Search

Aim: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT‐proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC‐HF). Methods and results: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT‐proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT‐proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1–Q3) NT‐proBNP level was 1675 (812–3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80–1.09), > median 0.81 (0.73–0.90) (p‐interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90–1.15) and > median 0.88 (0.80–0.96) (p‐interaction = 0.035). There was an interaction between treatment and NT‐proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT‐proBNP (p‐interaction = 0.086). Conclusions: In GALACTIC‐HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT‐proBNP levels, especially in patients without AF/AFL. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016‐002299‐28. [ABSTRACT FROM AUTHOR]

Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor–neprilysin inhibitor, a beta‐blocker, a mineralocorticoid receptor antagonist and a sodium–glucose co‐transporter 2 (SGLT2) inhibitor. However, the conventional approach to the implementation is based on a historically‐driven sequence that is not strongly evidence‐based, typically requires ≥6 months, and frequently leads to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2–4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease‐of‐use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over up‐titration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated three‐step approach, which consists of the simultaneous initiation of a beta‐blocker and an SGLT2 inhibitor, followed 1–2 weeks later by the initiation of sacubitril/valsartan, and 1–2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be re‐ordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence‐based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Sotagliflozin is a dual inhibitor of sodium-glucose co-transporter (SGLT) 1 and 2, although it is approximately 20-fold more selective for SGLT2.1 SGLT1 contributes to glucose reabsorption in the gastrointestinal tract, whereas SGLT2 has this function in the proximal renal tubule.2 The effects of sotagliflozin in heart failure were recently studied in the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure trial (SOLOIST-WHF).3 SOLOIST-WHF had a complex history including withdrawal of the major sponsor, a resulting shortfall in funding and the impact of the novel coronavirus disease pandemic. Concerns have been raised about administration of SGLT2 inhibitors in hospitalized patients and the risk of diabetic ketoacidosis.11,12 Despite all patients in SOLOIST-WHF having type 2 diabetes, in the safety analysis only 2 of 605 patients in the sotagliflozin group experienced diabetic ketoacidosis compared with 4 of 611 patients in the placebo group. SOLOIST-WHF and updated meta-analysis: sodium-glucose co-transporter 2 inhibitors should be initiated in patients hospitalized with worsening heart failure. [Extracted from the article]

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men.Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes.Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men.Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01920711. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to: (i) report the baseline characteristics of patients enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, (ii) compare DAPA-HF patients to participants in contemporary heart failure (HF) registries and in other recent HF trials, and (iii) compare individuals with diabetes, pre-diabetes and a normal glycated haemoglobin (HbA1c) in DAPA-HF.Methods and Results: Adults with HF in New York Heart Association functional class ≥ II, a left ventricular ejection fraction ≤ 40%, an elevated N-terminal pro-B-type natriuretic peptide concentration and receiving standard treatment were eligible for DAPA-HF, which is comparing dapagliflozin 10 mg once daily to matching placebo. In patients without a history of diabetes, previously undiagnosed diabetes was defined as a confirmed HbA1c ≥ 6.5%. Among patients without known or undiagnosed diabetes, pre-diabetes was defined as a HbA1c ≥ 5.7% The remainder of patients, with a HbA1c < 5.7%, were defined as normoglycaemic. Of the 4744 patients (mean age 66 years; 23% women) randomized, 42% had known diabetes and 3% undiagnosed diabetes. Of the remainder, 67% had pre-diabetes and 33% normal HbA1c. Overall, DAPA-HF patients were generally similar to those in recent registries and in relevant trials and had high levels of background therapy: 94% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 96% beta-blocker, and 71% mineralocorticoid receptor antagonist; 26% had a defibrillator. Patients with diabetes had worse HF status, more co-morbidity, and greater renal impairment but received similar HF therapy. Patients with diabetes received non-insulin hypoglycaemic therapy alone in 49%, insulin alone in 11%, both in 14%, and none in 26%.Conclusions: Patients randomized in DAPA-HF were similar to those in other contemporary HF with reduced ejection fraction (HFrEF) registries and trials. These patients were receiving recommended HFrEF therapy and those with diabetes were also treated with conventional glucose-lowering therapy. Consequently, DAPA-HF will test the incremental efficacy and safety of dapagliflozin in HFrEF patients with and without diabetes.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124. [ABSTRACT FROM AUTHOR]

