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Continuous automatic optimisation of cardiac resynchronisation therapy (CRT), stimulating only the left ventricle to fuse with intrinsic right bundle conduction (synchronised left ventricular stimulation), might offer better outcomes than conventional CRT in patients with heart failure, left bundle branch block, and normal atrioventricular conduction. This study aimed to compare clinical outcomes of adaptive CRT versus conventional CRT in patients with heart failure with intact atrioventricular conduction and left bundle branch block. This global, prospective, randomised controlled trial was done in 227 hospitals in 27 countries across Asia, Australia, Europe, and North America. Eligible patients were aged 18 years or older with class 2–4 heart failure, an ejection fraction of 35% or less, left bundle branch block with QRS duration of 140 ms or more (male patients) or 130 ms or more (female patients), and a baseline PR interval 200 ms or less. Patients were randomly assigned (1:1) via block permutation to adaptive CRT (an algorithm providing synchronised left ventricular stimulation) or conventional biventricular CRT using a device programmer. All patients received device programming but were masked until procedures were completed. Site staff were not masked to group assignment. The primary outcome was a composite of all-cause death or intervention for heart failure decompensation and was assessed in the intention-to-treat population. Safety events were collected and reported in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT02205359 , and is closed to accrual. Between Aug 5, 2014, and Jan 31, 2019, of 3797 patients enrolled, 3617 (95·3%) were randomly assigned (1810 to adaptive CRT and 1807 to conventional CRT). The futility boundary was crossed at the third interim analysis on June 23, 2022, when the decision was made to stop the trial early. 1568 (43·4%) of 3617 patients were female and 2049 (56·6%) were male. Median follow-up was 59·0 months (IQR 45–72). A primary outcome event occurred in 430 of 1810 patients (Kaplan-Meier occurrence rate 23·5% [95% CI 21·3–25·5] at 60 months) in the adaptive CRT group and in 470 of 1807 patients (25·7% [23·5–27·8] at 60 months) in the conventional CRT group (hazard ratio 0·89, 95% CI 0·78–1·01; p=0·077). System-related adverse events were reported in 452 (25·0%) of 1810 patients in the adaptive CRT group and 440 (24·3%) of 1807 patients in the conventional CRT group. Compared with conventional CRT, adaptive CRT did not significantly reduce the incidence of all-cause death or intervention for heart failure decompensation in the included population of patients with heart failure, left bundle branch block, and intact AV conduction. Death and heart failure decompensation rates were low with both CRT therapies, suggesting a greater response to CRT occurred in this population than in patients in previous trials. Medtronic. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF. Methods and results: In this pre‐defined secondary analysis of EMPEROR‐Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF. Conclusions: In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. Methods: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. Results: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66–1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48–0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (P interaction=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. Conclusions: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02937454. [ABSTRACT FROM AUTHOR]

Aims: Empagliflozin improves cardiovascular and renal outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but its efficacy and safety across patient's age is not well established. Methods and results: We assessed the effects of empagliflozin (10 mg daily) versus placebo, on top of standard HF therapy, in symptomatic HFrEF patients with a left ventricular ejection fraction ≤40% and increased natriuretic peptides stratified by age (<65, 65–74, ≥75 years). The primary endpoint was a composite of cardiovascular death or HF hospitalization. Key secondary endpoints included first and recurrent HF hospitalizations and slope of change in estimated glomerular filtration rate (eGFR); the latter was supported by an analysis of a renal composite endpoint (chronic dialysis or renal transplantation or profound and sustained reduction in eGFR). Of 3730 patients, 38% were <65 years, 35% were 65–74 years and 27% were ≥75 years. Compared with placebo, empagliflozin reduced the primary endpoint consistently across the three age groups (hazard ratio 0.71 [95% confidence interval 0.57–0.89] for <65 years, 0.72 [0.57–0.93] for 65–74 years, 0.86 [0.67–1.10] for ≥75 years, interaction p‐trend test = 0.24). The effects of empagliflozin were also consistent across age groups for key secondary endpoints of first and recurrent HF hospitalization (p‐trend = 0.30), the rate of decline in eGFR (p‐trend = 0.78) and the renal composite (p‐trend = 0.94). Adverse events (AEs), serious AEs and AEs leading to drug discontinuation increased with age in both treatment arms, but empagliflozin did not increase their incidence over placebo within each age group. Conclusion: The efficacy and safety of empagliflozin in improving cardiovascular and renal outcomes in HFrEF was consistent across the spectrum of age, including older patients (aged ≥75). [ABSTRACT FROM AUTHOR]

