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Background: Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.Methods: In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Results: Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61 [0.47-0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40-1.13] versus 0.70 [0.52-0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41-0.98] versus 0.70 [0.51-0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Conclusions: Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150. [ABSTRACT FROM AUTHOR]

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

Yet, low doses of drugs for HFrEF yield important benefits to reduce morbidity and mortality, and target doses are often only modestly more effective than low starting doses in reducing the risk of cardiovascular death. 5 Fifth, and importantly, because much of the benefits of foundational treatments are seen within 30 days of initiating treatment, the algorithm should achieve therapy with all 4 classes of drugs within 4 weeks. If physicians prioritize the achievement of target doses of each drug class before initiating treatment with the next, it may take >=6 months to prescribe all recommended treatments. [Extracted from the article]

The article discusses the cardiovascular outcomes of sodium glucose-cotransporter-2 inhibitors (SGLT-2i). SGLT-2i inhibit glucose uptake in the proximal renal tubule which lead to increased glycosuria and in turn a decrease in blood glucose. It was noted that in both EMPA-REG OUTCOME and the CANVAS Program, SGLT-2i resulted in reduction in the 3-component major adverse cardiovascular event outcome.

Background--Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results--We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B- type natriuretic peptide and troponin) versus enalapril. Conclusions--Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. [ABSTRACT FROM AUTHOR]

Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08-3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42-0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings. Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. [ABSTRACT FROM AUTHOR]

The author reflects on disease management programs in cardiology. It explores the paper by Stewart and colleagues published in the issue of the periodical "Circulation," in which the researchers summarized the results of three trials on value of nurse-led, multidisciplinary, home-based intervention in cardiovascular diseases. The author discusses the role of guidelines to the implementation of disease management programs.

Background: Many studies have explored whether individual plasma protein biomarkers improve cardiovascular disease risk prediction. We sought to investigate the use of a plasma proteomics-based approach in predicting different cardiovascular outcomes., Methods: Among 51 859 UK Biobank participants (mean age, 56.7 years; 45.5% male) without cardiovascular disease and with proteomics measurements, we examined the primary composite outcome of fatal and nonfatal coronary heart disease, stroke, or heart failure (major adverse cardiovascular events), as well as additional secondary cardiovascular outcomes. An exposome-wide association study was conducted using relative protein concentrations, adjusted for a range of classic, demographic, and lifestyle risk factors. A prediction model using only age, sex, and protein markers (protein model) was developed using a least absolute shrinkage and selection operator-regularized approach (derivation: 80% of cohort) and validated using split-sample testing (20% of cohort). Their performance was assessed by comparing calibration, net reclassification index, and c statistic with the PREVENT (Predicting Risk of CVD Events) risk score., Results: Over a median 13.6 years of follow-up, 4857 participants experienced first major adverse cardiovascular events. After adjustment, the proteins most strongly associated with major adverse cardiovascular events included NT-proBNP (N-terminal pro B-type natriuretic peptide; hazard ratio [HR], 1.68 per SD increase), proADM (pro-adrenomedullin; HR, 1.60), GDF-15 (growth differentiation factor-15; HR, 1.47), WFDC2 (WAP four-disulfide core domain protein 2; HR, 1.46), and IGFBP4 (insulin-like growth factor-binding protein 4; HR, 1.41). In total, 222 separate proteins were predictors of all outcomes of interest in the protein model, and 86 were selected for the primary outcome specifically. In the validation cohort, compared with the PREVENT risk factor model, the protein model improved calibration, net reclassification (net reclassification index +0.09), and c statistic for major adverse cardiovascular events (+0.051). The protein model also improved the prediction of other outcomes, including ASCVD ( c statistic +0.035), myocardial infarction (+0.023), stroke (+0.024), aortic stenosis (+0.015), heart failure (+0.060), abdominal aortic aneurysm (+0.024), and dementia (+0.068)., Conclusions: Measurement of targeted protein biomarkers produced superior prediction of aggregated and disaggregated cardiovascular events. This study represents an important proof of concept for the application of targeted proteomics in predicting a range of cardiovascular outcomes.