The authors discuss the serendipitous story of sodium-glucose transporter 2 (SGLT2) inhibitors and heart failure that stems from the Empaglifozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients trial. Highlights include the efficacy of dapagliflozin based on ejection fraction, mechanisms to mediate the cardiorenal benefits of SGLT2 inhibitors, and the use of an SGLT2 inhibitor as part of routine secondary prevention.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown.Design and Methods: The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multicentre, parallel group, randomized, double-blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N-terminal pro B-type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 . The trial is event-driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient-reported outcomes. A total of 4744 patients have been randomized.Conclusions: DAPA-HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%).Methods and Results: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'.Conclusions: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group. [ABSTRACT FROM AUTHOR]

This paper tackles several statistical controversies that are commonly faced when reporting a major clinical trial. Topics covered include: multiplicity of data, interpreting secondary endpoints and composite endpoints, the value of covariate adjustment, the traumas of subgroup analysis, assessing individual benefits and risks, alternatives to analysis by intention to treat, interpreting surprise findings (good and bad), and the overall quality of clinical trial reports. All is put in the context of topical cardiology trial examples and is geared to help trialists steer a wise course in their statistical reporting, thereby giving readers a balanced account of trial findings. [ABSTRACT FROM AUTHOR]

This paper is a practical guide to the essentials of statistical analysis and reporting of randomized clinical trials (RCTs). It is the first in a series of 4 educational papers on statistical issues for RCTs, which will also include statistical controversies in RCT reporting and interpretation, the fundamentals of design for RCTs, and statistical challenges in the design and monitoring of RCTs. Here, we concentrate on displaying results in tables and figures, estimating treatment effects, expressing uncertainty using confidence intervals, and using p values wisely to assess the strength of evidence for a treatment difference. The various methods and their interpretation are illustrated by recent, topical cardiology trial results. [ABSTRACT FROM AUTHOR]

Aims and Methods: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.Results: A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.Conclusion: ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril. [ABSTRACT FROM AUTHOR]

This review describes the role of neprilysin (also known as neutral endopeptidase or enkephalinase) in the degradation of natriuretic and other vasoactive peptides, including bradykinin and adrenomedullin. The initial development of neprilysin inhibitors, then angiotensin converting enzyme-neprilysin inhibitors and, most recently, the angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 (sacubitril valsartan) as an extension of the nurohumoral basis for the treatment of heart failure is also summarised. Finally, the implications of the compelling benefits of LCZ696 compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) is discussed. [ABSTRACT FROM AUTHOR]

Objectives: The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion. Background: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients. Methods: This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m2, and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality). Results: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups. Conclusions: In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m2 and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180) [Copyright &y& Elsevier]

Aims This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. Methods and results Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L. Conclusion The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity. [ABSTRACT FROM AUTHOR]

We will shortly celebrate the 25th anniversary of the publication of the Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS), a clinical trial which revolutionized the treatment of heart failure and highlighted the importance of the renin–angiotensin–aldosterone system (RAAS) in the pathophysiology of heart failure (Figure 1). In this article I will give a brief, historical overview of this exciting quarter-century of discovery related to the RAAS. My focus is on the treatment of heart failure in patients with a low left ventricular ejection fraction. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. Background: Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. Methods: We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. Results: Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. Conclusions: Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310) [ABSTRACT FROM AUTHOR]

Aims: In chronic heart failure (HF), aldosterone antagonists have been shown to improve survival in patients with low ejection fraction and moderate-to-severe symptoms [New York Heart Association (NYHA) classes III and IV]. Efficacy of these agents was also shown when they were administered to patients with left ventricular dysfunction and signs and symptoms of CHF early after acute myocardial infarction. It is not known whether the selective aldosterone antagonist eplerenone can improve outcomes in mildly symptomatic patients. The Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF) was designed to evaluate the effect of eplerenone on mortality and morbidity in patients with chronic systolic HF in NYHA class II. [ABSTRACT FROM PUBLISHER]

Objectives: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. Background: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. Methods: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. Results: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. Conclusions: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin. [Copyright &y& Elsevier]

