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Aims: 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. Methods and results: 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). Conclusions: 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: 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. Methods and results: 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. Conclusion: 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: 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. Methods and results: 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). Conclusion: 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 a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end‐systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. Conclusions: EMPRESS‐MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI. [ABSTRACT FROM AUTHOR]

Aims: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. Methods and results: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation <20% or ferritin <100 μg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between‐group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between‐group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow‐up (defined as haemoglobin >16.5 g/dL [men] or >16 g/dL [women]). Conclusions: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron‐deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one. [ABSTRACT FROM AUTHOR]

Aims: 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. Methods and results: 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. Conclusions: 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]

Aims: 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. Methods and results: 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. Conclusions: 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: 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]

Background: The sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown. Objective: We performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. Design: Prospective randomized placebo-controlled trial. Participants: A total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes. Intervention: Dapagliflozin 10 mg versus placebo once daily. Main Measures: Primary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. Key Results: Median follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope. Conclusions: Dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit. Trial Registry: clinicaltrials.gov NIH Trial Registry Number: NCT03036150 [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]

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: Red cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON‐HF. Methods and results: PARAGON‐HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5–15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT‐proBNP concentration, more advanced New York Heart Association class, and worse Kansas City Cardiomyopathy Questionnaire scores. There was a graded relationship between quartiles of RDW at randomization and the primary endpoint, with a significantly higher risk associated with increasing RDW, even after adjustment for NT‐proBNP and other prognostic variables {Quartile 1, reference; Quartile 2, rate ratio 1.03 [95% confidence interval (CI) 0.83 to 1.28]; Quartile 3, 1.25 [1.01 to 1.54]; Quartile 4, 1.70 [1.39 to 2.08]}. This association was seen for each of the secondary outcomes, including cardiovascular and all‐cause death. Compared with valsartan, sacubitril/valsartan reduced RDW at 48 weeks [mean change −0.09 (95% CI −0.15 to −0.02)]. The effect of sacubitril/valsartan vs. valsartan was not significantly modified by RDW levels at randomization. Conclusions: RDW, a routinely available and inexpensive biomarker, provides incremental prognostic information when added to established predictors. Compared with valsartan, sacubitril/valsartan led to a small reduction in RDW. [ABSTRACT FROM AUTHOR]

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]

Aim: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. Methods and results: In this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post‐furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. Conclusions: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload. [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are often treated with calcium channel blockers (CCBs), although the safety of CCBs in these patients is uncertain. We aimed to investigate the association between CCB use and clinical outcomes in patients with HFmrEF/HFpEF; CCBs were examined overall, as well as by subtype (dihydropyridine and non‐dihydropyridine). Methods and results: We pooled individual patient data from four large HFpEF/HFmrEF trials. The association between CCB use and outcomes was assessed. Among the 16 954 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13 402 (79.0%) had HFpEF (LVEF ≥50%). Altogether, 5874 patients (34.6%) received a CCB (87.6% dihydropyridines). Overall, the risks of death and HF hospitalization were not higher in patients treated with a CCB, particularly dihydropyridines. The risk of pump failure death was significantly lower (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60–0.96), while the risk of stroke was higher (HR 1.26, 95% CI 1.06–1.50) in patients treated with a CCB compared to those not. These risks remained different in patients treated and not treated with a CCB after adjustment for other prognostic variables. Although the majority of patients were treated with dihydropyridine CCBs, the pattern of outcomes was broadly similar for both dihydropyridine and non‐dihydropyridine CCBs. Conclusion: Although this is an observational analysis of non‐randomized treatment, there was no suggestion that CCBs were associated with worse HF outcomes. Indeed, CCB use was associated with a lower incidence of pump failure death. [ABSTRACT FROM AUTHOR]

Aims: Although trials have proven the group‐level effectiveness of various therapies for heart failure with reduced ejection fraction (HFrEF), important differences in absolute effectiveness exist between individuals. We developed and validated the LIFEtime‐perspective for Heart Failure (LIFE‐HF) model for the prediction of individual (lifetime) risk and treatment benefit in patients with HFrEF. Methods and results: Cox proportional hazards functions with age as the time scale were developed in the PARADIGM‐HF and ATMOSPHERE trials (n = 15 415). Outcomes were cardiovascular death, heart failure (HF) hospitalization or cardiovascular death, and non‐cardiovascular mortality. Predictors were age, sex, New York Heart Association class, prior HF hospitalization, diabetes mellitus, extracardiac vascular disease, systolic blood pressure, left ventricular ejection fraction, N‐terminal pro‐B‐type natriuretic peptide, and glomerular filtration rate. The functions were combined in life‐tables to predict individual overall and HF hospitalization‐free survival. External validation was performed in the SwedeHF registry, ASIAN‐HF registry, and DAPA‐HF trial (n = 51 286). Calibration of 2‐ to 10‐year risk was adequate, and c‐statistics were 0.65–0.74. An interactive tool was developed combining the model with hazard ratios from trials to allow estimation of an individual's (lifetime) risk and treatment benefit in clinical practice. Applying the tool to the development cohort, combined treatment with a mineralocorticoid receptor antagonist, sodium–glucose cotransporter 2 inhibitor, and angiotensin receptor–neprilysin inhibitor was estimated to afford a median of 2.5 (interquartile range [IQR] 1.7–3.7) and 3.7 (IQR 2.4–5.5) additional years of overall and HF hospitalization‐free survival, respectively. Conclusion: The LIFE‐HF model enables estimation of lifelong overall and HF hospitalization‐free survival, and (lifetime) treatment benefit for individual patients with HFrEF. It could serve as a tool to improve the management of HFrEF by facilitating personalized medicine and shared decision‐making. [ABSTRACT FROM AUTHOR]

