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A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted., Competing Interests: Dr Packer reports personal fees for consulting from 89bio, AbbVie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Relypsa, and Salamandra, all outside the submitted work. Dr Anker reports grants from Vifor and Abbott Vascular; personal fees for consultancies, trial committee work, or lectures from Vifor, Abbott Vascular, Actimed, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GlaxoSmithKline, HeartKinetics, Impulse Dynamics, Occlutech, Pfizer, Regeneron, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is a named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but does not benefit personally from the patents, all outside the submitted work. Dr Butler reports personal consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Janssen, Daxor Edwards, Element Science, Eli Lilly, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, LivaNova, Medscape, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Secretome, Sequana, SQ Innovation, Tenex, Tricoq, and Vifor; and honoraria from Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Impulse Dynamics, and Vifor, all outside the submitted work. Dr Mentz reports grants from American Regent, AstraZeneca, Amgen, Bayer, Merck, Novartis, Zoll, and Cytokinetics; and personal consulting fees from Pharmacosmos, Vifor, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Abbott, Medtronic, Zoll, Boston Scientific, Cytokietics, Respicardia, Roche, Vifor, Sanofi, and Windtree, all outside the submitted work. Dr Cleland reports grants from Bristol Myers Squibb, British Heart Foundation, Medtronic, Pharma Nord, Vifor, and Pharmacosmos; personal consulting fees from Abbott, Biopeutics, Innolife, NI Medical, Novartis, and Servier; honoraria for committee or advisory boards from Idorsia and Medtronic; honoraria for lectures from AstraZeneca and Boehringer Ingelheim; and stock options or holdings in Heartfelt Limited and Viscardia, all outside the submitted work. Dr Kalra reports grants from Pharmacosmos and the British Heart Foundation; personal consulting fees from Amgen, Boehringer Ingelheim, Pharmacosmos, Servier, and CSL Vifor; and honoraria for lectures from AstraZeneca, Bayer, Novartis, Pfizer, Pharmacosmos, CLS Vifor, and Amgen, all outside the submitted work. Dr Ponikowski reports personal fees for consultancies, trial committee work, or lectures from Astra Zeneca, Bayer, Boehringer Ingelheim, Pfizer, Vifor Pharma, Amgen, Servier, Novartis, Novo Nordisk, Pharmacosmos, Abbott Vascular, Radcliffe Group, and Charite University, all outside the submitted work.