Abstract: Background: We describe the baseline characteristics of subjects randomised in the largest placebo-controlled, morbidity-mortality trial to date in patients with heart failure and preserved ejection fraction — the irbesartan in heart failure with preserved systolic function trial (I-PRESERVE). Methods and results: 4133 patients with a mean age of 72 years (a third were 75 years or older) were randomised and 60% were women. The mean (SD) LVEF was 59 (9)% and almost 80% of patients were in NYHA Class III or IV. Approximately 80% of patients were also overweight or obese. Heart failure was reported by investigators to have a hypertensive aetiology in 64% of patients. Prior myocardial infarction was relatively uncommon (24%), as was coronary revascularisation (13%). Atrial fibrillation and diabetes each occurred in between a quarter and a third of patients. The following treatments were used at baseline: diuretic 83%, beta-blocker 59%, calcium channel blocker 40%, ACE inhibitor 25%, spironolactone 15% and digoxin 14%. Conclusions: Patients in I-PRESERVE are broadly representative of those seen in epidemiological studies and, because of this, the results of this trial should be generally applicable to “real world” patients with heart failure and preserved ejection fraction. [Copyright &y& Elsevier]

Abstract: Background: The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin–angiotensin–aldosterone system (RAAS) together. Methods and results: 2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49). The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline. Conclusions: An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely. [Copyright &y& Elsevier]

With an increasing burden of cardiovascular disease and many promising novel treatments in development, the need for efficient systems to evaluate treatments has never been greater. To understand whether a treatment should be used in practice, we need to know whether it makes patients live longer, feel better, prevents adverse events, or does these things with better tolerability or lower cost. But therapeutic development is expensive, inefficient, and is generally focused on short-term treatment effects, rather than on prevention and on long-term impact. Could measures of disease progression, combined with trends on clinical outcomes and post-marketing surveillance to assess safety, serve as the foundation for therapeutic development? Experience and principles of clinical research tell us no. Especially in the field of heart failure, numerous treatments have appeared promising based on disease markers, yet caused harm when tested in studies that assessed clinical outcomes. The intersection of complex human disease, intended and unintended targets of therapy, and overall risk and benefit make it impossible to accurately predict the effect on clinical outcomes based on impact on a disease marker. While reliable measures of disease progression are important to guide which treatments to study in trials, clinical outcome trials must remain the basis for informing clinicians on which treatments improve clinical outcomes. Improved reliability and capacity require the development of more efficient clinical trial methods, streamlined regulatory processes, rational use of privacy protection, leveraging of electronic medical records, and recruitment of a larger proportion of the clinical community to participate in clinical trials. [Copyright &y& Elsevier]

Impaired endothelial function in isolated human uremic resistance arteries. Background. Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography. Methods. Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 μmol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP). Results. Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels. Conclusions. The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic... [ABSTRACT FROM AUTHOR]

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine. Background. Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the l-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. Methods. In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using l-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. Results. In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 μg/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to l-NMMA (4 μmol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (- 39.5; -15.7 to -52.8; P =... [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Cardiovascular‐kidney‐metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown.In this PARAGON‐HF post‐hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end‐stage kidney disease, or kidney‐related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33–4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99).Cardiovascular‐kidney‐metabolic multimorbidity was common in PARAGON‐HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden.Clinical Trial Registration: ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Aims: We examined the effectiveness of a novel cardiopulmonary management wearable sensor (worn for less than 5 mins) at measuring congestion and correlated the device findings with established clinical measures of congestion. Methods and results: We enrolled three cohorts of patients: (1) patients with heart failure (HF) receiving intravenous diuretics in hospital; (2) patients established on haemodialysis, and (3) HF patients undergoing right heart catheterization (RHC). The primary outcomes in the respective cohorts were a Spearman correlation between (1) change in weight and change in thoracic impedance (TI) (from enrolment, 24 h after admission to discharge) in patients hospitalized for HF; (2) lung ultrasound B‐lines and volume removed during dialysis with device measured TI, and (3) pulmonary capillary wedge pressure (PCWP) and sub‐acoustic diastolic, third heart sound (S3) in the patients undergoing RHC. A total of 66 patients were enrolled. In HF patients (n = 25), change in weight was correlated with both change in device TI (Spearman correlation [rsp] = −0.64, p = 0.002) and change in device S3 (rsp = −0.53, p = 0.014). In the haemodialysis cohort (n = 21), B‐lines and TI were strongly correlated before (rsp = −0.71, p < 0.001) and after (rsp = −0.77, p < 0.001) dialysis. Volume of fluid removed by dialysis was correlated with change in device TI (rsp = 0.49, p = 0.024). In the RHC cohort (n = 20), PCWP measured at one time point and device S3 were not significantly correlated (rsp = 0.230, p = 0.204). There were no device‐related adverse events. Conclusions: A non‐invasive device was able to detect changes in congestion in patients with HF receiving decongestion therapy and patients having fluid removed at haemodialysis. The cardiopulmonary management device, which measures multiple parameters, is a potentially useful tool to monitor patients with HF to prevent hospitalizations. [ABSTRACT FROM AUTHOR]