Aim: Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre‐specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status. Methods and results: Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild‐to‐moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08–1.51). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status (no COPD: HR 0.82 [95% CI 0.72–0.93]; COPD: HR 0.82 [95% CI 0.62–1.10]; pinteraction = 0.98). Consistent effects were observed for heart failure, cardiovascular, and all‐cause hospitalization, and deaths, and composites of these. Dapagliflozin, as compared with placebo, improved the Kansas City Cardiomyopathy Questionnaire scores from baseline to 8 months to a similar extent in patients with and without mild‐to‐moderate COPD (pinteraction ≥ 0.63). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status. Conclusions: Mild‐to‐moderate COPD is common in patients with HFmrEF/HFpEF and is associated with worse outcomes. The beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, regardless of COPD status. Clinical Trial Registration: ClinicalTrials.gov NCT03619213. [ABSTRACT FROM AUTHOR]

Aim: Although education in self‐management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self‐rated knowledge of self‐management is associated with outcomes. The aim of this study was to assess the relationship between patient‐reported knowledge of self‐management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: Using individual patient data from three recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the 'self‐efficacy' questions of the Kansas City Cardiomyopathy Questionnaire. One question quantifies patients' understanding of how to prevent heart failure exacerbations ('prevention' question) and the other how to manage complications when they arise ('response' question). Self‐reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox‐proportional hazard models were used to evaluate time‐to‐first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above‐defined groups. Of patients (n = 17 629) completing the 'prevention' question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) patients had poor, fair, and good self‐rated knowledge, respectively. Of those completing the 'response' question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients had poor, fair, and good self‐rated knowledge, respectively. For both questions, patients with 'poor' knowledge were older, more often female, and had a worse heart failure profile but similar treatment. The rates (95% confidence interval) per 100 person‐years for the primary composite outcome for 'poor', 'moderate' and 'good' self‐rated knowledge in answer to the 'prevention' question were 12.83 (12.11–13.60), 12.08 (11.53–12.65) and 11.55 (11.00–12.12), respectively, and for the 'response' question were 12.88 (12.13–13.67), 12.22 (11.60–12.86) and 11.56 (11.07–12.07), respectively. The lower event rates in patients with 'good' self‐rate knowledge were accounted for by lower rates of cardiovascular (and all‐cause) death and not hospitalization for worsening heart failure. Conclusions: Poor patient‐reported 'self‐efficacy' may be associated with higher rates of mortality. Evaluation of knowledge of 'self‐efficacy' may provide prognostic information and a guide to which patients may benefit from further education about self‐management. [ABSTRACT FROM AUTHOR]

Aims: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium–glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy. Methods and results: Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, evidence‐based beta‐blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0–1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow‐up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person‐years for patients on 0–1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0–1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events. Conclusions: In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0‐1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de‐escalation of other therapies. [ABSTRACT FROM AUTHOR]

Aim: Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF). Methods and results: Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM‐HF, DAPA‐HF) and HFpEF (TOPCAT, PARAGON‐HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ‐OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4% anaemia; the corresponding proportions in HFpEF (n = 6563) were: 54.0% AF, 48.7% CKD, 43.4% diabetes, 53.3% obesity, 28.6% angina, 14.7% COPD, 10.2% stroke, and 6.5% anaemia. HFpEF patients had lower KCCQ domain scores and KCCQ‐OSS (67.8 vs. 71.3) than HFrEF patients. Physical limitations, social limitations and quality of life domains were reduced more than symptom frequency and symptom burden domains. In both HFrEF and HFpEF, COPD, angina, anaemia, and obesity were associated with the lowest scores. An increasing number of comorbidities was associated with decreasing scores (e.g. KCCQ‐OSS 0 vs. ≥4 comorbidities: HFrEF 76.8 vs. 66.4; HFpEF 73.7 vs. 65.2). Conclusions: Cardiac and non‐cardiac comorbidities are common in both HFrEF and HFpEF patients and most are associated with reductions in health status although the impact varied among comorbidities, by the number of comorbidities, and by HF phenotype. Treating/correcting comorbidity is a therapeutic approach that may improve the health status of patients with HF. [ABSTRACT FROM AUTHOR]

