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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: 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: To describe the baseline characteristics of participants in the FINEARTS‐HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS‐HF trial is comparing the effects of the non‐steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. Methods and results: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34–84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) was 1041 (interquartile range 449–1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large‐scale HFmrEF/HFpEF trials, FINEARTS‐HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium–glucose cotransporter 2 inhibitors and angiotensin receptor–neprilysin inhibitors than previous trials. Conclusions: FINEARTS‐HF has enrolled a broad range of high‐risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population. [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: 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]

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]

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: 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]

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]

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]

Aims Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF. Methods and results Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81–19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77–13.48) in those without [hazard ratio 1.37 (1.26–1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96–15.48) and 9.37 (9.06–9.70) [hazard ratio 1.49 (1.36–1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg). Conclusion Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population. [ABSTRACT FROM AUTHOR]

Aims Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. Methods and results In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (P interaction = 0.64) or loop diuretic dose (P interaction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55–0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86–1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of −6.5% (95% CI: −9.4 to −3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of −2.5 mg/year; 95% CI: −1.5, −3.7, P < 0.001). Conclusion In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time. [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: Seasonal influenza vaccination is strongly recommended in patients with heart failure (HF). The NUDGE‐FLU trial recently found two electronic behavioural nudging letter strategies – a letter highlighting potential cardiovascular benefits of vaccination and a repeated letter at day 14 –effective in increasing influenza vaccination in Denmark. The aims of this pre‐specified analysis was to further examine vaccination patterns and effects of these behavioural nudges in patients with HF including potential off‐target effects on guideline‐directed medical therapy (GDMT) use. Methods and results: The nationwide NUDGE‐FLU trial randomized 964 870 Danish citizens ≥65 years to usual care or nine different electronic nudging letter strategies. Letters were delivered through the official Danish electronic letter system. The primary endpoint was the receipt of an influenza vaccine; additional outcomes for this analysis included GDMT use. In this analysis, we also assessed influenza vaccination rates in the overall Danish HF population including those <65 years (n = 65 075). During the 2022–2023 season, influenza vaccination uptake was 71.6% in the overall Danish HF population but this varied considerably with only 44.6% uptake in those <65 years. A total of 33 109 NUDGE‐FLU participants had HF at baseline. Vaccination uptake was higher among those on higher levels of baseline GDMT (≥3 classes: 85.3% vs. ≤2 classes: 81.9%; p < 0.001). HF status did not modify the effects of the two overall successful nudging strategies on influenza vaccination uptake (cardiovascular gain‐framed letter: pinteraction = 0.37; repeated letter: pinteraction = 0.55). No effect modification was observed across GDMT use levels for the repeated letter (pinteraction = 0.88), whereas a trend towards attenuated effect among those on low levels of GDMT was observed for the cardiovascular gain‐framed letter (pinteraction = 0.07). The letters had no impact on longitudinal GDMT use. Conclusions: Approximately one in four patients with HF did not receive influenza vaccination with a pronounced implementation gap in those <65 years where less than half were vaccinated. HF status did not modify the effectiveness of cardiovascular gain‐framed and repeated electronic nudging letters in increasing influenza vaccination rates. No unintended negative effects on longitudinal GDMT use were observed. Clinical Trial Registration: ClinicalTrials.gov NCT05542004. [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]