Aim: Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non‐steroidal MRA finerenone. The FINEARTS‐HF trial is designed to evaluate the long‐term efficacy and safety of the selective non‐steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. Methods: FINEARTS‐HF is a global, multicentre, event‐driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II–IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) ≥300 pg/ml (or B‐type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT‐proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. Conclusions: The FINEARTS‐HF trial will determine the efficacy and safety of the non‐steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. Clinical Trial Registration: ClinicalTrials.gov NCT04435626 and EudraCT 2020‐000306‐29. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study.From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo.While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose‐lowering therapy (GLT) in this population is uncertain.DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre‐specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow‐up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50–1.00; 1 GLT: HR 1.04, 95% CI 0.80–1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56–0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59–0.92) and without background metformin use (HR 0.89, 95% CI 0.72–1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69–1.16) and without background insulin use (HR 0.78, 95% CI 0.65–0.95; pinteraction = 0.45). Dapagliflozin was well‐tolerated irrespective of the number of background GLTs.Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first‐line SGLT2i among individuals with T2D and HF, irrespective of background GLT. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods and results Conclusions Although much is known about the usefulness of heart failure (HF)‐specific instruments for assessing patient well‐being, less is known about the value of generic instruments for the measurement of health‐related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5‐dimension 5‐level (EQ‐5D‐5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores.We performed a patient‐level pooled analysis of the DAPA‐HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ‐5D‐5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator‐reported (New York Heart Association class) and patient‐self‐reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N‐terminal pro‐B‐type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ‐5D‐5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72–0.91) in Q2, 0.74 (0.65–0.84) in Q3, and 0.62 (0.54–0.72) in Q4. The risk of each component of the composite outcome, and all‐cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ‐5D‐5L VAS and index scores across the range of ejection fraction.Both higher (better) EQ‐5D‐5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ‐5D‐5L VAS and index scores, irrespective of ejection fraction. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Although recent randomized clinical trials have demonstrated the advantages of heart failure (HF) therapy in both frail and not frail patients, there is insufficient information on the use of HF therapy based on frailty status in a real‐world setting. The aim was to examine how frailty status in HF patients associates with use of HF therapy and with clinical outcomes.Patients with new‐onset HF between 2014 and 2021 were identified using the nationwide Danish registers. Patients across the entire range of ejection fraction were included. The associations between frailty status (using the Hospital Frailty Risk Score) and use of HF therapy and clinical outcomes (all‐cause mortality, HF hospitalization, and non‐HF hospitalization) were evaluated using multivariable‐adjusted Cox models adjusting for age, sex, diagnostic setting, calendar year, comorbidities, pharmacotherapy, and socioeconomic status. Of 35 999 participants (mean age 69.1 years), 68% were not frail, 26% were moderately frail, and 6% were severely frail. The use of HF therapy was significantly lower in frailer patients. The hazard ratio (HR) for angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker initiation was 0.74 (95% confidence interval 0.70–0.77) and 0.48 (0.43–0.53) for moderate frailty and severe frailty, respectively. For beta‐blockers, the corresponding HRs were 0.74 (0.71–0.78) and 0.51 (0.46–0.56), respectively, and for mineralocorticoid receptor antagonists, 0.83 (0.80–0.87) and 0.58 (0.53–0.64), respectively. The prevalence of death and non‐HF hospitalization increased with frailty status. The HR for death was 1.55 (1.47–1.63) and 2.32 (2.16–2.49) for moderate and severe frailty, respectively, and the HR for non‐HF hospitalization was 1.37 (1.32–1.41) and 1.82 (1.72–1.92), respectively. The association between frailty status and HF hospitalization was not significant (HR 1.08 [1.02–1.14] and 1.08 [0.97–1.20], respectively).In real‐world HF patients, frailty was associated with lower HF therapy use and with a higher incidence of clinical outcomes including mortality and non‐HF hospitalization. [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON‐HF. Methods and results: In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON‐HF. The effects of sacubitril/valsartan, compared with valsartan, were assessed according to the number of medications at baseline: 683 non‐polypharmacy (<5 medications); 2750 polypharmacy (5–9 medications), and 1360 hyper‐polypharmacy (≥10 medications). The primary outcome was total HF hospitalizations and cardiovascular deaths. Patients with hyper‐polypharmacy were older, had more severe limitations due to HF (worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores), and had greater comorbidity. The non‐adjusted risk of the primary outcome was significantly higher in patients taking more medications, and similar trends were seen for HF hospitalization and cardiovascular and all‐cause death. The effect of sacubitril/valsartan versus valsartan on the primary outcome from the lowest to highest polypharmacy category was (as a rate ratio): 1.19 (0.76–1.85), 0.94 (0.77–1.15), and 0.77 (0.61–0.96) (pinteraction = 0.16). Treatment‐related adverse events were more common in patients in the higher polypharmacy categories but not more common with sacubitril/valsartan, versus valsartan, in any polypharmacy category. Conclusions: Polypharmacy is very common in patients with HFpEF, and those with polypharmacy have worse clinical status and a higher rate of non‐fatal and fatal outcomes. The benefit of sacubitril/valsartan was not diminished in patients taking a larger number of medications at baseline. [ABSTRACT FROM AUTHOR]