Aim: Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapies have improved. In light of these competing influences, we examined long‐term trends in the risk of HF hospitalization (HFH) following a first AMI occurring in Scotland over 25 years. Methods and results: All patients in Scotland discharged alive after a first AMI between 1991 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow‐up 1 year, maximum 26 years). A total of 175 672 people with no prior history of HF were discharged alive after a first AMI during the period of study. A total of 21 445 (12.2%) patients had a first HFH during a median follow‐up of 6.7 years. Incidence of HFH (per 1000 person‐years) at 1 year following discharge from a first AMI decreased from 59.3 (95% confidence interval [CI] 54.2–64.7) in 1991 to 31.3 (95% CI 27.3–35.8) in 2015, with consistent trends seen for HF occurring within 5 and 10 years. Accounting for the competing risk of death, the adjusted risk of HFH at 1 year after discharge decreased by 53% (95% CI 45–60%), with similar decreases at 5 and 10 years. Conclusion: The incidence of HFH following AMI in Scotland has decreased since 1991. These trends suggest that better treatment of AMI and secondary prevention are having an impact on the risk of HF at a population level. [ABSTRACT FROM AUTHOR]

Aim: Eplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from the EMPHASIS‐HF trial. Methods and results: The EMPHASIS‐HF trial was a double‐blind randomized clinical trial assessing the effect of eplerenone in patients (n = 2737, mean age 68.6 ± 7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone versus placebo on the primary composite endpoint (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post‐randomization. A significant reduction in the primary composite endpoint was observed 26 days after randomization (hazard ratio 0.58; 95% confidence interval, 0.34–1.00, p = 0.049). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history ≥18 months (day 24), estimated glomerular filtration rate <60 ml/min (day 12), ischaemic HF aetiology (day 28), age ≥65 years (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction ≥30% (day 28) or already treated with beta‐blockers (day 25). Conclusions: Eplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline‐directed medical therapy. [ABSTRACT FROM AUTHOR]

Aims: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. Methods and results: Mid‐regional pro‐adrenomedullin (MR‐proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1–Q3) baseline MR‐proADM concentrations were 0.80 (0.59–0.99) nmol/L in HFrEF and 0.88 (0.68–1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR‐proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan‐treated patients (median 2%). Greater increases in MR‐proADM were associated with higher Sac/Val doses. Changes in MR‐proADM correlated weakly with changes in N‐terminal pro‐B‐type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR‐proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. Conclusions: MR‐proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR‐proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. Clinical Trial Registration: PROVE‐HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588. [ABSTRACT FROM AUTHOR]

Aims: To determine the cost‐effectiveness of dapagliflozin, added to usual care, in patients with heart failure (HF) with mildly reduced or preserved ejection fraction for the UK, German and Spanish payers using detailed patient‐level data from the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial. Methods and results: A lifetime Markov state‐transition cohort model was developed. Quartiles of the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) defined health states and monthly transition count data informed transition probabilities. Multivariable generalized estimating equations captured the incidence of HF hospitalizations and urgent HF visits, while cardiovascular deaths and all‐cause mortality were estimated using adjusted parametric survival models. Health state costs were assigned to KCCQ‐TSS quartiles (2021 British pound [GBP]/Euro) and patient‐reported outcomes were sourced from DELIVER. Future values of costs and effects were discounted according to country‐specific rates. In the UK, dapagliflozin treatment was predicted to increase quality‐adjusted life years (QALYs) and life‐years by 0.231 and 0.354, respectively, and extend the time spent in the best quartile of KCCQ‐TSS by 4.2 months. Comparable outcomes were projected for Germany and Spain. The incremental cost‐effectiveness ratios were £7761, €9540 and €5343/QALY in the UK, Germany and Spain, respectively. According to regional willingness‐to‐pay thresholds, 91%, 89% and 92% of simulations in the UK, Germany and Spain, respectively, were cost‐effective following probabilistic sensitivity analyses. Conclusion: Dapagliflozin, added to usual care, is very likely cost‐effective for HF with mildly reduced or preserved ejection fraction in several European countries. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM‐HF trial. Forty‐four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss‐of‐function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM‐associated gene tiers. Clinical features were compared between carriers and non‐carriers. Of the 1412 HFrEF participants with whole‐exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier‐1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier‐1 variants only and 12.6% (29/229) had tier‐1, ‐2 or ‐3 variants. Compared to non‐carriers, tier‐1 carriers were younger (4 years; adjusted p‐value [padj] = 4 × 10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj = 3.2 × 10−3), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10−3), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM‐HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Aims: It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure. Methods and results: Aldosterone, cystatin C, high‐sensitivity troponin T (hs‐TnT), galectin‐3, growth differentiation factor‐15 (GDF‐15), kidney injury molecule‐1, matrix metalloproteinase‐2 and ‐9, soluble suppression of tumourigenicity‐2, tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM‐HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT‐HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all‐cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow‐up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs‐TnT, GDF‐15, cystatin C and TIMP‐1. When all biomarkers were added simultaneously to the PREDICT‐HF models, only hs‐TnT remained an independent predictor of all three endpoints. GDF‐15 also remained predictive of the primary endpoint; TIMP‐1 was the only other predictor of both cardiovascular and all‐cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification. Conclusions: None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables. [ABSTRACT FROM AUTHOR]