Background: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown., Methods: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes., Results: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P <0.05)., Conclusions: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674., Competing Interests: Disclosures Dr Hernandez has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intellia, Intercept, MyoKardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev; and has received research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck, Novartis, Novo Nordisk, and Verily. Dr Bhatt has served on advisory boards for ANGIOWave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; on the board of directors for American Heart Association New York City, ANGIOWave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC accreditation oversight committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); is named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, which was assigned to Lexicon (neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (editor, Braunwald’s Heart Disease); has served as site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as trustee for American College of Cardiology; and performed unfunded research for FlowCo. Dr Butler has served as a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Goto reports serving as Associate Editor for Circulation and receipt of a steering committee fee from the Duke Clinical Research Institute for EMPACT-MI. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Amir reports serving as National PI-Steering committee member for the study and participated in paid lectures and advisory board meetings and clinical trials in Dr Amir’s department at Boehringer Ingelheim. Dr Beyes-Genis has lectured or participated in advisory boards for Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, and Vifor. Dr Bahit reports modest honorarium from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Bauersachs received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, and Roche not related to this article; and research support for Dr Bauersachs’ department from Zoll, CVRx, Abiomed, Norgine, and Roche, not related to this article. Dr Schou reports lecture fees from Novartis, Astra Zeneca, Bohringer, and Novo Nordisk. Dr Steg reports research grants from Amarin and Sanofi; clinical trial participation for Amarin, Amgen, AstraZeneca, Idorsia, Janssen, Novartis, Novo-Nordisk, and Sanofi; consulting or speaking for Amarin, Amgen, and Novo-Nordisk; and serving as senior associate editor at Circulation. Dr Parikh reports serving as a consultant for Medtronic, Inc and receipt of an institutional research grant from Abbott and Edwards Lifesciences. Dr Januzzi reports participation as a trustee of the American College of Cardiology, board member of Imbria Pharmaceuticals, and director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, BBMS, HeartFlow Inc, Innolife, and Roche Diagnostics, and consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Janssen, Medtronic, Novartis, Prevencio, Quidel/Ortho, Roche Diagnostics, and Vascular Dynamics; and participates in clinical end point committees or data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Medtronic, Pfizer, Roche Diagnostics, and Takeda. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) or speaker or consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and salary support or honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and TIMI Study Group (Brigham Health). Dr van der Meer reports support from the European Research Council (ERC CoG 101045236, DISSECT-HF); the UMCG, which employs Dr van der Meer, received consultancy fees or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis. Dr Petrie reports research funding from Boehringer Ingelheim, Roche, SQ Innovations, Astra Zeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and consultancy or trial committee participation from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. Dr Parkhomenko reports research grants and personal fees from Bayer, Amgen, Astra Zeneca, Boehringer Ingelheim, BMS/Pfizer, and Daiichi-Sankyo. Dr Vinereanu reports research grants and consultancy fees from Boehringer Ingelheim and research grants from Bayer Healthcare, Novartis, and Servier Pharmaceuticals LLC. Dr Zieroth reports research grant support, served on advisory boards for, or had speaker engagements with AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Salubrisbio, Servier, and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis and Pfizer; nonindustry participation includes Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, and Translational Medicine Academy. Dr Jones reports research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and the National Institutes of Health. Drs Seide, Mattheus, Zwiener, Sumin, Gasior, Jamal, and Brueckmann are employees of Boehringer Ingelheim.

Competing Interests: Disclosures None.

Background: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects., Methods: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others., Results: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary ( P interaction =0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia., Conclusions: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02937454., Competing Interests: Disclosures Dr Filippatos has received personal fees from Servier (lecture and registry committee member), Novartis (lecture fees and trial/registry committee member), and Boehringer Ingelheim (lecture and trial committee member). Dr Ponikowski has received research grants and personal fees from Vifor Pharma (principal investigator of AFFIRM-AHF [a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure]; participation in clinical trials); personal fees from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, BMS, and Impulse Dynamics (participation in clinical trials). Dr Farmakis has received speaker honoraria and/or consultation fees from Abbott Laboratories, Bayer, Boehringer Ingelheim, Leo, Novartis, and Orion, outside the submitted work. Dr Anker has received grants from Abbott Vascular and Vifor International; and personal fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bioventrix, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Edwards, Impulse Dynamics, Janssen, Novartis, Occlutech, Respicardia, Servier, Vectorious and V-Wave, all outside the submitted work. Dr Butler has received personal fees from Vifor Pharma, Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and V-Wave Limited (consultant). Drs Fabien and Waechter have received personal fees from Vifor Pharma (Vifor Pharma employee). Dr Macdougall has received personal fees for consulting from Vifor Pharma and GlaxoSmithKline and played a leadership/fiduciary role in the ASCEND trial steering committee for GlaxoSmithKline. Dr Metra has received personal fees from Vifor Pharma (executive committee member), Amgen (executive committee member and national principal investigator), AstraZeneca, Abbott Vascular, Bayer (participation in advisory boards), Servier (participation in advisory boards and speeches at sponsored symposia), Edwards Therapeutics (speeches at sponsored symposia), Actelion (DMC member), LivaNova (executive committee member), and Windtree Therapeutics (executive committee member and advisory board). Dr Ruschitzka reports personal fees from Vifor for his role in the clinical event adjudication committee for Vifor in 2016 during the conduct of the study; he has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation in, and a steering committee member of, clinical trials, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research, educational, and/or travel grants from Abbott, Amgen, AstraZeneca, Bayer, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Daiichi, Diatools AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Labormedizinisches Zentrum, Medtronic, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, V-Wave, Vascular Medical, Vifor, Wissens Plus, and ZOLL. Research and educational grants do not impact Dr Ruschitzka’s personal remuneration. The University Medical Center Groningen, which employs Dr van der Meer, has received research grants and fees from Vifor Pharma (executive committee, speaker); research grants from AstraZeneca, Ionis, Pfizer, Novo Nordisk, and Pharma Nord; and speaker fees from Novartis, Novo Nordisk, Pharmacosmos, BridgeBio and Abbott. Dr Jankowska has received research grants and personal fees from Vifor Pharma (co-principal investigator of the AFFIRM trial); personal fees from Bayer, Novartis, Abbott, Boehringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cardiac Dimensions, Fresenius, and Gedeon Richter. Drs Kirwan and Rosano declare no competing interests.