Background: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).Methods: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed.Results: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score.Conclusions: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT03057951. [ABSTRACT FROM AUTHOR]

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated.Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; Pinteraction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m2 in patients without diabetes; Pinteraction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (Pinteraction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT03057951. [ABSTRACT FROM AUTHOR]

Aims: This prespecified analysis of the FIDELIO‐DKD trial compared the effects of finerenone, a selective non‐steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF). Methods and results: Patients with T2D and CKD (urine albumin‐to‐creatinine ratio ≥30–5000 mg/g and estimated glomerular filtration rate [eGFR] ≥25–<75 ml/min/1.73 m2), without symptomatic HF with reduced ejection fraction (New York Heart Association II–IV) and treated with optimized renin–angiotensin system blockade were randomized to finerenone or placebo. The composite cardiovascular (CV) outcome (CV death, non‐fatal myocardial infarction, non‐fatal stroke, or hospitalization for HF) and composite kidney outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) were analysed by investigator‐reported medical history of HF. Of 5674 patients, 436 (7.7%) had a history of HF. Over a median follow‐up of 2.6 years, the effect of finerenone compared with placebo on the composite CV outcome was consistent in patients with and without a history of HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50–1.06 and HR 0.90, 95% CI 0.77–1.04, respectively; interaction p = 0.33). The effect of finerenone on the composite kidney outcome did not differ by history of HF (HR 0.79, 95% CI 0.52–1.20 and HR 0.83, 95% CI 0.73–0.94, respectively; interaction p = 0.83). Conclusion: In FIDELIO‐DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes.Methods: Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m2, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m2), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators).Results: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50-0.93]; P=0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70-0.95]; P=0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56-0.90]; P=0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups.Conclusions: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02545049. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.Methods: Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.Results: The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.Conclusions: In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models.Objectives: This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study.Methods: Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m2 and received optimized doses of renin-angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF.Results: Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53-0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively).Conclusions: In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. (EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993). [ABSTRACT FROM AUTHOR]

Background: The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. We report the effect of finerenone on individual cardiovascular outcomes and in patients with and without history of atherosclerotic cardiovascular disease (CVD).Methods: This randomized, double-blind, placebo-controlled trial included patients with type 2 diabetes and urine albumin-to-creatinine ratio 30 to 5000 mg/g and an estimated glomerular filtration rate ≥25 to <75 mL per min per 1.73 m2, treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite cardiovascular outcome included time to cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified cardiovascular analyses included analyses of the components of this composite and outcomes according to CVD history at baseline.Results: Between September 2015 and June 2018, 13 911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 [95% CI, 0.75-0.99]; P=0.034), with no significant interaction between patients with and without CVD (hazard ratio, 0.85 [95% CI, 0.71-1.01] in patients with a history of CVD; hazard ratio, 0.86 [95% CI, 0.68-1.08] in patients without a history of CVD; P value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone versus 0.8% with placebo in patients with CVD and 2.2% with finerenone versus 1.0% with placebo in patients without CVD).Conclusions: Among patients with chronic kidney disease and type 2 diabetes, finerenone reduced incidence of the composite cardiovascular outcome, with no evidence of differences in treatment effect based on preexisting CVD status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02540993. [ABSTRACT FROM AUTHOR]

The article discusses the ambiguity in defining iron deficiency in heart failure patients, focusing on the differentiation between absolute and functional iron deficiency. Topics include discrepancies in defining iron deficiency in heart failure trials, considerations of ferritin levels and transferrin saturation, and the impact of intravenous iron treatment on mortality.

Aim: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. Materials and Methods: We performed a post‐hoc analysis of pooled patient‐level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR‐Reduced and EMPEROR‐Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. Results: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63‐0.86; using insulin, hazard ratio 0.81, 95% CI 0.66‐1.00, pinteraction =.49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction =.75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction =.30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow‐up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50‐0.88). Conclusions: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes. [ABSTRACT FROM AUTHOR]

Anticoagulation for atrial fibrillation may be challenging in patients with active malignancies in whom thromboembolic or bleeding risk may be quite higher than in non-cancer patients.10 In addition, proper adjustment of ongoing anticancer therapies may also be required after arrhythmia development. B This article refers to 'Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study' by M.S. Anker I et al i ., published in this issue on pages 145-153. b Cardiovascular (CV) disease is increasingly being recognized as an important part of the clinical spectrum of patients with cancer, representing the second most common cause of death in these patients.1,2 Coexisting CV disorders and CV complications of anticancer therapies may thus have an impact on the outcomes of these patients, a fact that gave rise to the concept and new field of Cardio-Oncology.3 Among CV manifestations of patients with malignancies, arrhythmias hold a prominent position. Arrhythmias in cancer: rhythm is going to get you!. [Extracted from the article]