Aims: Dapagliflozin resulted in significant and sustained reductions in first and recurrent heart failure (HF) hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied. Methods and results: In the DELIVER and DAPA‐HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring intensive care unit stay, intravenous vasoactive therapies, invasive/non‐invasive ventilation, mechanical fluid removal or mechanical circulatory support were categorized as complicated. The balance was classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 854 (71%) were uncomplicated and 355 (29%) were complicated. Of the total 799 HF hospitalizations reported in DAPA‐HF, 453 (57%) were uncomplicated and 346 (43%) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in‐hospital mortality both in DELIVER (16.7% vs. 2.3%, p < 0.001) and DAPA‐HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total 'uncomplicated' (DELIVER: rate ratio [RR] 0.67, 95% confidence interval [CI] 0.55–0.82 and DAPA‐HF: RR 0.69, 95% CI 0.54–0.87) and 'complicated' HF hospitalizations (DELIVER: RR 0.82, 95% CI 0.63–1.06 and DAPA‐HF: RR 0.75, 95% CI 0.58–0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76, 95% CI 0.58–0.99 and DAPA‐HF: RR 0.58, 95% CI 0.42–0.80) or ≥5 days (DELIVER: RR 0.71, 95% CI 0.58–0.86 and DAPA‐HF: RR 0.77, 95% CI 0.62–0.94). Conclusion: A substantial proportion of hospitalizations (∼30–40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics. Such patients experienced significantly higher in‐hospital mortality. Treatment with dapagliflozin consistently reduced HF hospitalizations regardless of severity of inpatient course or LOS. Clinical Trial Registration: ClinicalTrials.gov, DELIVER (NCT03619213) and DAPA‐HF (NCT03036124). [ABSTRACT FROM AUTHOR]

Although the development of therapies and tools for the improved management of heart failure (HF) continues apace, day‐to‐day management in clinical practice is often far from ideal. A Cardiovascular Round Table workshop was convened by the European Society of Cardiology (ESC) to identify barriers to the optimal implementation of therapies and guidelines and to consider mitigation strategies to improve patient outcomes in the future. Key challenges identified included the complexity of HF itself and its treatment, financial constraints and the perception of HF treatments as costly, failure to meet the needs of patients, suboptimal outpatient management, and the fragmented nature of healthcare systems. It was discussed that ongoing initiatives may help to address some of these barriers, such as changes incorporated into the 2021 ESC HF guideline, ESC Heart Failure Association quality indicators, quality improvement registries (e.g. EuroHeart), new ESC guidelines for patients, and the universal definition of HF. Additional priority action points discussed to promote further improvements included revised definitions of HF 'phenotypes' based on trial data, the development of implementation strategies, improved affordability, greater regulator/payer involvement, increased patient education, further development of patient‐reported outcomes, better incorporation of guidelines into primary care systems, and targeted education for primary care practitioners. Finally, it was concluded that overarching changes are needed to improve current HF care models, such as the development of a standardized pathway, with a common adaptable digital backbone, decision‐making support, and data integration, to ensure that the model 'learns' as the management of HF continues to evolve. [ABSTRACT FROM AUTHOR]