Background: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure)., Methods: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level., Results: Overall, 3048 participants had baseline ET-1 measurements: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28-4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53-2.50] for T3 and 1.36 [95% CI, 1.06-1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, -3.19 [95% CI, -3.66 to -2.72] mL/min per 1.73 m 2 per y, T2, -2.08 [95% CI, -2.52 to -1.63] and T1 -2.35 [95% CI, -2.79 to -1.91]; P =0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25-0.01; P =0.029)., Conclusions: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03036124., Competing Interests: Disclosures K.F.D. reported that his employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials. He has received speaker honoraria from AstraZeneca and Radcliffe Cardiology, has served on an advisory board for Us2.ai and Bayer AG, served on a clinical end point committee for Bayer AG, and has received research grant support from Boehringer Ingelheim, AstraZeneca, and Novartis (paid to his institution). R.T.C reports speaker honoraria from AstraZeneca and has served on an advisory board for Bayer AG. P.S.J reported his employer being paid by AstraZeneca for his time working on the study and receiving personal fees from, and his employer being paid by, Novartis; grants and personal fees from Boehringer Ingelheim; personal fees from Cytokinetics and Vifor Pharma outside the submitted work; and being the director of Global Clinical Trials Partners Ltd. A.H. is an employee of AstraZeneca. H.J.L.H reports grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial paid to his institution from AstraZeneca; research grants paid to his employer from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk for clinical trials; consulting fees, paid to his employer from Abbvie, Boehringer Ingelheim, Travere Pharmaceuticals, and Novo Nordisk; fees for steering committee membership paid to his employer from Bayer, Chinook, CSL Pharma, Janssen, and Gilead; honoraria for lectures from AstraZeneca and Mitsubishi Tanabe; and has received honoraria for advisory board participation for Merck (paid to his employer), Mitsubishi Tanabe, and Mundipharma. P.J. reports research support from Abbott Laboratories, Amgen, Inc, AstraZeneca, LP, Daiichi-Sankyo, Inc, GlaxoSmithKline, Merck & Co., Inc, Regeneron, Roche Diagnostics Corporation, and Siemens Healthineers. L.K. has received other support from AstraZeneca and personal fees from Novartis and Bristol Myers Squibb as a speaker. M.N.K. reported receiving grants and personal fees from AstraZeneca and Boehringer Ingelheim and personal fees from Sanofi, Amgen, Novo Nordisk, Merck, Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, Amarin, and Eli Lilly outside the submitted work. F.A.M. reported receiving personal fees from AstraZeneca during the conduct of the study. P.P. reported receiving personal fees and fees to his institution for participation as an investigator in clinical trials from AstraZeneca during the conduct of the study and from Boehringer Ingelheim, Servier, Novartis, Berlin-Chemie, Bayer, Renal Guard Solutions, Pfizer, Respicardia, Cardiorentis, and Cibiem; grants, personal fees, and fees to his institution from Impulse Dynamics; and fees to his institution from Vifor, Corvia, and Revamp Medical outside the submitted work. S.D.S. reported receiving grants from AstraZeneca during the conduct of the study and grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya outside the submitted work. M.S., O.B., and P.J.G. are employees and/or shareholders of AstraZeneca. N.S. reports personal fees from Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novo Nordisk, Pfizer, and Sanofi; grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and a grant from Roche Diagnostics, outside the submitted work. P.W. reports grant income from Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, and Novartis; and personal fees from Novo Nordisk outside the submitted work. M.S.S. reported receiving grants and personal fees from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis; personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis; and grants from Daiichi-Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. D.A.M. reports grants to the TIMI Study Group from Abbott Laboratories, Amgen, AnthosTherapeutics, AstraZeneca, BRAHMS, Eisai, GlaxoSmithKline, Medicines Company, Merck, Novartis, Pfizer, Roche Diagnostics, Quark, Siemens, and Takeda, and consultant fees from InCardia, Merck & Co, Novartis, and Roche Diagnostics. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; and personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; personal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, the Corpus, Translation Research Group, and Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. The other authors report no conflicts.