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. The sodium glucose-co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known., Methods: FINEARTS-HF was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction (LVEF) ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity based on baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during trial use of SGLT2i in time-varying analyses., Results: Among 6,001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6-years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio 0.83; 95% confidence interval 0.60 to 1.16) and without an SGLT2i at baseline (rate ratio 0.85; 95% confidence interval 0.74 to 0.98); P interaction =0.76. In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% vs. 20.1%; hazard ratio 0.86; confidence interval 0.76 to 0.97). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary endpoint., Conclusions: The treatment benefits of the non-steroidal MRA finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a non-steroidal MRA may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction.

Background: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction)., Methods: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events., Results: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype., Conclusions: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711., Competing Interests: Dr Jhund reports receiving grant support from Boehringer Ingelheim and fees for serving on an advisory board from Cytokinetics. Dr Anand reports receiving fees for serving on a steering committee from AstraZeneca, ARCA biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end-point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. Dr Claggett received consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia Medical, Gilead Sciences, and MyoKardia. Dr Desai received consulting fees from Abbott, Boehringer Ingelheim, DalCor Pharmaceuticals, and Regeneron; grant support, paid to Brigham and Women’s Hospital, consulting fees, and fees for serving on an advisory board from Alnylam Pharmaceuticals and AstraZeneca; consulting fees and fees for serving on a steering committee from Biofourmis; consulting fees and fees for serving on a data and safety monitoring committee from Boston Scientific; fees for serving on an advisory board from Corvidia; and fees for serving on an advisory board and consulting fees from Relypsa. Drs Chiang, Gong, and Lefkowitz are employed by Novartis Pharmaceuticals. Dr Lam received grant support and fees for serving on an advisory board from Boston Scientific and Roche Diagnostics; grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer; grant support from Medtronics; grant support and fees for serving on a steering committee from Vifor Pharma; fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis; fees for serving on an advisory board from Amgen, Boehringer Ingelheim, and Abbott Diagnostics; consulting fees from Merck and Stealth BioTherapeutics; fees for serving on a steering committee from Janssen Research and Development; lecture fees and consulting fees from Menarini; and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure. Dr Maggioni received fees for serving on a study committee from Bayer and Fresenius. Dr Packer received consulting fees from AbbVie, Akcea Therapeutics, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead Sciences, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance Biopharma. Dr Rouleau received consulting fees from AstraZeneca. Dr van Veldhuisen received fees for serving on a steering committee and travel support from ARCA Biopharma and Corvia Medical. Dr Zannad received fees for serving on a steering committee from Janssen, Bayer, Boston Scientific, CVRx, and Boehringer Ingelheim; consulting fees from Amgen, Vifor Pharma–Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck; and consulting fees and fees for serving on a steering committee from AstraZeneca and serving as founder of cardiorenal and CVCT. Dr Zile received fees for serving on a steering committee from Abbott and Ironwood Pharma; consulting fees from Boston Scientific and MyoKardia; grant support and fees for serving on a steering committee from CVRx and Medtronic; fees for serving on an eligibility committee from EBR Systems and V-Wave; fees for serving on a clinical-events committee from Endotronics; and fees for serving on a data and safety monitoring board from Merck. Dr Solomon received grant support, paid to Brigham and Women’s Hospital, and consulting fees from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics; grant support, paid to Brigham and Women’s Hospital, from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; and fees for serving on a data and safety monitoring board from Janssen. Dr McMurray reports that his employer, Glasgow University, has been paid by Novartis for serving as an executive committee member and coprincipal investigator of ATMOSPHERE, PARADIGM-HF, and PARAGON-HF trials and executive/steering committee member of the PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan) and for meetings/presentations related to these trials, aliskiren, and sacubitril-valsartan. Novartis has also paid for his travel and accommodation for some of these meetings. Glasgow University has also been paid by Novartis for advisory board; by Bayer for serving as a steering committee member of the PANACHE trial using neladenoson bialanate (BAY 1067197); by Cardiorentis for serving as a steering committee member and end-point committee chair for the TRUE-AHF trial and attending meetings related to this trial; by Cardiorentis for travel and accommodation to attend some of these meetings; by Amgen for serving as steering committee member for the ATOMIC-HF and COSMIC-HF trials and attending meetings related to this trial; by Amgen for travel and accommodation for some of these meetings; by Oxford University (which received a grant from Bayer, which manufactures acarbose) for serving as a steering committee member for the ACE trial (using acarbose) and attending meetings related to this trial; by Theracos for serving as principal investigator for the BEST trial and attending meetings related to this trial; by Theracos for travel and accommodation to attend some of these meetings; by Abbvie (which manufactures atrasentan) for serving as steering committee member for the SONAR trial (using atrasentan) and to attend meetings related to this trial; by Abbvie for his travel and accommodation to attend some of these meetings; by DalCor Pharmaceuticals for serving as steering committee member for the Dal-GenE trial and to attend meetings related to this trial; by Pfizer for serving on the data safety monitoring committee for the SPIRE trial and to attend meetings related to this trial; by Merck for serving on the data safety monitoring committee for the MK-3102 program, for the VICTORIA trial, and to attend meetings related to these trials; by AstraZeneca (which markets dapagliflozin) for serving as principal investigator of DAPA-HF and coprincipal investigator of DELIVER (trials using dapagliflozin on heart failure) and to attend meetings related trial; by AstraZeneca for his travel and accommodation to attend meetings; by GSK for serving as coprincipal investigator and steering committee member for the Harmony-Outcomes trial (albiglutide) and the trials ASCEND-D and ASCEND-ND, using daprodustat, respectively, and to attend meetings related to these trials; by GSK for his travel and accommodation to attend some of the meetings; by BMS for serving as a steering committee member for the STAND-UP clinical trial (using an HNO donor) on heart failure and to attend meetings related to this trial; and by Kings College Hospital (which has received a grant from KRUK and Vifor-Fresenius, which manufactures intravenous iron) for serving as steering committee member for the PIVOTAL trial (using intravenous iron) and for running the end-point adjudication committee for this trial, to attend meetings related to PIVOTAL, and for his travel and accommodation for to attend some of the meetings. All payments were made through consultancies with Glasgow University, and Dr McMurray has not received any personal payments in relation to the trials or drugs. The other authors report no conflicts. The study supporters 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; or decision to submit the manuscript for publication.

