DELIVERing Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure
2022; Lippincott Williams & Wilkins; Volume: 146; Issue: 16 Linguagem: Inglês
10.1161/circulationaha.122.062022
ISSN1524-4539
AutoresCarolyn S.P. Lam, Scott D. Solomon,
Tópico(s)Heart rate and cardiovascular health
ResumoHomeCirculationVol. 146, No. 16DELIVERing Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBDELIVERing Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure Carolyn S.P. Lam and Scott D. Solomon Carolyn S.P. LamCarolyn S.P. Lam Correspondence to: Carolyn S.P. Lam, MBBS, PhD, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Email E-mail Address: [email protected] https://orcid.org/0000-0003-1903-0018 National Heart Center Singapore and Duke-National University of Singapore (C.S.P.L.) University Medical Center Groningen, The Netherlands (C.S.P.L.). and Scott D. SolomonScott D. Solomon Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, Email E-mail Address: [email protected] https://orcid.org/0000-0003-3698-9597 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D.S.). Originally published27 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.062022Circulation. 2022;146:1193–1195Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 27, 2022: Ahead of Print For decades, ejection fraction (EF) has been the principal metric we use to clinically characterize cardiac function, and yet its use to phenotype heart failure (HF) has hindered our understanding of the syndrome and its possible therapies. Results from clinical trials of candesartan, spironolactone, and sacubitril/valsartan in HF have shown attenuation of treatment benefit in the highest range of EF. These observations have led to a fundamental question: is the attenuation of benefit observed with increasing EF because of specific properties of the tested therapies, or is this a more fundamental property of the syndrome itself?This question is more significant in light of the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure) trial in which the SGLT2 (sodium-glucose cotransporter 2) inhibitor dapagliflozin reduced cardiovascular death or worsening HF across the full spectrum of HF, without attenuation at the upper end of EF. In DELIVER, 1891 (30%) patients had EF ≥60%; the hazard ratio for the primary outcome was 0.78 (95% CI, 0.62–0.98) versus 0.83 (95% CI, 0.73–0.95) among patients with EF 65% in the EMPEROR-Preserved trial, a post hoc finding that contrasted with the lack of significant heterogeneity by prespecified EF subgroups in primary analyses of EMPEROR-Preserved, as well as a lack of significant linear relationship between continuous EF and the effect of empagliflozin on the primary end point in the pooled EMPEROR trials; furthermore, results appeared to vary with different post hoc EF cutpoints, showing benefit in the EF >72.5% subgroup despite lack of benefit in the 62.5–67.5% and 67.5–72.5% subgroups—all suggesting that previous finding may have been because of chance.3So why might SGLT2 inhibitors have been successful in an EF range where other therapies have failed? The mechanism of action of SGLT2 inhibitors in HF, although incompletely understood, is clearly distinct from that of prior therapies that focused on reverse left ventricular remodeling via blocking the deleterious effects of neurohormonal activation (such as renin–angiotensin–aldosterone inhibitors), or on augmenting endogenous neurohormonal pathways (such as neprilysin inhibitors). Although these neurohormonal agents have also been shown to have favorable kidney effects, their established role in reducing left ventricular size in those with dilated ventricles (ie, reverse remodeling) is likely central to their mechanism of action, resulting in reduced ventricular wall stress and reduction in natriuretic peptides. In contrast, evidence of reverse left ventricular remodeling with SGLT2 inhibitors is sparse and inconsistent despite overwhelming evidence of their clinical outcome benefits. Natriuretic peptide lowering with SGLT2 inhibitors is similarly much less profound than with neurohormonal agents. On the other hand, there is strong evidence of the kidney protective effects of SGLT2 inhibitors.4 SGLT2 inhibitors may work, at least in part, by fundamentally addressing kidney function and its role in hemodynamic homeostasis, counteracting the congestive state that defines HF regardless of EF or extent of left ventricular remodeling.What are the implications for other therapies in HF? Treatment approaches that address aspects of the HF syndrome apart from left ventricular remodeling may similarly be expected to be effective across the EF spectrum. For instance, cardiac rehabilitation, by addressing peripheral mechanisms of physical function and frailty, was beneficial in HF regardless of EF.5Do the findings of DELIVER call for a different approach to the treatment of HF? Although many have debated the pros and cons of EF, EF has anchored decades of trial evidence on which therapeutic advances in HF were made, and remains key for determining appropriate medications and devices, predicting the expected therapeutic response, and prognostication among patients with HF. Yet, these new data suggest that we may have become myopic in our focus on EF and may need to take a step back remembering that regardless of EF, all patients have HF, a syndrome in which multiple organ systems (heart, vasculature, kidneys, lungs, skeletal muscles) play a part. Viewed this way (Figure), therapy may begin with those that address the presenting congestive state that defines the HF syndrome, including diuretics and SGLT2 inhibitors, as well as the precipitants