Aims: Patients recently hospitalized for heart failure (HF) often have unstable haemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized. Methods and results: We examined the effects of dapagliflozin versus placebo on estimated glomerular filtration rate (eGFR) slope (acute and chronic), 1‐month change in systolic blood pressure, and the occurrence of serious hypovolaemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization. The 654 (90 randomized during hospitalization, 147 1–7 days post‐discharge and 417 8–30 days post‐discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization (median [interquartile range] 55 [43, 71] vs. 60 [47, 75] ml/min/1.73 m2). Dapagliflozin consistently reduced the risk of all‐cause (pinteraction = 0.20), cardiac‐related (pinteraction = 0.75), and HF‐specific (pinteraction = 0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo‐corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (−2.0 [−4.1, +0.1] vs. −3.4 [−3.9, −2.9] ml/min/1.73 m2, pinteraction = 0.12). Dapagliflozin's effect to slow chronic eGFR decline was similar regardless of recent hospitalization (pinteraction = 0.57). Dapagliflozin had a minimal effect on 1‐month systolic blood pressure and to a similar degree in patients with and without recent hospitalization (−1.3 vs.−1.8 mmHg, pinteraction = 0.64). There was no treatment‐related excess in renal or hypovolaemic serious adverse events, irrespective of recent HF hospitalization. Conclusion: In patients recently hospitalized with HF, initiation of dapagliflozin had minimal effects on blood pressure and did not increase renal or hypovolaemic serious adverse events, yet afforded long‐term cardiovascular and kidney protective effects. These data suggest that the benefit to risk ratio favours initiation of dapagliflozin among stabilized patients hospitalized or recently hospitalized for HF. Clinical Trial Registration: ClinicalTrials.gov NCT03619213. [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure experience a high burden of symptoms and physical limitations, and poor quality of life. Dapagliflozin reduces heart failure hospitalization and cardiovascular death in patients with reduced, mildly reduced, and preserved ejection fractions. We examined the effects of dapagliflozin on health status, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), across the full spectrum of left ventricular ejection fraction (LVEF). Methods and results: Participant‐level data were pooled from the DAPA‐HF and DELIVER trials. Both trials were randomized, global, double‐blind, placebo‐controlled trials of patients with symptomatic heart failure and elevated natriuretic peptides. DAPA‐HF and DELIVER included patients with LVEF ≤40% and LVEF >40%, respectively. KCCQ was evaluated at randomization and at 4 and 8 months post‐randomization; the effect of dapagliflozin versus placebo on KCCQ total symptom score (TSS) was a pre‐specified secondary outcome in both trials. Interaction testing was performed to assess potential heterogeneity in the effects of dapagliflozin versus placebo on KCCQ‐TSS, clinical summary score (CSS), overall summary score (OSS), and physical limitation score (PLS), by continuous LVEF using restricted cubic splines. Responder analyses examining the proportion of patients with meaningful deterioration (≥5 point decline) and meaningful improvements (≥5 point increase) in KCCQ‐TSS was assessed across LVEF categories. Of 11 007 randomized participants, 10 238 (93%) had full data on KCCQ‐TSS at randomization. Benefits of dapagliflozin versus placebo on KCCQ‐TSS, ‐CSS, ‐OSS, ‐PLS, at 8 months were consistent across the full range of LVEF (pinteraction = 0.19, 0.10, 0.12, 0.10, respectively). In responder analyses, fewer dapagliflozin‐ versus placebo‐treated patients had clinically meaningful deteriorations in KCCQ‐TSS (overall: 21% vs. 23%; LVEF ≤40%: 21% vs. 29%; LVEF 41–60%: 21% vs. 26%; LVEF >60%: 22% vs. 27%). A greater proportion of patients randomized to dapagliflozin experienced at least small improvements in KCCQ‐TSS (overall: 50% vs. 45%; LVEF ≤40%: 48% vs. 41%; LVEF 41–60%: 51% vs. 49%; LVEF >60%: 53% vs. 45%). The effects of dapagliflozin versus placebo on clinically meaningful deteriorations and improvements in health status by KCCQ‐TSS were consistent across the full spectrum of LVEF assessed continuously (pinteraction = 0.20 and 0.64, respectively). Across the LVEF spectrum, the number needed to treat to affect ≥5 point improvement in health status assessed by KCCQ‐TSS was 20. Health status declines preceding a HF hospitalization by ∼10 points were observed in both trials, evident up to 3 months prior to hospitalization. Conclusions: In participant‐level pooled analyses of DAPA‐HF and DELIVER, dapagliflozin improved all key domains of health status across the full range of LVEF. Clinically meaningful improvements in health status were also observed consistently across LVEF, including in those with LVEF >60%. Clinical Trial Registration: NCT03036124 and NCT03619213. [ABSTRACT FROM AUTHOR]