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: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF. Methods and results: An individual‐patient‐data meta‐analysis of three randomized trials (HOMAGE, Aldo‐DHF, and TOPCAT) was performed comparing spironolactone (9–12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e′ ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo‐DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo‐DHF, and 134 (13.6%) from TOPCAT. The pooled‐cohort patient's median age was 71 (66–77) years and 39% were women. Median LAVi was 29 (24–35) ml/m2, LVMi 100 (84–118) g/m2, IVS thickness 12 (10–13) mm, E/e′ ratio 11 (9–13), and LVEF 64 (59–69)%. Spironolactone reduced LAVi by −1.1 (−2.0 to −0.1) ml/m2 (p = 0.03); LVMi by −3.6 (−6.4 to −0.8) g/m2 (p = 0.01); IVS thickness by −0.2 (−0.3 to −0.1) mm (p = 0.01); E/e′ ratio by −1.3 (−2.4 to −0.2) (p = 0.02); and increased LVEF by 1.7 (0.8–2.6)% (p < 0.01). No treatment‐by‐study heterogeneity was found except for E/e′ ratio with a larger effect in Aldo‐DHF and TOPCAT (interaction p < 0.01). Conclusions: Spironolactone improved cardiac structure and function of patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aim Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). Methods and results The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70–0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88–1.03; P -value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. Conclusion In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values. [ABSTRACT FROM AUTHOR]

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non‐users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non‐users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF. [ABSTRACT FROM AUTHOR]

Aims Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Methods and results In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N -terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60–3.45]; fifth quintile HR 3.73 (95% CI 2.58–5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75–0.91). Conclusion It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively. [ABSTRACT FROM AUTHOR]

Aims: Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline‐directed medical therapy (GDMT) in patients with new‐onset or worsening HF. Methods and results: Left atrial diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8 ± 12.1 years, 22.3% female) enrolled in BIOSTAT‐CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9‐month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.87–0.93; p < 0.001) and up‐titration to higher doses of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) (OR 0.56; 95% CI 0.34–0.92; p = 0.022) were independently associated with lower likelihood of LAAR. LAAR was associated with an increased risk of the composite of all‐cause mortality or HF hospitalization (log‐rank p = 0.007 and adjusted hazard ratio 1.73, 95% CI 1.22–2.45, p = 0.002). The association was more pronounced in patients without a history of atrial fibrillation (p for interaction = 0.009). Conclusion: Among patients enrolled in BIOSTAT‐CHF, LAAR was associated with an unfavourable outcome and was prevented by ACEi/ARB up‐titration. Changes in LA dimension may be a useful marker of response to treatment and improve risk stratification in patients with HF. [ABSTRACT FROM AUTHOR]

Aims: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double‐blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin‐converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan. Methods: We performed genome‐wide association studies in 2727 patients of European ancestry from CHARM‐Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan‐treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome‐wide gene‐level collapsing analysis from whole‐exome sequencing data with the composite cardiovascular endpoint. Results: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM‐Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55–2.35; P = 1.7 × 10−9). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome‐wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene‐level collapsing analysis. Conclusions: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings. [ABSTRACT FROM AUTHOR]

Aims Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. Methods and results The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium–glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. Conclusion Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62–1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05–2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan. Conclusions: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711 [ABSTRACT FROM AUTHOR]

Aims: Sodium–glucose co‐transporter 2 (SGLT2) inhibitors, originally developed as glucose‐lowering agents, have been shown to reduce heart failure hospitalizations in patients with type 2 diabetes without established heart failure, and in patients with heart failure with and without diabetes. Their role in patients with heart failure with preserved and mildly reduced ejection fraction remains unknown. Methods: Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) is an international, multicentre, parallel group, event‐driven, randomized, double‐blind trial in patients with chronic heart failure and left ventricular ejection fraction (LVEF) >40%, comparing the effect of dapagliflozin 10 mg once daily, vs. placebo, in addition to standard of care. Patients with or without diabetes, with signs and symptoms of heart failure, a LVEF >40%, elevation in natriuretic peptides and evidence of structural heart disease are eligible. The primary endpoint is time‐to‐first cardiovascular death or worsening heart failure event (heart failure hospitalization or urgent heart failure visit), and will be assessed in dual primary analyses – the full population and in those with LVEF <60%. The study is event‐driven and will target 1117 primary events. A total of 6263 patients have been randomized. Conclusions: DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction. [ABSTRACT FROM AUTHOR]