of decompensation. A determination of whether left ventricular remodeling and/or dyssynchrony is present—reflected as an EF below normal among other parameters—remains important for decisions regarding neurohormonal agents and device therapies. Cardiac imaging is critical, independent of EF assessment, for the recognition of differential diagnoses such as valve, pericardial, and infiltrative myocardial diseases requiring specific therapies. Treatment of comorbidities, cardiac rehabilitation, multidisciplinary management/monitoring, and advanced treatments remain crucial regardless of EF.Download figureDownload PowerPointFigure. Schematic showing a suggested approach to heart failure treatment across the ejection fraction spectrum, where some therapies are used in the presence of reduced LV contractility or eccentric LV remodeling, whereas others are used to address the congestive state regardless of ejection fraction. LV indicates left ventricular; RAAS, renin–angiotensin–aldosterone system; RV, right ventricular; and SGLT2, sodium-glucose cotransporter 2.Article InformationAcknowledgmentsDrs Lam and Solomon wrote, reviewed, and edited this article. Dr Solomon conceptualized this article.Sources of FundingNone.Disclosures Dr Lam reports receiving research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; serving as consultant or on the Advisory Board/Steering Committee/Executive Committee for Abbott Diagnostics, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corvia Medical, Cytokinetics, Darma Inc, Us2.ai, JanaCare, Janssen Research and Development LLC, Medtronic, Menarini Group, Merck, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Stealth BioTherapeutics, The Corpus, Vifor Pharma, and WebMD Global LLC; and holding positions as Cofounder and Nonexecutive Director of Us2.ai. Dr Solomon reports receiving grants paid to his institution for chairing PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) from Novartis; grants paid to Brigham and Women's Hospital from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Gilead, Celladon, Eidos, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood, Institute, Novartis, Sanofi Pasteur, and Theracos; and consulting fees from Alnylam, Amgen, AoBiome, AstraZeneca, Bayer, Bristol Myers Squibb, Cardiac Dimensions, Corvia, Cytokinetics, Daichi-Sankyo, Gilead, GSK, Ironwood, Janssen, Merck, MyoKardia, Novartis, Quantum Genomics, Roche, Takeda, Tenaya, and Theracos.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 1195.Correspondence to: Carolyn S.P. Lam, MBBS, PhD, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Email carolyn.lam@duke-nus.edu.sgScott D. Solomon, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, Email ssolomon@bwh.harvard.eduReferences1. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction.N Engl J Med. 2022; doi: 10.1056/NEJMoa2206286CrossrefGoogle Scholar2. Rosch S, Kresoja KP, Besler C, Fengler K, Rebecca Schober A, von Roeder M, Lucke C, Gutberlet M, Klingel K, Thiele H, et al. Characteristics of heart failure with preserved ejection fraction across the range of left ventricular ejection fraction.Circulation. 2022; 146:506–518. doi: 10.1161/CIRCULATIONAHA.122.059280LinkGoogle Scholar3. Butler J, Packer M, Filippatos G, Ferreira JP, Zeller C, Schnee J, Brueckmann M, Pocock SJ, Zannad F, Anker SD. Effect of empagliflozin in patients with HF across the spectrum of left ventricular EF.Eur Heart J. 2022; 43:416–426. doi: 10.1093/eurheartj/ehab798CrossrefMedlineGoogle Scholar4. Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, Suda N, Siwakoti K, Ahmad T, Jacoby D, et al. Empagliflozin in heart failure: diuretic and cardiorenal effects.Circulation. 2020; 142:1028–1039. doi: 10.1161/CIRCULATIONAHA.120.045691LinkGoogle Scholar5. Kitzman DW, Whellan DJ, Duncan P, Pastva AM, Mentz RJ, Reeves GR, Nelson MB, Chen H, Upadhya B, Reed SD, et al. Physical rehabilitation for older patients hospitalized for heart failure.N Engl J Med. 2021; 385:203–216. doi: 10.1056/NEJMoa2026141CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bak M and Choi J (2023) Optimization of guideline-directed medical treatment for heart failure patients with reduced ejection fraction, The Korean Journal of Internal Medicine, 10.3904/kjim.2023.223, 38:5, (595-606), Online publication date: 1-Sep-2023. Sevre K, Rist A, Wachtell K, Devereux R, Aurigemma G, Smiseth O, Kjeldsen S, Julius S, Pitt B, Burnier M, Kreutz R, Oparil S, Mancia G and Zannad F (2023) What Is the Current Best Drug Treatment for Hypertensive Heart Failure With Preserved Ejection Fraction? Review of the Totality of Evidence, American Journal of Hypertension, 10.1093/ajh/hpad073 Palazzuoli A, Correale M, Iacoviello M and Gronda E (2023) Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest, Journal of Clinical Medicine, 10.3390/jcm12020693, 12:2, (693) Cho J, Cho D, Youn J, Kim D, Park S, Jung M, Hyun J, Choi J, Cho H, Park S, Choi J, Chung W, Yoo B and Kang S (2023) Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Definition and Diagnosis, Korean Circulation Journal, 10.4070/kcj.2023.0046, 53:4, (195) Cho J, Cho D, Youn J, Kim D, Park S, Jung M, Hyun J, Choi J, Cho H, Park S, Choi J, Chung W, Yoo B and Kang S (2023) Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Definition and Diagnosis, International Journal of Heart Failure, 10.36628/ijhf.2023.0009, 5:2, (51) October 18, 2022Vol 146, Issue 16 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.062022PMID: 36029466 Originally publishedAugust 27, 2022 Keywordsheart failurePDF download Advertisement SubjectsHeart Failure
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