Background: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin., Methods: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction., Results: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly ( P interaction =0.77) with no sex-related differences in secondary outcomes (all P interaction >0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex ( P interaction >0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events., Conclusions: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Background: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction)., Methods: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed., Results: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; P interaction =0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; P interaction =0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score., Conclusions: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03057951.

Background: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline., Methods: Iron deficiency was defined as a ferritin level <100 ng/mL or a transferrin saturation <20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death., Results: Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P <0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron-replete patients (hazard ratio, 0.74 [95% CI, 0.58-0.92] versus 0.81 [95% CI, 0.63-1.03]; P -interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo., Conclusions: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03036124.

Background: In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial., Methods: Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min -1 ·1.73 m -2 were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models., Results: The mean change in eGFR between day 0 and 14 was -1.1 mL·min -1 ·1.73 m -2 (95% CI, -1.5 to -0.7) with placebo and -4.2 mL·min -1 ·1.73 m -2 (95% CI, -4.6 to -3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min -1 ·1.73 m -2 (95% CI, 2.6-3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07-2.69; P <0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59-0.91; P interaction <0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events., Conclusions: The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03036124.

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized)., Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model., Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P =0.03; 4.80 [95% CI, 0.00-9.61], P =0.05; 4.66 [95% CI, 0.32-9.01], P =0.04; 4.85 [95% CI, 0.77-8.92], P =0.02; and 4.40 points [95% CI, 0.33-8.48], P =0.03, respectively)., Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0415775.

Background: Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status., Methods: Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin., Results: The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P <0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score., Conclusions: In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Background: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin., Methods: Anemia was defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization Anemia). Adverse events reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization) and the time-updated hemoglobin relationship to outcomes., Results: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo ( P <0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, adverse event anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (versus placebo) on the primary outcome. In addition, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (versus placebo) on the primary outcome., Conclusions: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534.

Background: Patients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure)., Methods: The total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable Lei-Wei-Yang-Ying model., Results: Of 2371 participants randomly assigned to placebo, 318 experienced 469 hospitalizations for HF; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model, factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. In the Lei-Wei-Yang-Ying model, the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or cardiovascular death was 0.75 (95% CI, 0.65-0.88), P =0.0002. In the joint frailty model, the rate ratio for total HF hospitalizations was 0.71 (95% CI, 0.61-0.82), P <0.0001, whereas, for cardiovascular death, the hazard ratio was 0.81 (95% CI, 0.67-0.98), P =0.0282., Conclusions: Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HF and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Background: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events., Methods: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes., Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P -interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome ( P -interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia., Conclusions: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Background: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization., Methods: Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min -1 ·1.73 m -2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min -1 ·1.73 m -2 ) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time., Results: Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min -1 ·1.73 m -2 . The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59-0.86) versus 0.77 (0.64-0.93) in those with an eGFR ≥60 mL·min -1 ·1.73 m -2 (interaction P =0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44-1.16]; P =0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.40 to -0.77) versus placebo -2.85 (-3.17 to -2.53) mL·min -1 ·1.73 m -2 per year ( P <0.001). This was observed in those with and without type 2 diabetes ( P for interaction=0.92)., Conclusions: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events., Methods: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction ≤40% and elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide), were eligible. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or an urgent HF visit requiring intravenous therapy) or cardiovascular death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to the initiation of new, or the augmentation of existing, oral treatment., Results: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65-0.82]; P <0.0001). Each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat with dapagliflozin to prevent 1 experiencing an episode of fatal or nonfatal worsening was 16. Among the 4744 randomly assigned patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with intravenous therapy in 20 (0.4%), HF hospitalization in 489 (10.3%), and cardiovascular death in 295 (6.2%). The adjusted risk of death from any cause (in comparison with no event) after an outpatient worsening was hazard ratio, 2.67 (95% CI, 2.03-3.52); after an urgent HF visit, the adjusted risk of death was hazard ratio, 3.00 (95% CI, 1.39-6.48); and after a HF hospitalization, the adjusted risk of death was hazard ratio, 6.21 (95% CI, 5.07-7.62)., Conclusion: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03036124.