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity., Methods: The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment., Results: Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P =0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P =0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, -6.5, 13.0; P =0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P =0.079) and 3.1 (-0.1, 5.4; P =0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, -5.9, 9.0; P =0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P =0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P =0.036) for KCCQ-PLS, and 2.5 meters (-3.5, 8.4; P =0.50) for 6MWD., Conclusions: Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224., Competing Interests: Disclosures Dr McMurray has received payments through Glasgow University for work on clinical trials; consulting fees and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees from Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, and Servier; and has served as director of Global Clinical Trial Partners. Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trials; he has received speaker honoraria from AstraZeneca and Radcliffe Cardiology, has served on an advisory board for Us2.ai and Bayer AG, has served on a clinical end point committee for Bayer AG, and has received grant support from Boehringer Ingelheim, Roche Diagnostics, and AstraZeneca (paid to his institution). Dr De Boer has received research grants 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 Hammarstedt, Langkilde, Reicher, and Wilderäng are employees of AstraZeneca. Dr Kitzman reports receiving honoraria as a consultant for AbbVie, Bayer, Merck, Medtronic, Relypsa, Corvia Medical, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, and Novartis; grant funding from Novartis, Bayer, and AstraZeneca; and stock ownership in Gilead Sciences. 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 Senni reports consultancy fees from Novartis, Merck, Vifor Pharma, Abbott, Boehringer Ingelheim, Bioventrix, Servier, and Novo Nordisk. 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, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Verma holds a tier 1 Canada research chair in cardiovascular surgery and reports receiving research grants or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Otsuka, Pfizer, PhaseBio, S & L Solutions Event Management Inc, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and he is president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. 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; 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, Sarepta, Lexicon, Anacardio, and Akros.

