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Background: Optimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF., Objectives: The purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups., Methods: CHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates., Results: The authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment., Conclusions: Across a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death., Competing Interests: Funding Support and Author Disclosures CHAMP-HF was supported by Novartis Pharmaceuticals. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Rao has received salary support by a National Institutes of Health training grant (5T32HL069749-18). Dr Spertus has provided consultative services on patient-reported outcomes and evidence evaluation to Abbott, Alnylam, AstraZeneca, Bayer, Janssen, Bristol Meyers Squibb, Edwards, Terumo, Cytokinetics, and Imbria; holds research grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the American College of Cardiology Foundation, Bristol Meyers Squibb, Cytokinetics, Imbria, and Janssen; owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire; and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Butler is 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, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr DeVore has received research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent Inc, the National Heart, Lung, and Blood Institute, Novartis, and PCORI; he provides consulting services for Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll; and has received nonfinancial support from Abbott for educational activities. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns., Objectives: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk)., Methods: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6])., Results: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m 2 , 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily., Conclusions: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646)., Competing Interests: Funding Support and Author Disclosures The REALIZE-K trial was funded by AstraZeneca. Drs Kosiborod, Cherney, Connelly, Desai, Guimarães, Kuthi, Lala, Madrini, Merkely, Villota, Squire, Testani, Vaclavik, Verma, Wranicz, and Petrie have received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Mr Dahl, Mr Eudicone, and Ms Friberg are employees of, and hold or may hold stock in, AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sacubitril/valsartan is a foundational therapy for patients with heart failure. Although current U.S. Food and Drug Administration labeling does not provide guidance regarding initiation or continuation of sacubitril/valsartan in patients with worsening kidney function, guidelines identify estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 as a contraindication to therapy., Objectives: This study aims to assess the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min/1.73 m 2 ., Methods: The association between a deterioration in eGFR <30 mL/min/1.73 m 2 , efficacy and safety outcomes, and treatment with sacubitril/valsartan vs renin-angiotensin system inhibitor were evaluated using time updated Cox models in a post hoc parallel trial analyses of PARADIGM-HF and PARAGON-HF., Results: Among 8,346 randomized patients in PARADIGM-HF and 4,746 in PARAGON-HF, 691 (8.3%) and 613 (12.9%), respectively, had an eGFR <30 mL/min/1.73 m 2 at least once in follow-up. Patients experiencing such deterioration were at higher risk of the primary outcome in both PARADIGM-HF and PARAGON-HF. However, the incidence of the primary outcome remained lower with sacubitril/valsartan vs renin-angiotensin system inhibitor, regardless of deterioration in kidney function in both PARADIGM-HF (P interaction  = 0.50) and PARAGON-HF (P interaction  = 0.64). Rates of key safety outcomes were higher among patients experiencing eGFR deterioration; however, rates were similar between treatment groups including among those who remained on treatment., Conclusions: Patients experiencing deterioration of kidney function to a value below eGFR 30 mL/min/1.73 m 2 faced high risk of cardiovascular and kidney disease outcomes. Continuation of sacubitril/valsartan was associated with persistent clinical benefit and no incremental safety risk. These data support continuation of sacubitril/valsartan for heart failure treatment even when eGFR declines below this threshold (PARADIGM-HF [Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], NCT01035255; and PARAGON-HF [Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction], NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and PARAGON-HF trials were funded by Novartis. Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Beldhuis has received a grant from the Dutch Heart Foundation. Dr Claggett has received consulting fees from Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr McCausland has received research funding from NIDDK, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; has received consulting fees from GlaxoSmithKline, and Zydus Therapeutics; and has received expert witness fees from Rubin-Anders Scientific. Dr Neuen has received fees for advisory boards, steering committee roles, scientific presentations, and travel support from AstraZeneca, Bayer, Boehringer Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, the Limbic, Medscape, and Janssen, with all honoraria paid to The George Institute for Global Health. Dr Desai has received research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, GlaxoSmithKline, Merck, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, Veristat, and Zydus. Dr Rouleau has received consulting fees from AstraZeneca. Dr Zile has received fees for serving on a steering committee from Abbott and Ironwood Pharma; has received consulting fees from Boston Scientific and MyoKardia; has received grant support and fees for serving on a steering committee from CVRx and Medtronic; has received fees for serving on an eligibility committee from EBR Systems and V-Wave; has received fees for serving on a clinical events committee from Endotronics; and has received fees for serving on a data and safety monitoring board from Merck. Dr Packer has received consulting fees from 89bio, Abbvie, Actavis, Alderlyx, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra. Dr Lefkowitz is an employee of Novartis. Dr McMurray has received grants and his employer paid by AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; has received grants and his employer being paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion and grants from British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has received consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. Dr Vaduganathan has received research grant support, has served on advisory boards, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Pfeffer has reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction., Methods: This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487., Findings: 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%)., Interpretation: Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF., Funding: None., Competing Interests: Declaration of interests PSJ reports speakers fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices, and Roche Diagnostics; and is a director of Global Clinical Trial Partners. PSJ's employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk. BLC has received personal consulting fees from Alnylam, Bristol Myers Squibb (BMS), Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia, and Rocket, and has served on a data safety monitoring board for Novo Nordisk. MV has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. ASD has received institutional research grants (to Brigham and Women's Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer, and personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, and Zydus. CSPL has received research support from NovoNordisk and Roche Diagnostics; consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, BMS, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and non-executive Director of Us2.ai. BP is a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Lexicon, BMS, KBP Biosciences, Sarfez Pharmaceuticals, Pharmaceuticals, SQ Innovation, G3 Pharmaceuticals, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical; and holds stock or stock options in KBP Biosciences, Sarfez Pharmaceuticals, SQ Innovation, Sea Star Medical, Vifor, Prointel, and Brainstorm Medical. He holds US Patent 9931412 on site specific delivery of eplerenone to the myocardium, and US Patent pending 63/045,783 on histone modulating agents for the prevention and treatment of organ failure. MS has served on advisory boards for and has received consultancy fees and honoraria from Novartis, Abbott, Merck, MSD, Vifor, AstraZeneca, Cardurion, Novo Nordisk, Bayer, and Boehringer Ingelheim. SJS has received research grants from the US National Institutes of Health (NIH; U54 HL160273, X01 HL169712, R01 HL140731, and R01 HL149423), the American Heart Association (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BMS, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. AAV's employer received consultancy fees or research support from Adrenomed, Anacardio, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Corteria, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, Roche Diagnostics, and SalubrisBio. FZ reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and being the founder of Cardiovascular Clinical Trialists. SDS has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. JJVM reports payments through the University of Glasgow for work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, and Novartis; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal, British Heart Foundation, NIH/NHLBI, Boehringer Ingelheim, SQ Innovation, and Catalyze Group; personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J B Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; served on a data safety monitoring board for WIRB-Copernicus Group Clinical; and is a director of Global Clinical Trial Partners. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable.", Objectives: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a 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)., Methods: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death., Results: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; P interaction  = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category., Conclusions: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization., Competing Interests: Funding Support and Author Disclosures The DAPA-HF and DELIVER trials were funded by AstraZeneca. Profs McMurray and Jhund are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Butt has received Advisory Board honoraria from Bayer; has received consultant honoraria from Novartis and AstraZeneca; and has received travel grants from AstraZeneca. Dr Jhund’s employer the University of Glasgow has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials; he has received personal fees from Novartis and Cytokinetics, and has received grants from Boehringer Ingelheim. Dr Docherty has received honoraria from AstraZeneca; and has received a research grant to his institution from Boehringer Ingelheim. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Vaduganathan has received research grant support, has served on Advisory Boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Bachus is an employee and shareholder of AstraZeneca. Dr Hernandez has received research support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Novo Nordisk and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, GlaxoSmithKline, Myokardia, Merck, Novartis, Novo Nordisk, and Vifor. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer, and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer’s institution has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside of the submitted work). Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an Advisory Board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; has received personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; has received grants and personal fees from Alnylam and Novartis; and has received personal fees from Amgen outside the submitted work. Dr Køber has received compensation from Novartis for other services; has received compensation from Novo Nordisk for other services; and has received compensation from AstraZeneca for other services. Dr Ponikowski has received compensation from AstraZeneca for consultant services; has received compensation from Boehringer Ingelheim for consultant services; has received compensation from Servier for consultant services; has received compensation from AstraZeneca for other services; has received compensation from Pfizer for other services; has received compensation from Amgen for consultant services; has received compensation from Vifor Pharma for consultant services; has received compensation from Novartis for other services; and has received compensation from Abbott Vascular for other services. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and has received consulting honoraria for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees Abbott, Alkem Metabolics, AstraZeneca, 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; and is a director of Global Clinical Trial Partners Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF)., Objectives: The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race., Methods: PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor ([RASi], enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races., Results: Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; P interaction  = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%)., Conclusions: In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and PARAGON-HF trials were sponsored by Novartis. Dr Lu has received research funding from the Gottfried und Julia Bangerter-Rhyner Foundation, the SICPA Foundation, and the Société Académique Vaudoise. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Packer has received consulting fees from 89bio, AbbVie, Actavis, Alderlyx, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra. Dr Pfeffer has received the following research grant support Lexicon and Novartis, paid to his institution; has served as a consultant to Alexion, Alnylam, Apnimed, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Intellia, National Heart, Lung, and Blood Institute—Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (Master Protocol Committee), Novartis, and Novo Nordisk; and has equity in DalCor. Dr Lewis has received personal fees from Amgen and Dal-Cor. Dr Lam has received grants from Novo Nordisk and Roche Diagnostics; has served as a consultant for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb (BMS), CardioRenal, Cytokinetics, Darma, Echonous, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen, Medscape/WebMD, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, Recor Medical, Roche Diagnostics, Sanofi, and Siemens Healthcare; has served as cofounder and nonexecutive director of Us2.ai outside the submitted work; and has patents pending (PCT/SG2016/050217; method for diagnosis and prognosis of chronic heart failure) and issued (U.S. Patent No. 10 702 247; automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction and prognosis of heart disease). Dr Rouleau has served as a Data Monitoring Committee member; and has received consulting fees from Alexion, Intellia, BMS, AstraZeneca, Bayer, and Novartis. Dr Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Lefkowitz is an employee of Novartis Pharmaceuticals Corporation. Dr Desai has received research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, GlaxoSmithKline, Merck, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, Veristat, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has served as the director of Global Clinical Trial Partners; and his employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk. Dr McMurray has received grants, paid to his employer, from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; grants paid to his employer from Novartis, Amgen, BMS, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion; and grants from British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and PureTech Health. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Pabon has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR)., Objectives: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function., Methods: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death., Results: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m 2 , and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m 2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m 2 , respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m 2 , compared with patients with eGFR ≥60 mL/min/1.73 m 2 . Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death., Conclusions: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels., Competing Interests: Funding Support and Author Disclosures Dr Neuen is supported by an Australian National Health and Medical Research Council Emerging Leader Investigator Grant (grant number 2026621) and a Ramaciotti Foundation Health Investment Grant (grant number 2023HIG69). The funders had no role in the writing of the manuscript or decision to submit for publication. Dr Neuen has received fees for travel support, advisory boards, and scientific presentations from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, the Limbic, Janssen, Medscape, Novo Nordisk, and Travere Therapeutics; and has served on clinical trial committees for studies sponsored by AstraZeneca, Bayer, and CSL Behring. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardior, Cardurion, Corvia, CVRx, Cytokinetics, Intellia, Rocket, and Valo. Dr Beldhuis is supported by the Junior clinical scientist grant by the Dutch Heart Foundation; her employer is supported by an unrestricted medical grant by Novartis. Dr Myhre has served on advisory boards or had speaker engagements with Amarin, AmGen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Novartis, Novo Nordisk, Pharmacosmos, Roche, Sanofi, US2.ai, and Vifor. Dr Desai has received honoraria for consulting or speaking from Abbott, AstraZeneca, Alnylam, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam Pharma, Novartis, Parexel, Regeneron, River2Renal, Roche, scPharmaceuticals, Verily, Veristat, and Zydus; and has received institutional research grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer. Dr Mc Causland has received research funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon, which is paid directly to his institution; and he has received consulting fees from GlaxoSmithKline and Zydus Therapeutics. Dr McGrath has received research funding from Lexicon Pharmaceuticals and has served as a consultant to Alexion. Dr Anand has received consultancy fees from Amgen, ARCA, AstraZeneca, Boehringer Ingelheim, Boston Scientific, LivaNova, Novartis, Rockwell Medical, and Zensun. Dr Zile has received research funding from Novartis; and has served as a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronix, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Pfeffer has received research grant support (via institution) from Lexicon and Novartis; has been a consultant to Alnylam Pharmaceuticals, Apnimed, AstraZeneca, Boehringer Ingelheim, Eli Lilly Alliance, DalCor, Intellia, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, and Novo Nordisk; and holds equity in DalCor. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of Continuing Medical Education, Hikma Pharmaceuticals, Imagica health, Intas Pharma, JB Chemicals and Pharma, Lupin Pharma, Medscape or Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation plays a central role in the genesis and progression of heart failure with preserved ejection fraction (HFpEF). C-reactive protein (CRP) is widely used as means to assess systemic inflammation, and elevated levels of CRP have been associated with poor HF prognosis. Identification of chronic low-grade inflammation in outpatients can be performed measuring high-sensitivity CRP (hsCRP). The clinical characteristics and outcome associations of a pro-inflammatory state among outpatients with HFpEF requires further study., Aims: Using a biomarker subset of TOPCAT-Americas (NCT00094302), we aim to characterize HFpEF patients according to hsCRP levels and study the prognostic associations of hsCRP., Methods: hsCRP was available in a subset of 232 participants. Comparisons were performed between patients with hsCRP <2 mg/L and ≥ 2 mg/L. Cox regression models were used to study the association between hsCRP and the study outcomes., Results: Compared to patients with hsCRP <2 mg/L (n = 89, 38%), those with hsCRP ≥2 mg/L (n = 143, 62%) had more frequent HF hospitalizations prior to randomization, chronic obstructive pulmonary disease, orthopnea, higher body mass index, and worse health-related quality-of-life. A hsCRP level ≥ 2 mg/L was associated with an increased risk of cardiovascular death and HF hospitalizations: hsCRP ≥2 mg/L vs <2 mg/L adjusted HR 2.36, 95%CI 1.27-4.38, P = 0.006. Spironolactone did not influence hsCRP levels from baseline to month 12: gMean ratio = 1.11, 95%CI 0.87-1.42, P = 0.39., Conclusions: A hsCRP ≥2 mg/L identified HFpEF patients with a high risk of HF events and cardiovascular mortality. Spironolactone did not influence hsCRP levels at 12 months., (Copyright © 2024 Elsevier Ireland Ltd. All rights reserved.)

Background: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF., Objectives: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF., Methods: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF., Results: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; P interaction  = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use., Conclusions: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Bart has received research grant support (paid to institution) from AstraZeneca, Cardurion, and Daxor; and has participated in clinical trial committees for studies sponsored by Daxor and Nuwellis. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has received personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Lam has received supported from a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and us2.ai; and has served as cofounder and nonexecutive director of us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the advisory board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol-Myers Squibb, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and has served as a director of Global Clinical Trial Partners. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and us2.ai; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. Dr Vardeny has received research support from AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Cardior. Mr Kulac has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied., Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF., Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status., Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (P interaction  = 0.773) and by the number of CRM conditions (P interaction  = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum., Conclusions: CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures DELIVER was sponsored by AstraZeneca. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal Roche, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk; and is the Director of Global Clinical Trial Partners (GCTP). Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; and has received consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. Dr Lam has received support from a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Hernandez has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic; and has received verily consulting fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis, and NovoNordisk. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy., Objectives: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction., Methods: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death., Results: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; P interaction  = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (P interaction  = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status., Conclusions: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding support and author disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Goyal has received consulting fees from Sensorum Health. Dr Vaduganathan has received research grant support; has served on advisory boards or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, and Intellia, Rocket. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion; and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and has served as cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; 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, AstraZeneca, 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, Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia., Objectives: The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure)., Methods: Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia., Results: Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P < 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (OR: 0.70 [95% CI: 0.60-0.81]; P < 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan., Conclusions: Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255)., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and PARAGON-HF trials were funded by Novartis. Drs McMurray and Adamson are supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217). Dr Docherty has received funding to the University of Glasgow, Glasgow, United Kingdom, from AstraZeneca for DAPA-HF; and has received honoraria for lectures from AstraZeneca and Eli Lilly. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. Dr Desai has received personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Merck, Regeneron, and Relypsa; and has received grants and personal fees from AstraZeneca, Alnylam, and Novartis, outside of the submitted work. Drs Lefkowitz and Rizkala are employees of Novartis. Dr Rouleau has received grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. Dr Swedberg has consulted for Novartis. Dr Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos; and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr Packer has received consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, DalCor, GlaxoSmithKline, KBP Biosciences, Novartis, Pfizer, Theracos; and has received personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, Servier. Dr Curtain has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Although patients with heart failure with preserved ejection fraction (HFpEF) (left ventricular ejection fraction ≥50%) comprise nearly half of those with chronic heart failure, evidence-based treatment options for this population have historically been limited. Recently, however, emerging data from prospective, randomized trials enrolling patients with HFpEF have greatly altered the range of pharmacologic options to modify disease progression in selected patients with HFpEF. In the context of this evolving landscape, clinicians are increasingly in need of practical guidance regarding the best approach to management of this growing population. In this review, the authors build on the recently published heart failure guidelines by integrating contemporary data from recent randomized trials to provide a contemporary framework for diagnosis and evidence-based treatment of patients with HFpEF. Where gaps in knowledge persist, the authors provide "best available" data from post hoc analyses of clinical trials or data from observational studies to guide management until more definitive studies are available., Competing Interests: Funding Support and Author Disclosures Dr Desai has received institutional research grants from AstraZeneca, Abbott, Alnylam, Bayer, and Novartis; has received consulting fees from Abbott, Alnylam, AstraZeneca, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Roche, Regeneron, Veristat, and Verily. Dr Lam has received a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr McMurray has received a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received payments through Glasgow University from work on clinical trials; has received fees for consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). Dr Redfield has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with symptomatic heart failure (HF) and previous heart failure hospitalization (HFH), hemodynamic-guided HF management using a wireless pulmonary artery pressure (PAP) sensor reduces HFH, but it is unclear whether these benefits extend to patients who have not been recently hospitalized but remain at risk because of elevated natriuretic peptides (NPs)., Objectives: This study assessed the efficacy and safety of hemodynamic-guided HF management in patients with elevated NPs but no recent HFH., Methods: In the GUIDE-HF (Hemodynamic-Guided Management of Heart Failure) trial, 1,000 patients with New York Heart Association (NYHA) functional class II to IV HF and either previous HFH or elevated NP levels were randomly assigned to hemodynamic-guided HF management or usual care. The authors evaluated the primary study composite of all-cause mortality and total HF events at 12 months according to treatment assignment and enrollment stratum (HFH vs elevated NPs) by using Cox proportional hazards models., Results: Of 999 evaluable patients, 557 were enrolled on the basis of a previous HFH and 442 on the basis of elevated NPs alone. Those patients enrolled by NP criteria were older and more commonly White persons with lower body mass index, lower NYHA class, less diabetes, more atrial fibrillation, and lower baseline PAP. Event rates were lower among those patients in the NP group for both the full follow-up (40.9 per 100 patient-years vs 82.0 per 100 patient-years) and the pre-COVID-19 analysis (43.6 per 100 patient-years vs 88.0 per 100 patient-years). The effects of hemodynamic monitoring were consistent across enrollment strata for the primary endpoint over the full study duration (interaction P = 0.71) and the pre-COVID-19 analysis (interaction P = 0.58)., Conclusions: Consistent effects of hemodynamic-guided HF management across enrollment strata in GUIDE-HF support consideration of hemodynamic monitoring in the expanded group of patients with chronic HF and elevated NPs without recent HFH. (Hemodynamic-Guided Management of Heart Failure [GUIDE-HF]; NCT03387813)., Competing Interests: Funding Support and Author Disclosures The GUIDE-HF trial was funded by Abbott. Dr Desai has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and is a consultant for Abbott, Alnylam, AstraZeneca, Axon Therapeutics, Avidity, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, Roche, and Verily. Dr Maisel has been a consultant to Abbott. Dr Mehra is a consultant for Abbott, Natera, Paragonix, Moderna, Janssen, Broadview Ventures, Mesoblast, and Baim Institute for Clinical Research; has served on the Clinical Events Committee for GUIDE-HF through the Baim Institute for Clinical Research; and holds stock in NuPulseCV, Leviticus, and FineHeart. Dr Zile has been a consultant for Abbott. Dr Ducharme has been a consultant for Abbott. Dr Paul has been a consultant for Abbott. Dr Sears has received research grants from Medtronic and Zoll; is a consultant for Abbott, Medtronic, and Milestone Pharmaceutical; and has received personal fees from Medtronic and Zoll. Dr Smart has received research grants from Amgen; and is a consultant for Abbott. Mr Henderson is employed by Abbott. Dr Johnson is employed by Abbott. Dr Adamson is employed by Abbott. Dr Costanzo has been a consultant for Abbott. Dr Lindenfeld has received research grants from AstraZeneca, Sensible Medical, and Volumetrix; and is a consultant for Abbott, Alleviant Medical, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: Black people have a higher incidence and prevalence of heart failure (HF) than White people, and once HF has developed, they may have worse outcomes. There is also evidence that the response to several pharmacologic therapies may differ between Black and White patients., Objectives: The authors sought to examine the outcomes and response to treatment with dapagliflozin according to Black or White race in a pooled analysis of 2 trials comparing dapagliflozin to placebo in patients with heart failure with reduced ejection fraction (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure])., Methods: Because most self-identified Black patients were enrolled in the Americas, the comparator group was White patients randomized in the same regions. The primary outcome was the composite of worsening HF or cardiovascular death., Results: Of the 3,526 patients randomized in the Americas, 2,626 (74.5%) identified as White and 381 (10.8%) as Black. The primary outcome occurred at a rate of 16.8 (95% CI: 13.8-20.4) in Black patients compared with 11.6 (95% CI: 10.6-12.7) per 100 person-years in White patients (adjusted HR: 1.27; 95% CI: 1.01-1.59). Compared with placebo, dapagliflozin decreased the risk of the primary endpoint to the same extent in Black (HR: 0.69; 95% CI: 0.47-1.02) and White patients (HR: 0.73 [95% CI: 0.61-0.88]; P interaction  = 0.73). The number of patients needed to treat with dapagliflozin to prevent one event over the median follow-up was 17 in White and 12 in Black patients. The beneficial effects and favorable safety profile of dapagliflozin were consistent across the range of left ventricular ejection fractions in both Black and White patients., Conclusions: The relative benefits of dapagliflozin were consistent in Black and White patients across the range of left ventricular ejection fraction, with greater absolute benefits in Black patients. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DAPA-HF and DELIVER trials were funded by AstraZeneca. Prof McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. Dr Butt has received advisory board honoraria from Bayer. Dr Docherty has received honoraria from AstraZeneca and a research grant to his institution from Boehringer Ingelheim. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside of the submitted work. Dr Fang has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr de Boer’s institution, the UMCG, has received research grants and fees (outside of the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside of the submitted work). Dr Hernandez has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Myokardia, Merck, Novartis, and Vifor. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Køber has received compensation from Novartis, Novo Nordisk, and AstraZeneca for other services. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research and Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Martinez has received personal fees from AstraZeneca. Dr Ponikowski has received compensation from AstraZeneca, Boehringer Ingelheim, Servier, Amgen, and Vifor Pharma for consultant services; and compensation from AstraZeneca, Pfizer, Novartis, and Abbott Vascular for other services. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals; and has done consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. Dr Vardeny has received either personal or institutional research support for DELIVER from AstraZeneca. Dr O’Meara or her institution has received financial support for clinical trials from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis; and has served as a consultant or speaker for Amgen, Boehringer Ingelheim, Novartis, and AstraZeneca. Dr Saraiva has received research grant support from Pfizer, Daichii Sankyo, Sanofi, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Janssen, Amgen, and Novartis; and has received honorarium from Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Amgen. Dr Shah has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, and Relypsa; has had speaker engagements with Novartis and Roche Diagnostics; and has participated on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Jhund's employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials. Dr Jhund has received personal fees from Novartis and Cytokinetics; and has received grants from Boehringer Ingelheim. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr McMurray has received payments through Glasgow University from work on clinical trials; consulting fees and fees for other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP)., (Copyright © 2023. Published by Elsevier Inc.)

Background: Optimizing systolic blood pressure (SBP) in heart failure (HF) with preserved ejection fraction carries a Class I recommendation but with limited evidence. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have antihypertensive effects across cardiovascular disease., Objectives: The authors examined the interplay between SBP and treatment effects of dapagliflozin on SBP and cardiovascular outcomes., Methods: The authors analyzed 6,263 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) participants and related baseline and mean achieved SBP categories (<120, 120-129, 130-139, ≥140 mm Hg) to the primary outcome (cardiovascular death or worsening HF), secondary outcomes, and safety events. They analyzed whether the blood pressure-lowering effects of dapagliflozin accounted for its treatment effects by adjusting for the change in SBP from baseline to 1 month., Results: The average age was 72 ± 10 years and 44% were women. SBP <120 mm Hg was associated with higher HF and mortality events, although amputation and stroke risk increased with higher SBP. Dapagliflozin reduced SBP by 1.8 (95% CI: 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and Kansas City Cardiomyopathy Questionnaire total symptom score was consistent across SBP (interaction P = 0.15 and P = 0.98, respectively). Adverse events between arms were similar across SBP categories. The treatment effect was not accounted for by reducing blood pressure., Conclusions: In DELIVER, risk by SBP was augmented in the lowest and highest categories and varied by endpoint examined. Dapagliflozin modestly decreased SBP compared with placebo. Dapagliflozin was similarly efficacious and safe across the range of baseline SBP. The beneficial effects of dapagliflozin were not accounted for the changes in SBP. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER study was funded by AstraZeneca. Dr Selvaraj was supported by the National Heart, Lung, and Blood Institute (K23HL161348), American Heart Association (#935275), Doris Duke Charitable Foundation (#2020061), and the Institute for Translational Medicine and Therapeutics (Translational Bio-Imaging Center award). Dr Vaduganathan has received research grant support from or served on the advisory board for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; had speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics; and served on the clinical trial committee for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, and Novartis. Dr Fang has received research grant support from the National Institutes of Health; has served as a consultant for Novartis, Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Abbott, Capricor, Windtree, and LabCorp; and has provided support to the American Heart Association, National Institutes of Health, Heart Failure Society of America, and Heart Rhythm Society. Dr Vardeny has received institutional research support for the DELIVER study from AstraZeneca and has received institutional research support from Bayer. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Parxel, Regeneron, Roche, and Verily. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Lam was supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Martinez has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gador, Milestone, Novartis, Pfizer, and St Luke’s University. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hemodynamically-guided management using an implanted pulmonary artery pressure sensor is indicated to reduce heart failure (HF) hospitalizations in patients with New York Heart Association (NYHA) functional class II-III with a prior HF hospitalization or those with elevated natriuretic peptides., Objectives: The authors sought to evaluate the effect of left ventricular ejection fraction (EF) on treatment outcomes in the GUIDE-HF (Hemodynamic-GUIDEd management of Heart Failure) randomized trial., Methods: The GUIDE-HF randomized arm included 1,000 NYHA functional class II-IV patients (with HF hospitalization within the prior 12 months or elevated natriuretic peptides adjusted for EF and body mass index) implanted with a pulmonary artery pressure sensor, randomized 1:1 to a hemodynamically-guided management group (treatment) or a control group (control). The primary endpoint was the composite of HF hospitalizations, urgent HF visits, and all-cause mortality at 12 months. The authors assessed outcomes by EF in guideline-defined subgroups ≤40%, 41%-49%, and ≥50%, within the trial specified pre-COVID-19 period cohort., Results: There were 177 primary events (0.553/patient-year) in the treatment group and 224 events (0.682/patient-year) in the control group (HR: 0.81 [95% CI: 0.66-1.00]; P = 0.049); HF hospitalization was lower in the treatment vs control group (HR: 0.72 [95% CI: 0.57-0.92]; P = 0.0072). Within each EF subgroup, primary endpoint and HF hospitalization rates were lower in the treatment group (HR <1.0 across the EF spectrum). Event rate reduction by EF in the treatment groups was correlated with reduction in pulmonary artery pressures and medication changes., Conclusions: Hemodynamically-guided HF management decreases HF-related endpoints across the EF spectrum in an expanded patient population of patients with HF. (Hemodynamic-GUIDEd Management of Heart Failure [GUIDE-HF]; NCT03387813)., Competing Interests: Funding Support and Author Disclosures Funding was provided by Abbott. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Expanding specialty palliative care within complex health systems involves consideration of patients' unmet needs, clinicians' perceptions of palliative care, and the availability of palliative care resources. Prior to this quality improvement (QI) project, palliative care services in our health system primarily served oncology patients., Intervention: We undertook a prospective strategic planning process that included executive sponsorship and engagement of institutional leaders and clinicians to help define which palliative care services were most needed by the health system., Measures: We interviewed and surveyed a broad range of clinicians including physicians, nurse practitioners, and social workers., Outcomes: The two most prominent themes that emerged from the stakeholder engagement process were clinicians' wish for specialty-aligned interprofessional palliative care teams and for expansion of nononcology palliative care access., Conclusion: Careful needs assessment and stakeholder engagement can result in goal-directed and data-driven expansion of palliative care services within tertiary health care systems., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels., Objectives: The purpose of this study was to assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF., Methods: This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non-atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events., Results: Among the 6,262 included patients (mean: 71.7 years and 3,516 [56%] men), the median baseline concentration of NT-proBNP was 716 (Q1-Q3: 469-1,280) ng/L and 1,399 (Q1-Q3: 962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log 2 NTpro-BNP was 1.53 [95% CI: 1.46-1.62] and Q4 vs Q1: 3.46 [95% CI: 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P value for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles., Conclusions: Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Myhre has consulted for Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; speaker engagements with AstraZeneca, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, and Novartis. Dr Jhund’s employer has been remunerated for his work on the DELIVER and DAPA-HF trials by AstraZeneca; consulting and speaker fees from Novartis, AstraZeneca, and Boehringer Ingelheim; research funding from Boehringer Ingelheim; and remuneration for clinical trial work from NovoNordisk and Bayer. Dr De Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the advisory board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. Dr Martinez has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gador, Milestone, Novartis, Pfizer, and St Lukes University. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer, and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Parxel, Regeneron, Roche, and Verily. Drs Lindholm, Petersson, and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Miao has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction., Methods: We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527., Findings: Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73-0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77-1·00]) and first hospitalisation for heart failure (0·74 [0·67-0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72-0·82]), cardiovascular death (0·87 [0·79-0·95]), first hospitalisation for heart failure (0·72 [0·67-0·78]), and all-cause mortality (0·92 [0·86-0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction., Interpretation: SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting., Funding: None., Competing Interests: Declaration of interests MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; received speaker fees from AstraZeneca, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. KFD's employer has been remunerated by AstraZeneca for clinical trial work. KFD also reports speakers’ fees from AstraZeneca and research funding from Boehringer Ingelheim. KFD, PSJ, and JJVM are funded by a British Heart Foundation Centre of Research Excellence Grant. BLC has received consulting fees from Boehringer Ingelheim. PSJ's employer has been remunerated by AstraZeneca, Bayer, and Novo Nordisk for clinical trial work. PSJ also reports consulting and speakers’ fees from Novartis, AstraZeneca, and Boehringer Ingelheim; and research funding Boehringer Ingelheim. RadB has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. AFH reports research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic, and Verily; and consulting Fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis and NovoNordisk. SEI has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. MNK reports research grant support from AstraZeneca and Boehringer Ingelheim; and consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board, steering committee, or executive committee for Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. FM has received personal fees from AstraZeneca. SJS reports research grants from the US National Institutes of Health, Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. ASD reports institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis; and consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Merck, Novartis, Parel, Regeneron, Roche, and Verily. JJVM has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart Lung and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta., (Copyright © 2022 Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background: Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them., Objectives: The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started., Methods: Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined., Results: At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P < 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P < 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002)., Conclusions: Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and ATMOSPHERE trials were funded by Novartis. All authors (except Drs Curtain, Campbell, and Jackson) or their institutions were paid by Novartis for their participation in one or both of these trials. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and is a consultant and endpoint committee member for Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Takeda, Cardiorentis, and Pharmacosmos. Dr Abraham has received research support from Abbott Vascular; and is a consultant for Abbott Vascular. Dr Desai has received research grant support from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has received consulting fees from Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Lupin Pharma, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr Dickstein has served as a member of the executive steering committee for the ATMOSPHERE trial. Dr Kober has received honoraria from Novartis, Boehringer, Novo, and AstraZeneca. Dr Rouleau has received grants and consulting fees from Novartis; and has received consulting fees from AstraZeneca. Dr Swedberg has received consulting for Novartis. Dr Zile has received research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi-Pasteur, and Theracos; and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr Jhund has received consulting, advisory board, and speaker fees from Novartis; has received advisory board fees from Cytogenetics; and a has received grant from Boehringer Ingelheim. Dr McMurray has received support from British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, DalCor, GlaxoSmithKline, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial., Background: Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes., Methods: A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death., Results: History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan., Conclusions: History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARAGON-HF study was sponsored by Novartis; no additional funding was provided for this analysis. Dr Cikes has received institutional grants or contracts from Novartis, Abbott, and Corvia; payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Novartis, GE Healthcare, Pfizer, Bayer, Boehringer Ingelheim, AstraZeneca, Teva Pharmaceutical Industries, Sanofi, and LivaNova; and participation on advisory boards for Pfizer, Boehringer Ingelheim, Bayer, and Novartis. Dr Planinc has received an educational grant from Boehringer Ingelheim; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Sanofi Aventis, Pfizer, Bayer, Teva Pharmaceuticals, Krka-Farma, Servier-Pharma, Sandoz, Mylan, and AstraZeneca; has received support for attending meetings and/or travel from Pfizer, Bayer, and Abbott; and has participated on advisory boards for Novartis and Boehringer Ingelheim. Dr Claggett has received consulting fees from Amgen, Boehringer Ingelheim, Corvia, Myokardia, and Novartis. Dr Cunningham has received grant support from the United States National Heart Lung and Blood Institute (T32HL094301). Dr Sweitzer has received salary support from Novartis for work as PARAGON-HF national leader, Merck for work as national leader, and the American Heart Association for work as journal editorship; and has received research support from the National Institutes of Health. Dr Shah has received institutional grants from Actelion, AstraZeneca, Corvia, Pfizer, and Novartis; has received royalties or licenses from UpToDate; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapies, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eidos, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr Packer has received consulting fees from Abbvie, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; has received payment for expert testimony from Actavis; and has received support for attending meetings and/or travel from Boehringer Ingelheim. Dr Pfeffer has received institutional research grant support from Novartis for serving on the PARAGON-HF Steering Committee and as Study Chair of PARADISE-MI; has received personal consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, CinCor, Corvidia, DalCor, GlaxoSmithKline, Innovative Science Solutions, Jazz, Lexicon, MyoKardia, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, Pfizer, Pharmascience, Roche, Sanofi, Servier, and Takeda; has received support for attending meetings and/or travel from Novartis, Novo Nordisk, and A+ (third party to AstraZeneca); and has received stock options from DalCor and Peerbridge. Dr Zile has received grants, consulting fees and participation on a data safety monitoring board or advisory board as part of the committees for the PARAGON-HF and PARADIGM trials. Dr Anand has received consulting fees from Novartis, Amgen, ARCA, Boehringer Ingelheim, AstraZeneca, and LivaNova; and has participated on a data safety monitoring board or advisory board for Boston Scientific. Dr Chiang is a Novartis employee receiving wages and stocks from Novartis as part of an annual wage package. Dr Lam has received research grants from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received consulting fees from Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Janssen R & D, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, St Luke, and Us2.ai; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Medscape/WebMD Global, Novartis, Radcliffe, and Roche Diagnostics; has a patent pending PCT/SG2016/050217; has a patent application number 16/216,929; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Boston Scientific, Novartis, Novo Nordisk, and Roche Diagnostics; and has nonexecutive director role and stock or stock options for Us2.ai. Dr Redfield has received steering committee membership for PARAGON-HF without personal compensation. Dr Desai has received institutional research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received personal consulting fees from Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, DalCor Pharma, Lupin Pharma, Lexicon, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr McMurray has received institutional support from Novartis; has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and The Corpus; and has received other institutional funding from Cytokinetics, KBP Biosciences, AstraZeneca, Amgen, Bayer, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Glaxo Smith Kline, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, and Alnylam. Dr Solomon has received an institutional grant from Novartis for conduct of the PARAGON trial; has received institutional grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos; and has received consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information., Background: Through inhibition of neprilysin, Sac/Val may increase BNP concentrations., Methods: In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12., Results: Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P < 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P < 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P < 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%])., Conclusions: In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)., Competing Interests: Funding Support and Author Disclosures The EVALUATE-HF and PROVE-HF studies were funded by Novartis AG. Dr Myhre is supported by research grants from the South-Eastern Norway Regional Health Authority. Dr Januzzi is supported by the Hutter Family Professorship. Dr Myhre has served on advisory boards and is a consultant for AmGen, AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk, and has received honoraria. Dr Prescott is an employee of Novartis Pharmaceuticals. Dr Fang is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, and Capricor; and serves on the Board of Directors for the Heart Failure Society of America. Dr Mitchell is the owner of Cardiovascular Engineering, Inc, and receives grant support from and is a consultant for Novartis, Merck, Bayer, Servier, and U.S. National Institutes of Health (NIH). Dr Ward is an employee of Novartis Pharmaceuticals. Dr Desai has received research support (through Brigham and Women’s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and is a consultant for Abbott, Alnylam, Amgen, AstraZeneca, Biofourmis, Boehringer Ingelheim, Boston Scientific, Cytokinetics, DalCor Pharma, Lexicon, Lupin, Merck, Novartis, Relypsa, Regeneron, and Sun Pharma. Dr Solomon has received support from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, Theracos, and is a consultant for Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda, and Theracos. Dr Januzzi is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, and has received support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; and is a consultant for Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure)., Background: Black patients may respond differently to certain treatments for HFrEF than White patients., Methods: Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death., Results: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients., Conclusions: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)., Competing Interests: Funding Support and Author Disclosures DAPA-HF was funded by AstraZeneca. Dr McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217). Dr Docherty’s employer (University of Glasgow) has been remunerated by AstraZeneca for involvement in the DAPA-HF trial; and he has also received speaker fees from AstraZeneca and Eli Lilly. Dr Ogunniyi has received research grants from AstraZeneca, Boehringer Ingelheim, and Zoll and Advisory Board fees from Pfizer. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. Dr Diez has received personal fees from AstraZeneca. Dr Howlett has received research grants from University Hospital Foundation, Pfizer, and Novartis; consulting fees from AstraZeneca, Bayer, Novartis, Merck, Janssen, Otsuka, Servier, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Akcea, Alnylam, and Pfizer; speaker fees from AstraZeneca, Bayer, Novartis, Merck, Janssen, Servier, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer; and has participated on a Data Safety Monitoring Board or Advisory Board for Novartis, AstraZeneca, and Medtronic. Dr Nicolau has received research grants and personal fees from Vifor Pharma (National Lead Investigator [NLI]/Steering Committee [SC] member for AFFIRM); research grants from AstraZeneca (NLI), Bayer (Principal Investigator [PI] Compass), Esperion and CLS Behring (NLI/SC member), DalCor (NLI), Janssen (NLI/SC member), Novartis (PI, consultant), Novo Nordisk (PI), and Sanofi (NLI, PI, Advisory Board); and personal fees from Amgen (consultant), Bayer, Daiichi-Sankyo (speaker), Novartis, Sanofi, and Servier (speaker, Advisory Board). Dr O’Meara or her institution has received financial support for clinical trials from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis; has served as a consultant or speaker for Amgen, Boehringer Ingelheim, Novartis, and AstraZeneca. Dr Verma has received personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group during the conduct of the study; grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Merck; grants from Bristol Myers Squibb; and personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, and Sanofi. Dr Inzucchi has received personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi/Lexicon, Merck, VTV Therapeutics, and Abbott/Alere; and personal fees from AstraZeneca and Zafgen. Dr Køber has received financial from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. Dr Kosiborod has received personal fees from AstraZeneca and Vifor Pharma; grants, personal fees, and other from AstraZeneca; grants and personal fees from Boehringer Ingelheim; and personal fees from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Janssen, Bayer, Applied Therapeutics, and Eli Lilly. Dr Lindholm is an employee of AstraZeneca. Dr Martinez has received personal fees from AstraZeneca. Dr Bengtsson is an employee of AstraZeneca. Dr Ponikowski has received personal fees and other from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; personal fees from Pfizer, Servier, Respicardia, and Berlin-Chemie; financial support from Amgen; and grants, personal fees, and other from Vifor Pharma. Dr Sabatine has received grants from Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, Dal-Cor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis; 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. Dr Sjöstrand is an employee of AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr Langkilde is an employee of AstraZeneca. Dr Jhund’s employer (University of Glasgow) has been remunerated by AstraZeneca for involvement in the DAPA-HF and DELIVER trials; has received speaker and Advisory Board fees from Novartis; and Advisory Board fees and grants from Boehringer Ingelheim. Dr McMurray’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF, DELIVER, and DETERMINE trials as well as Amgen, Boehringer Ingelheim, Cytokinetics, DalCor, GlaxoSmithKline, Pfizer, Theracos, and Novartis; has received other support from Bayer, Bristol Myers Squibb, Cardurion, KBP Biosciences, Ionis, and Alnylam; has received speaker fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and is director of Global Clinical Trial Partners Ltd., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II-IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation., Methods: The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II-IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT03387813., Findings: Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74-1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (p interaction =0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66-1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80-1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70-1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61-0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications., Interpretation: Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group., Funding: Abbott., Competing Interests: Declaration of interests JL has received research grants from AstraZeneca, Sensible Medical, and Volumetrix and is a consultant for Abbott, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards, Impulse Dynamics, and VWave. ASD has received research grants from Alnylam, AstraZeneca, Bayer, and Novartis, is a consultant for Abbott and Alnylam, AstraZeneca, Amgen, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, DalCor Pharma, Lexicon, Merck, Novartis, Relypsa, and Regeneron, and has received personal fees from Lupin Pharma and Sun Pharma. KB is a consultant for Abbott and has received personal fees from Pfizer and Novartis. DH is a consultant for Abbott, has received personal fees from Abbott, and has served on advisory boards for Abbott. SRK is a consultant for Abbott and CareDx and has received personal fees from Abbott and CareDx. MRM is a consultant for Abbott, Medtronic, Janssen, Portola, Bayer, Triple Gene, and Baim Institute for Clinical Research, has served on advisory boards for Abbott and Mesoblast, has served on the Clinical Events Committee for GUIDE-HF through the Baim Institute for Clinical Research, and has stock in NuPulseCV, Leviticus, and FineHeart. SFS has received research grants from Medtronic and Zoll, is a consultant for Abbott, Medtronic, and Milestone Pharmaceuticals, and has received personal fees from Medtronic and Zoll. AJS is a consultant for Abbott and has received personal fees from Abbott. FS has received research grants from Amgen and is a consultant for Abbott. MRZ, AD, AM, SP, and MRC are consultants for Abbott. NJ, PS, GG, JH, and PBA are employees of Abbott. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: This study sought to evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF)., Background: Episodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain., Methods: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality., Results: Of 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040)., Conclusions: Like HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARAGON-HF trial was sponsored by Novartis. Dr. Vaduganathan has been supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Award UL 1TR002541); has received research grant support and/or serves on advisory boards for American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa; and has participated on clinical endpoint committees for studies sponsored by Galmed, Novartis (including the PARAGON-HF trial), and NIH. Dr. Cunningham has been supported by National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant (T32HL094301). Dr. Claggett has received consultancy fees from Amgen, Boehringer Ingelheim, Gilead, Novartis, AOBiome, and Corvia. Dr. Barkoudah has received research support from Bristol-Myers Squibb, Janssen, NIH, and payments made to Brigham and Women's Hospital for performing clinical endpoints adjudication and Advisory Board fees from Bristol-Myers Squibb, Janssen, Novartis, Pfizer, and Portola, and travel expenses from Alexion. Dr. Zannad has been supported by French National Research Agency Fighting Heart Failure grant ANR-15-RHU-0004, by the French PIA project “Lorraine Université d’Excellence” Functional Genomic, Epigenomic and ENvironment interplay to IMPACT the Understanding, diagnosis and management of healthy and pathological AGEing grant ANR-15-IDEX-04-LUE programmes, the Contrat de Plan Etat Région Lorraine, and the FEDER IT2MP; has received steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, Novartis, Janssen, Cellprothera and CVRx; advisory board personal fees from AstraZeneca, Vifor Fresenius, Cardior, Cereno pharmaceutical, Corvidia, Merck, Myokardia, NovoNordisk and Owkin; stock options at Cereno and G3Pharmaceutical; and is the founder of the Global Cardiovascular Clinical Trialist Forum. Dr. Pfeffer has received consulting fees from Amgen, AstraZeneca, Bayer, DalCor Pharma UK, Genzyme, Lilly, the Medicines Company, MedImmune, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Salix, Sanderling, Sanofi, Takeda, Teva, Thrasos, and Vericel; and has received research grant support from Amgen, Celladon, Novartis, and Sanofi. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin–angiotensin system in selected survivors of myocardial infarction with Novartis Pharmaceuticals on which Dr. Pfeffer is a co-inventor. His share of the licensing agreement is irrevocably transferred to charity. Drs. Rizkala and Sabarwal have been employees of Novartis. Dr. Rizkala owns shares in Novartis. Dr. McMurray has received payments from his employer, Glasgow University, for work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, KBP Biosciences, Novartis, Pfizer, and Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. Dr. Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos; and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, GlaxoSmithKline, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr. Desai has received research grant support from AstraZeneca, Alnylam, Bayer, and Novartis; and consulting fees and honoraria from Abbott, AstraZeneca, Alnylam, Boehringer Ingelheim, Boston Scientific, Biofourmis, Cytokinetics, DalCor Pharma, Merck, Novartis, Relypsa, and Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes., Objectives: The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations., Methods: From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls., Results: The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001)., Conclusions: Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)., Competing Interests: Author Disclosures The PROVE-HF Study was funded by Novartis Pharmaceuticals, Inc. Dr. Ibrahim is supported in part by the Dennis and Marilyn Barry Research Fund in Cardiology; and has received honoraria from Novartis and Roche Diagnostics. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; and has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Rocket Pharma, and SC Pharma. Dr. Claggett has received consulting income from Amgen, Boehringer Ingelheim, Corvia, Myokardia, and Novartis. Dr. Desai has received research funding to his institution from AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Amgen, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Merck, Novartis, Relypsa, and Regeneron. Dr. Solomon has received research 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 has consulted for 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. Drs. Prescott and Williamson are employees of Novartis Pharmaceuticals. Dr. Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from Applied Therapeutics, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial., Background: There are limited longitudinal data for depressive symptoms in patients with HFpEF., Methods: In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events., Results: At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014)., Conclusions: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)., Competing Interests: Author Disclosures The TOPCAT trial was funded by the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD (N01 HC45207). No additional funding was received to conduct this study. Dr. Chandra was supported by the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant (5T32HL094301-09). Dr. Desai received research grants from Novartis, Alnylam, AstraZeneca; has received consulting fees from Novartis, Alnylam, AstraZeneca, Abbott, Amgen, Relypsa, Biofourmis, Boston Scientific, Boehringer-Ingelheim, Corvidia, Merck, Novartis, Relypsa, Regeneron, and DalCor Pharma; and research grants from Novartis. Dr. Fang has served on steering committees for Novartis, Amgen, AstraZeneca, and J & J. Dr. Pitt has received consulting fees from Amorcyte, AstraZeneca, Aurasense, Bayer, BG Medicine, Gambro, Johnson & Johnson, Mesoblast, Novartis, Pfizer, Relypsa, and Takeda; research grant support from Forest Laboratories; holds stock in Aurasense, Relypsa, BG Medicine, and Aurasense; and has a pending patent related to site-specific delivery of eplerenone to the myocardium. Dr. Solomon has received research 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/NHLBI, Novartis, Sanofi Pasteur, Theracos, and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Dinaqor, Tremeau. Dr. Pfeffer has received research support from Novartis; serves as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Lewis has received funding from Novartis (research support), Merck, and Dal-Cor (consulting agreement). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial., Background: Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown., Methods: DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group., Results: A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan., Conclusions: Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause., Background: SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF)., Methods: Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis., Results: At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers)., Conclusions: Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF)., Background: MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain., Methods: The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization., Results: At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI., Conclusions: Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The authors examined efficacy and safety of spironolactone by age in the Americas region (N = 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial., Background: Heart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics., Methods: TOPCAT enrolled patients with heart failure and a left ventricular ejection fraction ≥45% who were age 50 or older with an estimated glomerular filtration rate ≥30 mL/min/1.73 m 2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories (<65, 65 to 74, and ≥75 years)., Results: The mean age was 72 ± 10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants ≥75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction = 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p < 0.001), particularly in older age groups (p interaction = 0.02). Findings in the whole TOPCAT cohort were consistent with results from the Americas region., Conclusions: In this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Published by Elsevier Inc.)

Objectives: This study sought to investigate the relationship between malnutrition and adverse cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF)., Background: Malnutrition is associated with poor prognosis in a wide range of illnesses, however, the prognostic impact of malnutrition in HFpEF patients is not well known., Methods: Baseline malnutrition risk was determined in 1,677 patients with HFpEF enrolled in the Americas regions of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial, according to 3 categories of the geriatric nutritional risk index (GNRI) as previously validated: moderate to severe, GNRI of <92; low, GNRI of 92 to <98; and absence of risk, GNRI of ≥98. The relationships between malnutrition risk and the primary composite outcome of CV events (CV death, heart failure hospitalization, or resuscitated sudden death) and all-cause death were examined., Results: Approximately one-third of patients were at risk for malnutrition (moderate to severe: 11%; low: 25%; and absence of risk: 64%). Over a median of 2.9-years' follow-up, compared to those with absent risk for malnutrition, moderate to severe risk was associated with significantly increased risk for the primary outcome, CV death and all-cause death (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.02 to 1.76; HR: 2.06; 95% CI: 1.40 to 3.03; and HR: 1.79; 95% CI: 1.33 to 2.42, respectively) after multivariate adjustment for age, sex, history of CV diseases, and laboratory biomarkers., Conclusions: Patients with HFpEF are at an elevated risk for malnutrition, which was associated with an increased risk for CV events in this population., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF)., Background: Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown., Methods: Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses., Results: Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro-B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses., Conclusions: These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study examined the relationship between income inequality and heart failure outcomes., Background: The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes., Methods: This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density., Results: Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively., Conclusions: Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF)., Background: Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease., Methods: This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms., Results: The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function., Conclusions: Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed the relationship between atrial fibrillation (AF) and outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, to evaluate whether AF modified the treatment response to spironolactone and whether spironolactone influenced post-randomization AF., Background: AF is common in heart failure with preserved ejection fraction (HFpEF) and likely contributes to increased risk of adverse outcomes., Methods: A total 1,765 patients enrolled in TOPCAT trial in North and South America were divided into 3 groups: no known AF, history of AF without AF at enrollment, and AF found on the electrocardiogram (ECG) at enrollment. We assessed outcomes and treatment response to spironolactone in all groups, and the association between post-randomization AF and outcomes in patients free of AF at baseline. The primary outcome of the TOPCAT trial was a composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization., Results: A total of 760 patients (43%) had a history of AF (18%) or AF on ECG at enrollment (25%). The highest adjusted risk was associated with AF at enrollment (primary outcome, hazard ratio: 1.34; 95% confidence interval: 1.09 to 1.65; p = 0.006; and an increased early risk of secondary outcomes). Neither history of AF nor AF at enrollment modified the beneficial treatment effect of spironolactone. Post-randomization AF, which occurred in 6.3% of patients, was not influenced by spironolactone treatment, but was associated with an increased early risk of the primary outcome (hazard ratio: 2.32; 95% confidence interval: 1.59 to 3.40; p < 0.0001) and secondary outcomes., Conclusions: AF at enrollment was associated with increased cardiovascular risk in HFpEF patients in the TOPCAT study. Post-randomization AF, which was associated with an increased risk of morbidity and mortality, was not influenced by spironolactone. (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the rates and predictors of SD or aborted cardiac arrest (ACA) in HFpEF., Background: Sudden death (SD) may be an important mode of death in heart failure with preserved ejection fraction (HFpEF)., Methods: We studied 1,767 patients with HFpEF (EF ≥45%) enrolled in the Americas region of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. We identified independent predictors of composite SD/ACA with stepwise backward selection using competing risks regression analysis that accounted for nonsudden causes of death., Results: During a median 3.0-year (25th to 75th percentile: 1.9 to 4.4 years) follow-up, 77 patients experienced SD/ACA, and 312 experienced non-SD/ACA. Corresponding incidence rates were 1.4 events/100 patient-years (25th to 75th percentile: 1.1 to 1.8 events/100 patient-years) and 5.8 events/100 patient-years (25th to 75th percentile: 5.1 to 6.4 events/100 patient-years). SD/ACA was numerically lower but not statistically reduced in those randomized to spironolactone: 1.2 events/100 patient-years (25th to 75th percentile: 0.9 to 1.7 events/100 patient-years) versus 1.6 events/100 patient-years (25th to 75th percentile: 1.2 to 2.2 events/100 patient-years); the subdistributional hazard ratio was 0.74 (95% confidence interval: 0.47 to 1.16; p = 0.19). After accounting for competing risks of non-SD/ACA, male sex and insulin-treated diabetes mellitus were independently predictive of composite SD/ACA (C-statistic = 0.65). Covariates, including eligibility criteria, age, ejection fraction, coronary artery disease, left bundle branch block, and baseline therapies, were not independently associated with SD/ACA. Sex and diabetes mellitus status remained independent predictors in sensitivity analyses, excluding patients with implantable cardioverter-defibrillators and when predicting SD alone., Conclusions: SD accounted for ∼20% of deaths in HFpEF. Male sex and insulin-treated diabetes mellitus identified patients at higher risk for SD/ACA with modest discrimination. These data might guide future SD preventative efforts in HFpEF. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]); NCT00094302., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)