Background: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ)., Methods: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months., Results: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P <0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P <0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P <0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score)., Conclusions: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

Background: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly., Methods: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min -1 ·1.73 m -2 . The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first., Results: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group., Conclusions: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

Background: Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO 2 ], an objective measure of exercise intolerance in HF, has not been examined., Methods: We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO 2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO 2 . Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO 2 data., Results: A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO 2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO 2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P =0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO 2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P =0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care., Conclusions: Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO 2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO 2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562., (© 2017 The Authors.)

Background: The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome., Methods and Results: We assessed 107 consecutive CHF patients (mean age, 61.9+/-10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0+/-11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2+/-.6.1 versus 0.6+/-0.6 L/min; P<0.0001) and a reduction in muscle mass (51.9+/-10.0 versus 60.3+/-8.8 kg; P<0.001). The ergoreflex was particularly overactive in cachectics (P<0.05), accompanied by marked muscle mass depletion (P<0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak V(O2), V(E)/V(CO2) slope), ejection fraction, and NYHA functional class (P<0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (r=-0.65), leg (r=-0.64), and total (r=-0.61) lean tissues (P<0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak V(O2), and V(E)/V(CO2) slope., Conclusions: Depleted peripheral muscle mass is associated with ergoreflex overactivity and exercise limitation in CHF, particularly in cachectic patients. The systemic activation of the muscle reflex system in CHF may reflect progression and deterioration of the clinical syndrome.

Background: Oscillatory breathing patterns characterized by rises and falls in ventilation with apnea (Cheyne-Stokes respiration [CSR]) or without apnea (periodic breathing [PB]) commonly occur during the daytime in chronic heart failure (CHF). We have prospectively characterized patients with cyclical breathing in terms of clinical characteristics, indices of autonomic control, prognosis, and the role of peripheral chemosensitivity., Methods and Results: To determine cyclical breathing pattern, power spectral analysis was applied to 30-minute recordings of respiration in 74 stable CHF patients. Analyses of heart rate variability and baroreflex sensitivity were used to assess autonomic balance. Peripheral chemosensitivity was assessed with the transient hypoxia method. We also determined whether the suppression of peripheral chemoreceptor activity (hyperoxia or dihydrocodeine) would influence the respiratory pattern. Cyclical respiration was found in 49 (66%) patients (22 [30%] CSR, 27 [36%] PB) and was associated with more advanced CHF symptoms, impaired autonomic balance, and increased chemosensitivity (0.80 and 0.75 versus 0.34 L. min(-1). %SaO(2)(-1), P<0.001, for CSR and PB versus normal breathing, respectively). Transient hyperoxia abolished oscillatory breathing in 7 of 8 patients. Dihydrocodeine administration decreased chemosensitivity by 42% (P=0.05), which correlated with improvement in respiratory pattern. Cyclical breathing predicted poor 2-year survival (relative risk 9.41, P<0.01, by Cox proportional hazards analysis), independent of peak oxygen consumption (P=0.04)., Conclusions: An oscillatory breathing pattern during the daytime is a marker of impaired autonomic regulation and poor outcome. Augmented activity of peripheral chemoreceptors may be involved in the genesis of this respiratory pattern. Modulation of peripheral chemosensitivity can reduce or abolish abnormal respiratory patterns and may be an option in the management of CHF patients with oscillatory breathing.