Aim: To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity. Materials and methods: A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low‐risk or high–very high‐risk (H‐/VH‐risk). Results: Of 12 986 patients analysed, 90.8% occupied the H‐/VH‐risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low‐risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72‐1.47); finerenone reduced the risk in the H‐/VH‐risk WC group (HR 0.85; 95% CI, 0.77‐0.93). For the kidney outcome, the risk was similar in the low‐risk WC group (HR 0.98; 95% CI, 0.66‐1.46) and reduced within the H‐/VH‐risk WC group (HR 0.75; 95% CI, 0.65‐0.87) with finerenone versus placebo. There was no significant heterogeneity between the low‐risk and H‐/VH‐risk WC groups for cardiovascular and kidney composite outcomes (P interaction =.26 and.34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H‐/VH‐risk WC patients may be because of the small size of the low‐risk group. Adverse events were consistent across WC groups. Conclusion: In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity. [ABSTRACT FROM AUTHOR]

The AdaptResponse trial is designed to test the hypothesis that preferential adaptive left ventricular-only pacing with the AdaptivCRT® algorithm reduces the incidence of the combined endpoint of all-cause mortality and intervention for heart failure (HF) decompensation, compared with conventional cardiac resynchronization therapy (CRT), among patients with a CRT indication, left bundle branch block (LBBB) and normal atrioventricular (AV) conduction. The AdaptResponse study is a prospective, randomized, controlled, single-blinded, multicentre, clinical trial (ClinicalTrials.gov Identifier: NCT02205359), conducted at up to 200 centres worldwide. Following enrolment and baseline assessment, eligible subjects will be implanted with a CRT system containing the AdaptivCRT algorithm, and randomized in a 1:1 fashion to either a treatment ('AdaptivCRT') or control ('Conventional CRT') group. The study is designed to observe a primary endpoint in 1100 patients ('event-driven') and approximately 3000 patients will be randomized. The primary endpoint is the composite of all-cause mortality and intervention for HF decompensation; secondary endpoints include all-cause mortality, intervention for HF decompensation, clinical composite score (CCS) at 6 months, atrial fibrillation, quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), health outcome measured by the EQ-5D instrument, all-cause readmission after a HF admission, and cost-effectiveness. The AdaptResponse clinical trial is powered to assess clinical endpoints and is expected to provide definitive evidence on the incremental utility of AdaptivCRT-enhanced CRT systems. [ABSTRACT FROM AUTHOR]

The AdaptResponse trial is designed to test the hypothesis that preferential adaptive left ventricular-only pacing with the AdaptivCRT® algorithm reduces the incidence of the combined endpoint of all-cause mortality and intervention for heart failure (HF) decompensation, compared with conventional cardiac resynchronization therapy (CRT), among patients with a CRT indication, left bundle branch block (LBBB) and normal atrioventricular (AV) conduction. The AdaptResponse study is a prospective, randomized, controlled, single-blinded, multicentre, clinical trial (ClinicalTrials.gov Identifier: NCT02205359), conducted at up to 200 centres worldwide. Following enrolment and baseline assessment, eligible subjects will be implanted with a CRT system containing the AdaptivCRT algorithm, and randomized in a 1:1 fashion to either a treatment (‘AdaptivCRT’) or control (‘Conventional CRT’) group. The study is designed to observe a primary endpoint in 1100 patients (‘event-driven’) and approximately 3000 patients will be randomized. The primary endpoint is the composite of all-cause mortality and intervention for HF decompensation; secondary endpoints include all-cause mortality, intervention for HF decompensation, clinical composite score (CCS) at 6 months, atrial fibrillation, quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), health outcome measured by the EQ-5D instrument, all-cause readmission after a HF admission, and cost-effectiveness. The AdaptResponse clinical trial is powered to assess clinical endpoints and is expected to provide definitive evidence on the incremental utility of AdaptivCRT-enhanced CRT systems. [ABSTRACT FROM AUTHOR]

Aims: There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. Methods and results: In the EMPEROR‐Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5‐ and 10‐point increase and 5‐point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ‐CSS score improved during follow‐up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5‐point increase in KCCQ‐CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ‐CSS, ‐TSS and ‐OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). Conclusion: Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients. [ABSTRACT FROM AUTHOR]