The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to "preserved" ejection fraction but referring to "below normal" ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the "mid range" may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with "reduced" (<40%), "mildly reduced," and "normal" (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients. Methods and results: In a prospective, two‐site study in adults hospitalized for AHF, four‐zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre‐discharge (LUS2). B‐lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P < 0.001), higher tricuspid annular plane systolic excursion (mean 17 vs. 15 mm, P = 0.021), and higher measures of filling pressures (median E/e′ 20 vs. 16, P < 0.001). B‐line number on LUS1 (median 6 vs. 6, P = 0.69) and admission N‐terminal pro‐B‐type natriuretic peptide levels (median 3932 vs. 3483 pg/mL, P = 0.77) were similar in women and men. In 121 patients with both LUS1 and LUS2 data, there was a similar and significant decrease in B‐lines from baseline to discharge in both women and men. The risk of the composite 90 day outcome increased with higher B‐line number on four‐zone LUS2: unadjusted hazard ratio for each B‐line tertile was 1.86 (95% confidence interval 1.08–3.20, P = 0.025) in women and 1.65 (95% confidence interval 1.03–2.64, P = 0.037) in men (interaction P = 0.72). Conclusions: Among patients with AHF, echocardiographic markers differed between women and men at baseline, whereas B‐line number on LUS did not. The dynamic changes in B‐lines during a hospitalization for AHF were similar in women and men. [ABSTRACT FROM AUTHOR]

In addition, the RV-ESA and PASP together with parameters of RV-PA coupling (TAPSE/PASP ratio and RVOT-VTI/PASP ratio) improved significantly in the PK-titration group as compared to the placebo group ( I Table i 1 and I Figure i 1). Our analyses demonstrated that 20 weeks of OM treatment in patients with HFrEF improved RV-SET, RV-VTI in both OM groups, and improved RV-ESA, RV afterload and RV-PA coupling only in the PK-titration group, whereas OM did not significantly improve TAPSE or RV-FAC. Right ventricular (RV) dysfunction due to post-capillary pulmonary hypertension is a common sequela of elevated left ventricular (LV) filling pressures in patients with heart failure (HF) which has been demonstrated to be associated with poor clinical outcomes.1-3 Measures of RV-pulmonary artery (RV-PA) coupling that evaluate indices of RV function and pulmonary hypertension severity have been shown to be associated with clinical outcomes.4,5 A phase 2 trial, COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure, NCT01786512) demonstrated that treatment with omecamtiv mecarbil (OM), a selective cardiac myosin activator, known as a myotrope, was related to an improved LV systolic function, beneficial reverse remodelling, sympathetic withdrawal and a reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with HF with reduced ejection fraction (HFrEF).6 In this research letter, we report the treatment effect of OM on RV structure and function together with RV-PA coupling in patients with HFrEF. [Extracted from the article]

Introduction: Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) and is associated with higher rates of hospitalization compared to those without AF. Whether routine electrocardiographic parameters are predictive of future hospitalizations with AF is not clear. Methods: The present study is an analysis of a prospective cohort of 2,759 patients without baseline AF from the Chronic Renal Insufficiency Cohort, a large prospective multicenter study of patients with nondialysis-dependent CKD. Unadjusted and adjusted Cox regression models were fit to examine the association of baseline categories of QTc, QRS, and PR intervals with time to first hospitalization with AF. Restricted cubic splines were used to display nonlinear associ-ations. Results: The mean age of subjects at baseline was 58 ± 11 years, 55% were male, and 44% were Black. The mean follow-up was 6.6 years during which 224 participants experienced a hospitalization with AF. The association of baseline QTc interval with risk of AF hospitalization was nonlinear, such that the lowest and highest quartiles of QTc (<407 and >431 ms, respectively) had higher adjusted risk of AF hospitalization, compared with the second quartile (407–416 ms) (aHR Q1:Q2 1.58, 95% CI 1.03–2.41; p = 0.03; aHR Q4:Q2 1.84, 95% CI 1.22–2.78; p < 0.01). Longer QRS was associated with a higher risk of hospitalization with AF among the subgroup of patients with a history of heart failure (HF). PR interval was not associated with AF hospitalization. Discussion/Conclusion: The association of QTc with risk for hospitalization with AF among patients with CKD is nonlinear, while the association of longer QRS with AF hospitalization is restricted to patients with baseline HF. Electrocardiography may represent a simple and widely accessible method for risk stratification of future AF in patients with CKD. [ABSTRACT FROM AUTHOR]