New guidelines have emphasized the primacy of starting the four key life‐saving therapies for patients with heart failure and reduced ejection fraction as quickly as possible, with titration to 'target dose' of these, as secondary consideration. In this article, we examine the reasons for this change in emphasis and revisit the evidence regarding the dosing of pharmacological therapy in heart failure. We demonstrate the early benefits obtained with even low doses of most of the foundational therapies for heart failure and reduced ejection fraction. We also clarify that the 'target dose' of those therapies requiring titration was a goal based on tolerability and often not reached in trials, i.e. the proven benefits of our foundational therapies were demonstrated with an average dose that was less than target and many patients in these trials were treated with sub‐target doses. [ABSTRACT FROM AUTHOR]

Bexagliflozin (bexa) is a potent and selective inhibitor of SGLT2. To demonstrate its effects in patients (pts) at increased risk of cardiovascular (CV) events, pts with type 2 diabetes (T2D) ≥40 years old with HbA1c 7.5-11 % and eGFR ≥45 were enrolled in 1 of 3 groups: 1) established atherosclerotic CVD 2) heart failure (HF) or 3) ≥55 years with ≥2 CV risk factors. The primary endpoint was change in HbA1c at wk 24. Secondary endpoints included change in SBP at 24 wks in pts with SBP ≥140 mmHg, weight loss at 48 wks in pts with BMI ≥25 kg/m2, and time to hospitalization for HF or CV death. MACE+ (CV death, myocardial infarction, stroke, or unstable angina) was tested in a non-inferiority analysis to demonstrate upper 95% CI <1.8. Pts were randomized 2:1 to bexa 20 mg or placebo qd. Follow-up continued until all pts completed ≥52 wks and when ≥134 subjects had a MACE+ event. CV endpoints and deaths were adjudicated and analyzed using Cox proportional hazards regression. Placebo-corrected changes from baseline in HbA1c, weight and SBP were analyzed using a mixed model repeated measures approach to account for missing data. 1700 pts were enrolled (62.6% Group1, 14.5% Group 2, 22.9% in Group 3) and followed for a median of 30 months. At baseline mean (SD) HbA1c was 8.32 (0.91)%; BMI 32.6 (6.0) kg/m2 (92%≥25); SBP 134 (16) mmHg (39% ≥140); eGFR 77.9 (19.5) (19% <60). The primary endpoint showed a placebo-corrected reduction in HbA1c of 0.48% (95% CI -0.56, -0.39), p<0.0001; SBP fell 3.0 mmHg (- 5.5, -0.4), p=0.02; and weight declined 2.7kg (-3.1, -2.2), p<0.0001. CV death or HF hosp. occurred in 48 (4.2%) pts on bexa and 31 (5.5%) on placebo: HR 0.74 (0.47, 1.17). MACE+ occurred in 90/1133 (7.9%) pts on bexa and 57/567 (10.1%) on placebo: HR 0.79 (95%CI 0.56, 1.09). In high-risk T2D pts, bexagliflozin was well tolerated and improved HbA1c, SBP, and weight. Non-inferiority was demonstrated for MACE+, with point-estimates for MACE+ and CV death or HF hosp similar to other SGLT2 inhibitors. Disclosure: J.J.V. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. M.W. Freeman: Research Support; Self; Theracos, Inc. J. Massaro: Consultant; Self; Theracos, Inc. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. P. Lock: None. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Lewis: Consultant; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Amgen, Novartis Pharmaceuticals Corporation, Theracos, Inc. Y.C. Halvorsen: Research Support; Self; Theracos, Inc. [ABSTRACT FROM AUTHOR]