Aims Exploratory assessment of the potential benefits of the novel soluble guanylate cyclase stimulator vericiguat on health status in patients with heart failure ( HF) with preserved ejection fraction. Methods and results The SOCRATES-PRESERVED trial randomized patients with chronic HF and ejection fraction ≥ 45% within 4 weeks of decompensation to 12 weeks of treatment with titrated doses of vericiguat (1.25, 2.5, 5, and 10 mg once daily) or placebo. Health status was assessed with the disease-specific Kansas City Cardiomyopathy Questionnaire ( KCCQ) and the generic health-related quality of life measure EQ-5D. In total, 477 patients were randomized 12.9 ± 9.0 days after hospitalization or if requiring outpatient treatment with intravenous diuretics for HF. Baseline KCCQ clinical summary score ( CSS), a combination of symptom and physical function domains, was 52.3 ± 20.4 in the 10 mg arm and 54.1 ± 23.0 in placebo, and EQ-5D US index score was 0.74 ± 0.2 and 0.73 ± 0.2, respectively. A larger proportion of patients treated with vericiguat in the 10 mg arm, compared with placebo, achieved clinically meaningful improvements in KCCQ-CSS (82.0% vs. 59.0%, number needed to treat = 4.35, P = 0.0052). Important domains of the KCCQ as well as EQ-5D scores demonstrated a dose-dependent relationship with vericiguat. In the 10 mg arm, the mean physical limitations domain increased by +17.2 ± 19.1 at 12 weeks, compared with +4.5 ± 21.6 in placebo ( P = 0.0009). The EQ-5D US index score increased by +0.064 ± 0.167 in the 10 mg arm, compared with a decrease of −0.009 ± 0.195 in placebo ( P = 0.0461). Improvements in KCCQ and EQ-5D scores paralleled physician-assessed NYHA class and clinical congestion. Conclusion Vericiguat, in exploratory hypothesis-generating analyses, was associated with clinically important improvements in patients' health status, as assessed by the KCCQ and EQ-5D. Further studies should be conducted to test the hypothesis that vericiguat improves physical functioning and health-related quality of life in patients with HF with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]

Aims: Exploratory assessment of the potential benefits of the novel soluble guanylate cyclase stimulator vericiguat on health status in patients with heart failure (HF) with preserved ejection fraction.Methods and Results: The SOCRATES-PRESERVED trial randomized patients with chronic HF and ejection fraction ≥ 45% within 4 weeks of decompensation to 12 weeks of treatment with titrated doses of vericiguat (1.25, 2.5, 5, and 10 mg once daily) or placebo. Health status was assessed with the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) and the generic health-related quality of life measure EQ-5D. In total, 477 patients were randomized 12.9 ± 9.0 days after hospitalization or if requiring outpatient treatment with intravenous diuretics for HF. Baseline KCCQ clinical summary score (CSS), a combination of symptom and physical function domains, was 52.3 ± 20.4 in the 10 mg arm and 54.1 ± 23.0 in placebo, and EQ-5D US index score was 0.74 ± 0.2 and 0.73 ± 0.2, respectively. A larger proportion of patients treated with vericiguat in the 10 mg arm, compared with placebo, achieved clinically meaningful improvements in KCCQ-CSS (82.0% vs. 59.0%, number needed to treat = 4.35, P = 0.0052). Important domains of the KCCQ as well as EQ-5D scores demonstrated a dose-dependent relationship with vericiguat. In the 10 mg arm, the mean physical limitations domain increased by +17.2 ± 19.1 at 12 weeks, compared with +4.5 ± 21.6 in placebo (P = 0.0009). The EQ-5D US index score increased by +0.064 ± 0.167 in the 10 mg arm, compared with a decrease of -0.009 ± 0.195 in placebo (P = 0.0461). Improvements in KCCQ and EQ-5D scores paralleled physician-assessed NYHA class and clinical congestion.Conclusion: Vericiguat, in exploratory hypothesis-generating analyses, was associated with clinically important improvements in patients' health status, as assessed by the KCCQ and EQ-5D. Further studies should be conducted to test the hypothesis that vericiguat improves physical functioning and health-related quality of life in patients with HF with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals. [ABSTRACT FROM AUTHOR]