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well‐established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON‐HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. Methods and results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo‐, normo‐, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4–5 mmol/L and >5 mmol/L, respectively. Both screening and time‐updated potassium (categorical and continuous spline‐transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time‐updated (but not screening) hypo‐ and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30–1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02–1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all‐cause, cardiovascular and non‐cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all‐cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow‐up. Conclusions: Both hypo‐ and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non‐cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death. [ABSTRACT FROM AUTHOR]

Aims: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non‐diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non‐DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature. Methods and results: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high‐sensitivity C‐reactive protein, pro‐collagen type III amino‐terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP‐1), and galectin‐3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high‐sensitivity troponin T (hs‐TnT), a marker of myocyte death, in DM patients. Elevated pro‐collagen type III amino‐terminal peptide and galectin‐3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs‐TnT and for TIMP‐1, with greater biomarker reductions among those with diabetes treated with spironolactone. Conclusions: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti‐fibrotic fashion in patients with diabetes, reflected by changes in hs‐TnT and TIMP‐1 levels over time. [ABSTRACT FROM AUTHOR]

Aims: We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). Methods and results: Aetiology was investigator‐reported and categorized as ischaemic or non‐ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4744 patients were randomized in DAPA‐HF, of whom 2674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13–1.63], but lower risk of HF hospitalization (HR 0.83, 95% CI 0.70–0.98) than non‐ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non‐ischaemic aetiology (HR 0.77, 95% CI 0.65–0.92, and HR 0.71, 95% CI 0.58–0.87, respectively; P for interaction = 0.55). Consistent benefits were observed for the components of the primary outcome and all‐cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) of ≥5 points (P for interaction = 0.32) and decreased the proportion with a deterioration in KCCQ‐TSS of ≥5 points (P for interaction = 0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology. Conclusions: Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non‐ischaemic aetiology. In addition, dapagliflozin was safe and well‐tolerated, irrespective of aetiology. [ABSTRACT FROM AUTHOR]

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]

Objective: The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial.Research Design and Methods: The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model.Results: At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not.Conclusions: In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure. [ABSTRACT FROM AUTHOR]

Aims: Colour tissue Doppler imaging (TDI) M‐mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and systolic ejection time (SET). The myocardial performance index (MPI) is defined as [(IVCT + IVRT)/SET]. Whether cardiac time intervals obtained by the TDI M‐mode method can be used to predict outcome in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. Methods and results: A total of 997 patients with HFrEF (mean age 67 ± 11 years, 74% male) underwent an echocardiographic examination including TDI. During a median follow‐up of 3.4 years (interquartile range 1.9–4.8 years), 165 (17%) patients died. The risk of mortality increased by 9% per 10 ms decrease in SET [per 10 ms decrease: hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06–1.13; P < 0.001]. The association remained significant even after multivariable adjustment for clinical and echocardiographic parameters (per 10 ms decrease: HR 1.06, 95% CI 1.01–1.11; P = 0.030). The MPI was a significant predictor in an unadjusted model (per 0.1 increase: HR 3.06, 95% CI 1.16–8.06; P = 0.023). However, the association did not remain significant after multivariable adjustment. No significant associations between IVCT or IVRT and mortality were found in unadjusted nor adjusted models. Additionally, SET provided incremental prognostic information with regard to predicting mortality when added to established clinical predictors of mortality in patients with HFrEF. Conclusion: In patients with HFrEF, SET provides independent and incremental prognostic information regarding all‐cause mortality. [ABSTRACT FROM AUTHOR]