Aims: Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. Methods and results: We assessed two‐dimensional speckle‐tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON‐HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values of circulating baseline N‐terminal pro‐B‐type‐natriuretic peptide. After a median follow‐up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02–1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction >0.1). Conclusions: In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF. [ABSTRACT FROM AUTHOR]

Aim: To assess the cost‐effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). Methods and results: Patient‐level data were pooled from HF trials (DAPA‐HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N‐terminal pro‐B‐type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost‐effectiveness ratio (ICER) was £6470 per quality‐adjusted life year (QALY) gained, well below the UK willingness‐to‐pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. Conclusions: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost‐effective intervention. [ABSTRACT FROM AUTHOR]

Aim: Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF. Methods and results: We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM‐HF, ATMOSPHERE and DAPA‐HF, and HF with preserved ejection fraction [HFpEF]: PARAGON‐HF and I‐PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all‐cause death were also examined. Each HF phenotype was categorized according to median BUN/creatinine ratio, generating four groups that is, HFpEF ≤ and >median BUN/creatinine ratio and HFrEF ≤ and >median BUN/creatinine ratio. The association between BUN/creatinine ratio and outcomes was evaluated using the Kaplan–Meier estimator and Cox proportional hazard models. Overall, 28 820 patients were analysed. The median (IQR) BUN/creatinine ratio was 20.1 (Q1–Q3 16.7–24.7) in HFpEF and 18.7 (15.2–22.8) in HFrEF. In both HFpEF and HFrEF, higher BUN/creatinine ratio was associated with older age, female sex, and diabetes, but similar estimated glomerular filtration rate (eGFR). The risk of each outcome examined was significantly higher in patients with BUN/creatinine ratio ≥median, compared to

Aims: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.Methods and Results: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate <60 mL/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe heart failure symptoms.Conclusions: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders. [ABSTRACT FROM AUTHOR]

The left panels represent health status trajectories preceding a hospitalization for HF; the right panels represent health status recovery after hospitalization for HF among those who survived to the end of the study. The blue lines represent patients who have experienced a hospitalization for HF; the black lines represent patients who were alive without hospitalization throughout study follow-up. Keywords: heart failure; patient reported outcome measures; quality of life EN heart failure patient reported outcome measures quality of life 1872 1874 3 06/17/22 20220621 NES 220621 Health-related quality of life (HRQOL) may dynamically change with heart failure (HF) progression and may forecast subsequent clinical events.[1] Measures of HRQOL are increasingly being adopted as trial end points and in clinical practice and offer promise to track longitudinal patient experience to identify those at impending risk for a clinical event. [Extracted from the article]

Aims: Neuropeptide Y (NPY) is the most abundant neuropeptide found in the heart and is released alongside norepinephrine following prolonged sympathetic activation, a process that is implicated in the pathophysiology of heart failure (HF). In patients with severely impaired left ventricular ejection fraction (LVEF) undergoing cardiac resynchronization therapy, higher levels of NPY measured in coronary sinus blood, are associated with poorer outcome. The aim was to examine the association of peripheral venous NPY levels and outcomes in a HF population with a range of LVEF, using a highly sensitive and specific assay. Methods and results: The association between NPY and the composite outcome of cardiovascular death or HF hospitalization, its components, and all‐cause mortality was examined using Cox regression analyses among 833 patients using a threshold of elevated NPY identified through binary recursive partitioning adjusted for prognostic variables including estimated glomerular filtration rate (eGFR), ejection fraction and B‐type natriuretic peptide (BNP). The mean value of NPY was 25.8 ± 18.2 pg/ml. Patients with high NPY levels (≥29 pg/ml) compared with low values were older (73 ± 10 vs. 71 ± 11 years), more often male (58.5% vs. 55.6%), had higher BNP levels (583 [261–1096] vs. 440 [227–829] pg/ml), lower eGFR (46.4 ± 13.9 vs. 52.4 ± 11.7 ml/min/1.73 m2), and were more often treated with diuretics. There was no associated risk of HF hospitalization with NPY levels ≥29 vs. <29 pg/ml. Higher NPY levels were associated with a greater risk of cardiovascular and all‐cause death (adjusted hazard ratio 1.56 [95% confidence interval 1.21–2.10], p = 0.003 and 1.30 [1.04–1.62], p = 0.02, respectively). There was no associated risk of HF hospitalization with higher NPY levels. Conclusions: Peripherally measured NPY is an independent predictor of all‐cause and cardiovascular death even after adjustment for other prognostic variables, including BNP. [ABSTRACT FROM AUTHOR]