, Kasahara S, Sato M, et al; CHART-2 Investigators. Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.Eur J Heart Fail. 2017; 19:1258–1269. doi: 10.1002/ejhf.807CrossrefMedlineGoogle Scholar5. Linde C, Curtis AB, Fonarow GC, Lee K, Little W, Tang A, Levya F, Momomura S, Manrodt C, Bergemann T, et al. Cardiac resynchronization therapy in chronic heart failure with moderately reduced left ventricular ejection fraction: lessons from the multicenter insync randomized clinical evaluation MIRACLE EF study.Int J Cardiol. 2016; 202:349–355. doi: 10.1016/j.ijcard.2015.09.023CrossrefMedlineGoogle Scholar6. Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis.Heart. 2018; 104:407–415. doi: 10.1136/heartjnl-2017-311652CrossrefMedlineGoogle Scholar7. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, et al; Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.Eur Heart J. 2018; 39:26–35. doi: 10.1093/eurheartj/ehx564CrossrefMedlineGoogle Scholar8. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371:993–1004. doi: 10.1056/NEJMoa1409077CrossrefMedlineGoogle Scholar9. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, et al; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.N Engl J Med. 2019; 381:1609–1620. doi: 10.1056/NEJMoa1908655CrossrefMedlineGoogle Scholar10. Solomon SD, Vaduganathan M, Claggett BL, Packer M, Zile M, Swedberg K, Rouleau J, Pfeffer MA, Desai A, Lund LH, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure.Circulation. 2020; 141:352–361. doi: 10.1161/CIRCULATIONAHA.119.044586LinkGoogle Scholar11. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O’Meara E, Shah SJ, McKinlay S, Fleg JL, et al; TOPCAT Investigators. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.Eur Heart J. 2016; 37:455–462. doi: 10.1093/eurheartj/ehv464CrossrefMedlineGoogle Scholar12. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.Lancet. 2003; 362:777–781. doi: 10.1016/S0140-6736(03)14285-7CrossrefMedlineGoogle Scholar13. McMurray JJV, Jackson AM, Lam CSP, Redfield MM, Anand IS, Ge J, Lefkowitz MP, Maggioni AP, Martinez F, Packer M, et al. Effects of sacubitril-valsartan, versus valsartan, in women compared to men with heart failure and preserved ejection fraction: insights from PARAGON-HF [published online November 17, 2019].Circulation. doi: 10.1161/CIRCULATIONAHA.119.044491Google Scholar14. Liang K, Yang L, Yin C, Xiao Z, Zhang J, Liu Y, Huang J. Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin.J Biol Chem. 2010; 285:935–942. doi: 10.1074/jbc.M109.051664CrossrefMedlineGoogle Scholar15. Wu Z, Zheng W, Sandberg K. Estrogen regulates adrenal angiotensin type 1 receptors by modulating adrenal angiotensin levels.Endocrinology. 2003; 144:1350–1356. doi: 10.1210/en.2002-221100CrossrefMedlineGoogle Scholar16. O’Donnell E, Floras JS, Harvey PJ. Estrogen status and the renin angiotensin aldosterone system.Am J Physiol Regul Integr Comp Physiol. 2014; 307:R498–R500. doi: 10.1152/ajpregu.00182.2014CrossrefMedlineGoogle Scholar17. Reddy YNV, Iyer SR, Scott CG, Rodeheffer RJ, Bailey K, Jenkins G, Batzler A, Redfield MM, Burnett JC, Pereira NL. Soluble neprilysin in the general population: clinical determinants and its relationship to cardiovascular disease.J Am Heart Assoc. 2019; 8:e012943. doi: 10.1161/JAHA.119.012943LinkGoogle Scholar18. Tan NY, Sangaralingham LR, Sangaralingham SJ, Yao X, Shah ND, Dunlay SM. Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.JACC Heart Fail. 2020; 8:43–54. doi: 10.1016/j.jchf.2019.08.003CrossrefMedlineGoogle Scholar19. Lam CS, McEntegart M, Claggett B, Liu J, Skali H, Lewis E, Køber L, Rouleau J, Velazquez E, Califf R, et al. Sex differences in clinical characteristics and outcomes after myocardial infarction: insights from the valsartan in acute myocardial infarction trial (VALIANT).Eur J Heart Fail. 2015; 17:301–312. doi: 10.1002/ejhf.238CrossrefMedlineGoogle Scholar20. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.N Engl J Med. 2001; 345:1667–1675. doi: 10.1056/NEJMoa010713CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Latado A (2022)(2022)(2022)(2022) Prognóstico de Insuficiência Cardíaca com Fração de Ejeção Intermediária: Uma História ou uma Versão?, Arquivos Brasileiros de Cardiologia, 10.36660/abc.20220170, 118:4, (701-702), Online publication date: 7-Apr-2022., Online publication date: 7-Apr-2022., Online publication date: 1-Apr-2022., Online publication date: 1-Apr-2022. Núñez J, Núñez E, Revuelta-López E, Miñana G, Barallat J, Bodi V, Sanchis J, Aimo A, Emdin M, Lupón J, Husser O and Bayes-Genis A (2021) The influence of sex and body mass index on the association between soluble neprilysin and risk of heart failure hospitalizations, Scientific Reports, 10.1038/s41598-021-85490-1, 11:1, Online publication date: 1-Dec-2021. Bozkurt B, Coats A, Tsutsui H, Abdelhamid C, Adamopoulos S, Albert N, Anker S, Atherton J, Böhm M, Butler J, Drazner M, Michael Felker G, Filippatos G, Fiuzat M, Fonarow G, Gomez‐Mesa J, Heidenreich P, Imamura T, Jankowska E, Januzzi J, Khazanie P, Kinugawa K, Lam C, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano G, Sakata Y, Seferović P, Starling R, Teerlink J, Vardeny O, Yamamoto K, Yancy C, Zhang J and Zieroth S (2021) Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure, European Journal of Heart Failure, 10.1002/ejhf.2115, 23:3, (352-380), Online publication date: 1-Mar-2021. Bozkurt B, Coats A, Tsutsui H, Abdelhamid M, Adamopoulos S, Albert N, Anker S, Atherton J, Böhm M, Butler J, Drazner M, Felker G, Filippatos G, Fonarow G, Fiuzat M, Gomez-Mesa J, Heidenreich P, Imamura T, Januzzi J, Jankowska E, Khazanie P, Kinugawa K, Lam C, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano G, Sakata Y, SeferoviĆ P, Starling R, Teerlink J, Vardeny O, Yamamoto K, Yancy C, Zhang J and Zieroth S (2021) Universal Definition and Classification of Heart Failure, Journal of Cardiac Failure, 10.1016/j.cardfail.2021.01.022, 27:4, (387-413), Online publication date: 1-Apr-2021. Ferrari R, Fucili A and Rapezzi C (2020) Understanding the results of the PARAGON‐HF trial, European Journal of Heart Failure, 10.1002/ejhf.1797, 22:9, (1531-1535), Online publication date: 1-Sep-2020. Vaz-Salvador P, Adão R, Vasconcelos I, Leite-Moreira A and Brás-Silva C (2022) Heart Failure with Preserved Ejection Fraction: a Pharmacotherapeutic Update, Cardiovascular Drugs and Therapy, 10.1007/s10557-021-07306-8 Margonato D, Mazzetti S, De Maria R, Gorini M, Iacoviello M, Maggioni A and Mortara A (2020) Heart Failure With Mid-range or Recovered Ejection Fraction: Differential Determinants of Transition, Cardiac Failure Review, 10.15420/cfr.2020.13, 6 Al Sudani H, Lo K, Essa H, Wattoo A, Gulab A, Akhtar H, Angelim L, Helfman B, Peterson E, Brousas S, Whybrow-Huppatz I, Yazdanyar A, Soman S, Sankaranarayanan R and Rangaswami J (2022) Differences in ejection fraction as inclusion criterion in randomized controlled trials among patients with heart failure with reduced ejection fraction: a systematic review, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2022.2085687, (1-4) Related articlesSacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart FailureScott D. Solomon, et al. Circulation. 2020;141:352-361Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection FractionJohn J.V. McMurray, et al. Circulation. 2020;141:338-351 February 4, 2020Vol 141, Issue 5 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.045008PMID: 32011927 Originally publishedFebruary 3, 2020 KeywordscardiomyopathyEditorialsneprilysinrenin-angiotensin systemheart failurevalsartansexventricular functionPDF download Advertisement SubjectsCardiomyopathyHeart Failure
Referência(s)