Aims: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM‐HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM‐HF. Methods and results: HF duration was categorized as 0–1, >1–2, >2–5, and >5 years. Outcomes were adjusted for prognostic variables, including N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0–1 year, 2523 (30%); >1–2 years, 1178 (14%); >2–5 years, 2054 (24.5%); and >5 years, 2644 (31.5%). Patients with longer‐duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co‐morbidity, and higher troponin‐T but similar NT‐proBNP levels. The primary outcome rate (per 100 person‐years) increased with HF duration: 0–1 year, 8.4 [95% confidence interval (CI) 7.6–9.2]; >1–2 years, 11.2 (10.0–12.7); >2–5 years, 13.4 (12.4–14.6); and >5 years, 14.2 (13.2–15.2); P < 0.001. The hazard ratio was 1.26 (95% CI 1.07–1.48), 1.52 (1.33–1.74), and 1.53 (1.33–1.75), respectively, for >1–2, >2–5, and >5 years, compared with 0–1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67–0.97) for 0–1 year and 0.73 (0.63–0.84) in the >5 year group. For the primary outcome, the number needed to treat for >5 years was 18, compared with 29 for 0–1 year. Conclusions: Patients with longer‐duration HF had more co‐morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long‐standing HF. [ABSTRACT FROM AUTHOR]

Aims: The importance of intra‐ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM‐HF and ATMOSPHERE trials. Methods and results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all‐cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non‐specific IVCD, 2588 (21.8%) 'mildly abnormal' QRS (110–129 ms) and 6506 (54.9%) QRS <110 ms. During a median follow‐up of 2.5 years, the risk of the primary composite endpoint was higher among those with a wide QRS, irrespective of morphology: hazard ratios (95% confidence interval) LBBB 1.36 (1.23–1.50), RBBB 1.54 (1.31–1.79), non‐specific IVCD 1.65 (1.40–1.94) and QRS 110–129 ms 1.35 (1.23–1.47), compared with QRS duration <110 ms. A total of 1234 (15.6%) patients developed new‐onset QRS widening ≥130 ms (6.1 per 100 patient‐years). Incident LBBB occurred in 495 (6.3%) patients (2.4 per 100 patient‐years) and was associated with a higher risk of the primary composite outcome [hazard ratio 1.42 (1.12–1.82)]. Conclusion: In patients with HFrEF, a wide QRS was associated with worse clinical outcomes irrespective of morphology. The annual incidence of new‐onset LBBB was around 2.5%, and associated with a higher risk of adverse outcomes, highlighting the importance of repeat electrocardiogram review. Trial Registration: ClinicalTrials.gov Identifier NCT0083658 (ATMOSPHERE) and NCT01035255 (PARADIGM‐HF). [ABSTRACT FROM AUTHOR]

Objective: To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).Research Design and Methods: We examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.Results: In the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58-0.88] vs. 0.86 [0.60-1.23]; interaction P = 0.39) and across GLT classes.Conclusions: In DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF. [ABSTRACT FROM AUTHOR]

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N‐terminal pro‐B‐type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC‐HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation. [ABSTRACT FROM AUTHOR]

Aims: We sought to determine sex‐based differences in biomarkers, self‐reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). Methods and results: This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE‐HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)‐23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P < 0.001) and faster pace of KCCQ change (P < 0.001) over the course of the trial. Women and men demonstrated similar degrees of reverse left ventricular remodelling following S/V initiation; however, women did so earlier than men with more consistent changes. These results remained unchanged with adjustment for relevant covariates. Reduction in NT‐proBNP was associated with reverse cardiac remodelling in both women and men. Treatment with S/V was well tolerated in all. Conclusions: In women with HFrEF, treatment with S/V was associated with significant NT‐proBNP reduction, health status improvement and reverse cardiac remodelling. [ABSTRACT FROM AUTHOR]