Aims: Sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors are effective across the spectrum of left ventricular ejection fraction (LVEF) in heart failure (HF); however, population‐wide medication use in eligible patients remains suboptimal. We evaluated the potential implications of optimal global implementation of SGLT‐2 inhibitors in HF. Methods and results: A decision analytical study was performed using the global prevalence of HF from the Global Burden of Disease 2017 report. Exclusion criteria were applied using the NHANES to ascertain an SGLT‐2 inhibitor‐eligible population, which was mapped onto global LVEF distributions from the REPORT‐HF registry. The number needed to treat for 3 years for the composite of worsening HF events and cardiovascular deaths was calculated from estimated event rates in the DAPA‐HF, EMPEROR‐Reduced, EMPEROR‐Preserved, and DELIVER trials and projected onto the eligible population. An estimated 49 329 000 (95% confidence interval [CI] 43 882 000–54 929 000) HF patients would be eligible for SGLT‐2 inhibitors across all LVEFs, including 25 651 000 (95% CI 22 818 000–28 563 000) with LVEF ≤40% and 23 678 000 (95% CI 21 063 000–26 366 000) with LVEF >40%. Optimal implementation of SGLT‐2 inhibitors would be projected to prevent/postpone 4 512 011 (95% CI 4 013 686–5 024 232) to 5 986 943 (95% CI 5 325 721–6 666 604) total worsening HF events and cardiovascular deaths over 3 years in patients with LVEF <40%. An additional 2 102 606 (95% CI 1 870 394–2 341 301) to 2 557 224 (95% CI 2 274 804–2 847 528) total worsening HF events and cardiovascular deaths would be prevented/postponed in patients with LVEF >40%. Among all eligible HF patients, irrespective of LVEF, 7 069 235 (95% CI 6 288 490–7 871 760) to 8 089 549 (95% CI 7 196 115–9 007 905) total worsening HF events and cardiovascular deaths would be prevented/postponed over this period. Conclusions: Optimal implementation of SGLT‐2 inhibitors globally in HF is projected to prevent/postpone approximately 7–8 million worsening HF events and cardiovascular deaths over 3 years. [ABSTRACT FROM AUTHOR]

Aims: Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure (HF). How risk related to comorbidities compares at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels. Methods and results: Using two clinical trials in HF – the Prospective comparison of ARNI (Angiotensin Receptor–Neprilysin Inhibitor) with ACEI (Angiotensin‐Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial (PARADIGM‐HF) and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure trials (ATMOSPHERE) – we identified the 10 most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions (PAF) for all‐cause death and relative excess risk due to interaction with Cox proportional hazard models. Of 15 066 patients in the study, 14 133 (93.7%) had at least one and 11 867 (78.8%) had at least two of the 10 most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease (PAD) in combination with stroke (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.28–2.33) and anaemia (HR 1.71; 95% CI 1.39–2.11). The combination of chronic kidney disease (CKD) and hypertension had the highest PAF (5.65%; 95% CI 3.66–7.61). Two pairs demonstrated significant synergistic interaction (atrial fibrillation with CKD and coronary artery disease, respectively) and one an antagonistic interaction (anaemia and obesity). Conclusions: In HF, the impact of multimorbidity differed at the individual patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with coexistent PAD and stroke were at greatest individual risk whereas, from a population perspective, coexistent CKD and hypertension mattered most. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) therapy trials usually exclude cancer patients. We examined the association between cancer history and outcomes in trial participants with HF and reduced (HFrEF) or preserved ejection fraction (HFpEF). Methods and results: We combined PARADIGM‐HF and ATMOSPHERE, which enrolled HFrEF patients (n = 15 415) and we pooled HFpEF patients (ejection fraction ≥45%) enrolled in PARAGON‐HF and CHARM‐Preserved (n = 7363). The associations between cancer history, cardiovascular (CV) death, HF hospitalization, non‐CV and all‐cause death in these trials were examined. Incident cancer diagnoses during these trials were also measured. There were 658 (4.3%) and 624 (8.5%) patients with a cancer history in the HFrEF and HFpEF trials, respectively. HFrEF patients with a cancer history had a higher risk of HF hospitalization (adjusted hazard ratio [HR] 1.28; 95% confidence interval [CI] 1.07–1.52, p = 0.007) and non‐CV death (adjusted HR 1.57; 95% CI 1.16–2.12, p = 0.003) than those without. The risks of other outcomes were similar. There were no differences in the risk of any outcome in HFpEF patients with and without a cancer history. Adjusting for age and sex, the incidence of new cancer in the HFrEF and HFpEF trials was 1.09 (95% CI 0.83–1.36) and 1.07 (95% CI 0.81–1.32) per 100 person‐years, respectively. Conclusions: Although participants in HFrEF trials with a cancer history had higher risks of HF hospitalization and non‐CV death than those without, the risks of CV and all‐cause death were similar. Outcomes in HFpEF patients with and without a cancer history were similar. Incident cancer diagnoses were similar in HFrEF and HFpEF trials. [ABSTRACT FROM AUTHOR]

Aims: Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin–angiotensin–aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non‐absorbed intestinal potassium binder proven to lower serum potassium concentrations. Methods and results: PRIORITIZE‐HF was an international, multicentre, parallel‐group, randomized, double‐blind, placebo‐controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID‐19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated. Conclusions: PRIORITIZE‐HF was terminated prematurely due to COVID‐19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium‐reducing agent SZC compared with placebo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT). RESEARCH DESIGN AND METHODS: We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200–5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs. RESULTS: The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54–0.96; P = 0.025). CONCLUSIONS: Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination. [ABSTRACT FROM AUTHOR]