Background: Respiratory gas exchange measurements in patients with chronic heart failure (CHF) at rest and during exercise commonly reveal prominent slow oscillations in ventilation (V(E)), measured oxygen uptake (VO(2)), and carbon dioxide production (VCO(2)), whose origin is not clear. Voluntary simulation of periodic breathing (PB) in normals has been reported to generate a different pattern of oscillations in gas exchange from that seen in spontaneous PB. This necessitates hypothesizing that PB is caused by a primary oscillation in tissue metabolism or in cardiac output., Methods and Results: We developed an automated method by which normal controls could be guided to breathe according to a PB pattern. The resultant metabolic oscillations closely matched those seen in spontaneous PB and had several interesting properties. At low workloads (including rest), the oscillations in VO(2) were as prominent as those in V(E) in both spontaneous PB (alpha(VO2)/alpha(VE)=0.92+/-0.04) and voluntary PB (0.93+/-0.07). However, at increased workload, the oscillations in VO(2) because less prominent than those in V(E) in spontaneous PB (intermediate workload 0.63+/-0.05, high workload 0.57+/-0.04; P<0.001) and voluntary PB (intermediate 0.66+/-0.03, high 0.48+/-0.03; P<0.001). There was no difference in the relative size of metabolic oscillations between voluntary and spontaneous PB at matched workloads (P>0.05 at low, intermediate, and high workloads). Furthermore, VO(2) peaked before V(E) in both spontaneous and voluntary PB. This time delay varied from 6.4+/-0.4 s at low ventilation, to 11.3+/-0.9 s at high ventilation (P<0.0001)., Conclusions: The magnitude and phase pattern of oscillations in gas exchange of spontaneous PB can be obtained by adequately matched voluntary PB. Therefore, the gas exchange features of PB are explicable by primary ventilatory oscillation.

Background: The precise mechanisms responsible for the sympathetic overactivity and blunted baroreflex control in chronic heart failure (CHF) remain obscure. Augmented peripheral chemosensitivity has recently been demonstrated in CHF. We evaluated the relation between peripheral chemoreflex sensitivity and autonomic activity in patients with CHF., Methods and Results: We studied in 26 stable patients with CHF the peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalations of pure nitrogen), autonomic balance (spectral analysis of heart rate variability [HRV]), and baroreflex sensitivity (bolus phenylephrine method and alpha index). To determine whether transient inactivation of peripheral chemoreceptors might influence autonomic balance, 12 patients underwent a second study during which they breathed 100% O2. Peripheral chemosensitivity correlated inversely with HRV power within the low-frequency band (0.04 to 0.15 Hz) (r=-.52, P=.006) and inversely with baroreflex sensitivity (r=-.60, P=.005). When the patients were divided into two groups according to the chemosensitivity of age-matched normal controls (above and below mean+2 SDs of chemosensitivity of control subjects), those above the normal range revealed more impaired autonomic balance, ie, lower baroreflex sensitivity (1.4 +/- 1.3 versus 5.0 +/- 1.5 ms/mm Hg, P<.0001) and depressed values of low-frequency power (2.5 +/- 1.8 versus 4.1 +/- 0.8 ln ms2, P<.005) compared with those with normal chemosensitivity. Transient hyperoxia did not alter heart rate or systolic pressure but resulted in an increase in HRV and an improvement in baroreflex sensitivity., Conclusions: A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.

Background: The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure., Methods and Results: Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over > or = 6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all P<.0001), cortisol, tumor necrosis factor (TNF)-alpha (both P<.002), and human growth hormone (P<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (P<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (P<.02 versus control subjects). Insulin, cortisol, TNF-alpha, and norepinephrine correlated independently with wasting in CHF (P<.05; multiple regression of these four factors versus percent ideal weight, R2=.50, P<.0001)., Conclusions: Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.