Aims: The associations between potassium level and outcomes, the effect of sacubitril–valsartan on potassium level, and whether potassium level modified the effect of sacubitril–valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM‐HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non‐cardiovascular death and heart failure hospitalization, were examined. Methods and results: A total of 8399 patients were randomized to either enalapril or sacubitril–valsartan. Potassium level at randomization and follow‐up was examined as a continuous and categorical variable (≤3.5, 3.6–4.0, 4.1–4.9, 5.0–5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K+ ≥5.5 mmol/L and hypokalaemia as K+ ≤3.5 mmol/L. Compared with potassium 4.1–4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84–3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10–1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non‐cardiovascular death and heart failure hospitalization. Sacubitril–valsartan had no effect on potassium overall. The benefit of sacubitril–valsartan over enalapril was consistent across the range of baseline potassium levels. Conclusions: Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death. [ABSTRACT FROM AUTHOR]

Aims: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).Methods and Results: Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001).Conclusion: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF. [ABSTRACT FROM AUTHOR]

Aims: The prevalence of liver function abnormalities is common in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We assessed the impact of liver function on prognosis and the effect of sacubitril/valsartan on measures of liver function in patients with HFrEF.Methods and Results: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled trial. We included 8232 HFrEF patients with available measures of liver function, including transaminases, alkaline phosphatase (ALP) and bilirubin; the primary endpoint was a composite of HF hospitalization and cardiovascular (CV) death. At screening, 11.6% of study patients had total bilirubin above the upper limit of normal (20.5 μmol/L) and 9.2% had ALP above the upper limit of normal (123 IU/L). Although ALP and albumin were associated with an increased risk of outcomes, among conventional test of liver function, total bilirubin was the strongest predictor for the primary endpoint [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04-1.15; P < 0.001], HF hospitalization (HR 1.14; 95% CI 1.07-1.22; P < 0.001); CV death (HR 1.07; 95% CI 1.00-1.14; P = 0.040), and all-cause death (HR 1.08; 95% CI 1.02-1.14; P = 0.009). All conventional measures of liver function were significantly improved in the sacubitril/valsartan group compared with the enalapril group after randomization (between-group reduction: total bilirubin 2.4%, 95% CI 0.7-4.2%, P = 0.007; aspartate aminotransferase 7.9%, 95% CI 6.7-9.0%, P < 0.001; alanine aminotransferase 7.7%; 95% CI 6.2-9.3%, P < 0.001; ALP 5.4%, 95% CI 4.4-6.4%, P < 0.001).Conclusion: Total bilirubin was a significant and independent predictor of CV death or HF hospitalization and all-cause mortality in patients with HFrEF enrolled in PARADIGM-HF. Sacubitril/valsartan improved measures of liver function compared with enalapril. [ABSTRACT FROM AUTHOR]

Drs Wong and Demers are of course correct that there is an association between frailty and age, but it is also well recognized that frailty can develop at any age. Article Information Disclosures J.H.B. reports advisory board honoraria from Bayer, consultant fees from Novartis, and travel grants from AstraZeneca. [Extracted from the article]

The article discusses the Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure (CONNECT-HF) in the U.S. and its significance in establishing the value of dissemination and implementation research on cardiometabolic medicine. Topics include the effect of a hospital and postdischarge quality improvement intervention compared with usual care on HF outcomes and care and the percentage of HF rehospitalization or all-cause mortality reported in the trial.

We thank Yu I et al i . for their comments on our research paper assessing the clinical and prognostic implications of left atrial (LA) structural changes after optimization of medical therapy in patients with heart failure (HF).[1] In the past decades, the concept of LA remodelling has evolved, and the contribution of the left atrium to the pathophysiology of HF has significantly grown.[[2], [4]] Indeed, changes in LA structure and function may be either a marker of HF severity and a mechanism actively contributing to the progression of cardiac dysfunction. They reported that discordant left-sided reverse remodelling (LA without LV reverse remodelling) showed comparable mortality and HF hospitalization risk to patients with both LA and LV reverse remodelling. [Extracted from the article]