Aims: To compare the cost‐effectiveness of immediate and 12‐month delayed initiation of dapagliflozin treatment in patients with a history of hospitalization for heart failure (HHF) from the UK, Canadian, German, and Spanish healthcare perspectives. Methods and results: A cost‐utility analysis was conducted using a decision‐analytic Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire scores, type 2 diabetes mellitus status and incidence of heart failure (HF) events. Patient‐level data for patients with prior HHF from the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial were used to inform the model inputs on clinical events and utility values. Healthcare costs were sourced from the relevant national reference databases and the published literature. Compared to standard therapy, immediate initiation of dapagliflozin decreased HHF (187 events), urgent HF visits (32 events) and cardiovascular mortality (18 events). Standard therapy was associated with lifetime costs of £13 224 and 4.02 quality‐adjusted life years (QALYs). Twelve‐month delayed initiation of dapagliflozin was associated with total discounted lifetime costs and QALYs of £16 660 and 4.61, respectively, compared to £16 912 and 4.66, respectively, for immediate initiation. Compared to standard therapy, immediate and 12‐month delayed initiation of dapagliflozin yielded an incremental cost‐effectiveness ratio (ICER) of £5779 and £5821, respectively. Compared to 12‐month delayed initiation, immediate initiation of dapagliflozin had an ICER of £5263. Results were similar from the Canadian, German, and Spanish healthcare perspectives. Conclusion: Both immediate and 12‐month delayed initiation of dapagliflozin are cost‐effective. However, immediate initiation provides greater clinical benefits, with almost 10% additional QALYs gain, compared to 12‐month delayed initiation of dapagliflozin and should be considered standard of care. [ABSTRACT FROM AUTHOR]

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]

Aims: As sacubitril/valsartan may potentiate early natriuresis, expert consensus documents recommend diuretic dose reduction on first initiation. However, there are limited data on the effects of sacubitril/valsartan on the background of varying diuretic regimens or on diuretic requirements over time in heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results: In this post hoc analysis of PARAGON‐HF, of the 4796 patients, background diuretic therapy was distributed as follows: 341 (7%) on no diuretic, 698 (15%) on non‐loop diuretic, and 3757 (78%) were on loop diuretics (1255, 1589, and 913 were on <40, 40 and >40 mg furosemide equivalent doses, respectively). The primary composite outcome of total HF hospitalizations and cardiovascular death was analysed using semiparametric proportional rates methods. The cumulative incidence of the primary composite outcome (first events) was lowest in patients on no diuretic and highest in those on >40 mg of loop diuretic (p < 0.001). The effects of sacubitril/valsartan (vs. valsartan) on the primary composite outcome (recurrent events) did not significantly vary by baseline diuretic use (pinteraction = 0.65). Treatment effects on safety outcomes were similar across diuretic categories. Sacubitril/valsartan reduced new loop diuretic initiations over the course of the trial (hazard ratio 0.83; 95% confidence interval 0.68–1.00, p = 0.055), with similar mean loop diuretic dose and rates of diuretic discontinuation between treatment groups in follow‐up. Patients randomized to sacubitril/valsartan experienced a slight early reduction in diuretic initiation or dose escalation at 30 days after initiation (net reduction 1.7%, p = 0.02), but these differences were not sustained beyond this timepoint. Conclusions: Patients with HFpEF on higher baseline diuretic doses were at heightened risk of HF events, but similarly benefited from sacubitril/valsartan with a consistent safety profile across a range of diuretic doses. Initiation of sacubitril/valsartan was associated with modestly lower new loop diuretic requirement in follow‐up. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to examine the association between patient‐reported symptoms and the extent of pulmonary congestion in acute heart failure (AHF). Methods and results: In this prospective, observational study, patient‐reported symptoms were assessed at baseline using the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) (range 0–100; 0 worst) in patients hospitalized for AHF. In a subset, patient‐reported dyspnoea at rest and on exertion was examined (range 0–10; 10 worst) at baseline. In addition, 4‐zone lung ultrasound (LUS) was performed at baseline at the time of echocardiography. B‐lines were quantified offline, blinded to clinical findings, by a core laboratory. Chest X‐ray (CXR) and physical examination findings were collected from the medical records. Among 322 patients (mean age 72, 60% men, mean left ventricular ejection fraction 39%) with AHF, the median KCCQ‐TSS score was 33 (interquartile range 18–48). Worse KCCQ‐TSS was associated with worse New York Heart Association class, dyspnoea at rest and on exertion, and peripheral oedema (p trend <0.001 for all). However, KCCQ‐TSS was not associated with the extent of pulmonary congestion, as assessed by the number of B‐lines on LUS, or findings on CXR, or physical examination (p trend >0.25 for all). Similarly, KCCQ‐TSS was not significantly associated with echocardiographic markers of left ventricular filling pressure, pulmonary pressure or with N‐terminal pro‐B‐type natriuretic peptide level. Conclusions: Among patients hospitalized for AHF, at baseline, KCCQ‐TSS was not associated with pulmonary congestion assessed by LUS, CXR, or physical examination. These findings suggest that the profound reduction in KCCQ‐TSS in patients with AHF may not be solely explained by pulmonary congestion. [ABSTRACT FROM AUTHOR]