Background: Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH., Methods: DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category., Results: Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories ( P interaction =0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time., Conclusions: aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213., Competing Interests: Disclosures 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 participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Selvaraj was supported by the National Heart, Lung, and Blood Institute (grant K23HL161348), American Heart Association (grant 935275), Doris Duke Charitable Foundation (grant 2020061), Mandel Foundation, and Duke Heart Center. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr de Boer has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche, and had speaker engagements with Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Hernandez 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 Novo Nordisk. Dr Desai reports institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and 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 reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc; and is director of Global Clinical Trial Partners. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. 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 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. 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, or 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 cofounder and non–executive director of Us2.ai. Drs Langkilde, Lindholm, and Petersson are employees of AstraZeneca. Dr Martinez has received personal fees from AstraZeneca. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer AG, Cardurion, Cytokinetics, Novartis, and Pfizer; and has received consulting fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen, as well as speaker fees from AstraZeneca, Bayer AG, and Boehringer Ingelheim. Dr Shah reports research grants from the National Institutes of Health (grants U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), 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. 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/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, 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. The other authors report no disclosures.

Background: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes., Methods: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models., Results: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal ("supranormal") LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion., Conclusions: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, and NCT01920711., Competing Interests: Disclosures T.K. received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, and Abiomed. I.S.A. reports receiving fees for serving on a steering committee from AstraZeneca, ARCA Biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. A.S.D. 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. M.P. reports 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. M.R.Z. reports research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. M.A.P. reports research grant support through Brigham and Women’s Hospital from Novartis; reports consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. S.D.S. 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, 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. W.T.A. has received personal fees from Abbott; has received consulting fees from Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and Respicardia; has received salary support from V-Wave Medical; and has received research support from the National Heart, Lung, and Blood Institute, all for studies performed within the heart failure arena. S.J.S. has received either personal or institutional research support from AstraZeneca. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.AI; and serves as cofounder and nonexecutive director of Us2.AI. P.S.J. reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc. P.S.J.’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. P.S.J. is a director of Global Clinical Trial Partners Ltd. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; and personal consultancy fees from Alnylam Pharma., Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation. J.J.V.M. receives 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 Continued Medical Education, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, JB Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. The other author reports no conflicts.

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

Background: How patient characteristics and outcomes vary according to the duration of heart failure (HF) is unknown in individuals with mildly reduced or preserved ejection fraction. We compared these, and the efficacy and safety of dapagliflozin, according to the time from diagnosis of HF in a prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure)., Methods: HF duration was categorized as ≤6 months, >6 to 12 months, >1 to 2 years, >2 to 5 years, or >5 years. The primary outcome was the composite of worsening HF or cardiovascular death. The effect of treatment was examined by HF duration category., Results: The number of patients in each category was as follows: 1160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1569 (>2 to 5 years), and 1692 (>5 years). Patients with longer-duration HF were older and had more comorbidities with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: ≤6 months, 7.3 (95% CI, 6.3 to 8.4); >6 to 12 months, 7.1 (6.0 to 8.5); >1 to 2 years, 8.4 (7.2 to 9.7); >2 to 5 years, 8.9 (7.9 to 9.9); and >5 years, 10.6 (9.5 to 11.7). Similar trends were seen for other outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI, 0.50 to 0.91); >6 to 12 months, 0.78 (0.55 to 1.12); >1 to 2 years, 0.81 (0.60 to 1.09); >2 to 5 years, 0.97 (0.77 to 1.22); and >5 years, 0.78 (0.64 to 0.96; P interaction =0.41). The absolute benefit was greatest in longest-duration HF; the number needed to treat for HF >5 years was 24 versus 32 for ≤6 months., Conclusions: Patients with longer-duration HF were older, had more comorbidities and symptoms, and had higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. Even patients with long-standing HF and generally mild symptoms are not stable, and it is not too late for such patients to benefit from a sodium-glucose cotransporter 2 inhibitor., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03619213.

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

Background: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI., Methods: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization., Results: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P =0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different., Conclusions: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02924727.

Background: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure)., Methods: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death., Results: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P <0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively ( P interaction =0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; P interaction =0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class., Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03619213.

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

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