Background: Acute hospitalizations are common in patients with chronic kidney disease (CKD) and often lead to decreases in health-related quality of life and increased care costs.Objective: To determine the effects of dapagliflozin on first hospitalizations and all (first and subsequent) hospitalizations and to explore effects on cause-specific hospitalizations.Design: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT03036150).Setting: 386 ambulatory practice sites in 21 countries from 2 February 2017 through 12 June 2020.Participants: Adults with an estimated glomerular filtration rate of 25 to 75 mL/min/1.73 m2 and a urinary albumin-creatinine ratio of 200 to 5000 mg/g, with and without type 2 diabetes.Intervention: Dapagliflozin, 10 mg once daily, or matching placebo (1:1 ratio).Measurements: The effects of dapagliflozin on first hospitalizations for any cause, all hospitalizations, and cause-specific (first and recurrent) hospitalizations were determined. The reported system organ class was used to evaluate reasons for admission. Hospitalizations were analyzed using Cox proportional hazards regression models (first hospitalization), the Lin-Wei-Yang-Ying method (all hospitalizations or death), and negative binomial models (cause-specific hospitalizations).Results: The study included 4304 patients (mean age, 61.8 years; 33.1% women). During a median follow-up of 2.4 years, 2072 hospitalizations were reported among 1224 (28.4%) participants. Compared with placebo, dapagliflozin reduced risk for a first hospitalization (hazard ratio, 0.84 [95% CI, 0.75 to 0.94]) and all hospitalizations or death (rate ratio, 0.79 [CI, 0.70 to 0.89]). There was no evidence that the effects of dapagliflozin on first and all hospitalizations varied by baseline presence of type 2 diabetes (P for interaction = 0.60 for each). Compared with placebo, dapagliflozin reduced the rate of admissions due to cardiac disorders, renal and urinary disorders, metabolism and nutrition disorders, and neoplasms.Limitations: This was a post hoc analysis and should be viewed as hypothesis-generating. Hospitalizations and causes were reported by site investigators and were not centrally adjudicated.Conclusion: Dapagliflozin reduced the risk for hospitalization for any cause in patients with CKD with and without type 2 diabetes.Primary Funding Source: AstraZeneca. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is associated with poor health‐related quality of life (HRQL). Patients with HF with preserved ejection fraction (HFpEF) have similar HRQL impairment as those with reduced ejection fraction. This study describes the impact of sacubitril/valsartan on HRQL in patients with HFpEF enrolled in the PARAGON‐HF trial. Methods and results: Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol (EQ‐5D) at randomization, 4, 8 months, and annually thereafter. Changes in HRQL scores were evaluated using repeated measures models adjusted for treatment, baseline values and region. The pre‐specified principal efficacy assessment was at 8 months at which time patients randomized to sacubitril/valsartan had borderline higher KCCQ clinical summary score (CSS) with least squares mean (LSM) adjusted difference of 1.0 (95% confidence interval [CI] 0.0, 2.1; p = 0.051). Including all visits up to 36 months, the LSM difference in KCCQ‐CSS favoured sacubitril/valsartan with average adjusted difference of 1.1 (95% CI 0.1, 2.0; p = 0.034). Patients treated with sacubitril/valsartan had greater odds of clinically meaningful improvement (≥5‐point increase) in KCCQ‐CSS (odds ratio 1.31; 95% CI 1.06, 1.61) at 8 months. At 8 months, there was no significant difference in the EQ visual analogue scale between the treatment arms, but sacubitril/valsartan was associated with higher EQ‐5D utility score (US‐based) with LSM adjusted difference of 0.01 (95% CI 0.00, 0.02; p = 0.019). Conclusion: Compared with valsartan, sacubitril/valsartan had a borderline benefit on KCCQ‐CSS at 8 months in patients with HFpEF. This benefit became more significant when data from all visits up to 36 months were included. This modest overall benefit was also supported by greater odds of patients reporting a clinically meaningful improvement in HRQL with sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

Aims: Biomarker‐driven prognostic models incorporating N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity cardiac troponin T (hs‐cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker‐driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR‐Preserved. Methods and results: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all‐cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON‐HF was used as a validation cohort. NT‐proBNP and hs‐cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin‐treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c‐statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT‐proBNP and hs‐cTnT were also the dominant predictors of all‐cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin‐treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all‐cause and cardiovascular mortality (c‐statistic = 0.72 for both). External validation provided c‐statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all‐cause death, and cardiovascular death, respectively. Conclusions: The combination of NT‐proBNP and hs‐cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool‐kit facilitates the ready implementation of these risk models in routine clinical practice. [ABSTRACT FROM AUTHOR]