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs. The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid-base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Aims The clinical characteristics, initial presentation, management, and outcomes of patients hospitalized with new-onset (first diagnosis) heart failure ( HF) or decompensation of chronic HF are poorly understood worldwide. REPORT-HF (International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) is a global, prospective, and observational study designed to characterize patient trajectories longitudinally during and following an index hospitalization for HF. Methods Data collection for the registry will be conducted at ∼300 sites located in ∼40 countries. Comprehensive data including demographics, clinical presentation, co-morbidities, treatment patterns, quality of life, in-hospital and post-discharge outcomes, and health utilization and costs will be collected. Enrolment of ∼20 000 adult patients hospitalized with new-onset (first diagnosis) HF or decompensation of chronic HF over a 3-year period is planned with subsequent 3 years follow-up. Perspective The REPORT-HF registry will explore the clinical characteristics, management, and outcomes of HF worldwide. This global research programme may have implications for the formulation of public health policy and the design and conduct of international clinical trials. [ABSTRACT FROM AUTHOR]

Aims Anaemia and iron deficiency are constituents of the cardio-renal syndrome in chronic heart failure ( CHF). We investigated the effects of i.v. iron in iron-deficient CHF patients on renal function, and the efficacy and safety of this therapy in patients with renal dysfunction. Methods and results The FAIR-HF trial randomized 459 CHF patients with iron deficiency (ferritin <100 µg/L, or between 100 and 299 µg/L if transferrin saturation was <20%): 304 to i.v. ferric carboxymaltose ( FCM) and 155 to placebo, and followed-up for 24 weeks. Renal function was assessed at baseline and at weeks 4, 12, and 24, using the estimated glomerular filtration rate ( eGFR, mL/min/1.73 m2), calculated from the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) formula. At baseline, renal function was similar between groups (62.4 ± 20.6 vs. 62.9 ± 23.4 mL/min/1.73 m2, FCM vs. placebo). Compared with placebo, treatment with FCM was associated with an increase in eGFR [treatment effect: week 4, 2.11 ± 1.21 ( P = 0.082); week 12, 2.41 ± 1.33 ( P = 0.070); and week 24, 2.98 ± 1.44 mL/min/1.73 m2 ( P = 0.039)]. This effect was seen in all pre-specified subgroups ( P > 0.20 for interactions). No interaction between the favourable effects of FCM and baseline renal function was seen for the primary endpoints [improvement in Patient Global Assessment ( P = 0.43) and NYHA class ( P = 0.37) at 24 weeks]. Safety and adverse event profiles were similar in patients with baseline eGFR <60 and ≥60 mL/min/1.73 m2. Conclusions Treatment of iron deficiency in CHF patients with i.v. FCM was associated with an improvement in renal function. FCM therapy was effective and safe in CHF patients with renal dysfunction. [ABSTRACT FROM AUTHOR]

Aims Therapy with i.v. iron in patients with chronic heart failure (CHF) and iron deficiency (ID) improves symptoms, functional capacity, and quality of life. We sought to investigate whether these beneficial outcomes are independent of anaemia. Methods and results FAIR-HF randomized 459 patients with CHF [NYHA class II or III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III)] and ID to i.v. iron as ferric carboxymaltose (FCM) or placebo in a 2:1 ratio. We analysed the efficacy and safety according to the presence or absence of anaemia (haemoglobin ≤120 g/L) at baseline. Of 459 patients, 232 had anaemia at baseline (51%). The effect of FCM on the primary endpoints of self-reported Patient Global Assessment (PGA) and NYHA class at week 24 was similar in patients with and without anaemia [odds ratio (OR) for improvement, 2.48 vs. 2.60, P = 0.97 for PGA and 1.90 vs. 3.39, P = 0.51 for NYHA). Results were also similar for the secondary endpoints, including PGA and NYHA at weeks 4 and 12, 6 min walk test distance, Kansas City Cardiomyopathy Questionnaire overall score, and European Quality of Life-5 Dimensions Visual Analogue Scale at most time points. Regarding safety, no differences were noticed in the rates of death or first hospitalization between FCM and placebo both in anaemic and in non-anaemic patients. Conclusions Treatment of ID with FCM in patients with CHF is equally efficacious and shows a similar favourable safety profile irrespective of anaemia. Iron status should be assessed in symptomatic CHF patients both with and without anaemia and treatment of ID should be considered. [ABSTRACT FROM AUTHOR]

The article presents the results of the adherence to guideline-directed medical and device therapy in outpatients (ATA) study that involved heart failure patients with reduced ejection fraction. It mentions the reports that have assessed the difference between routine clinical practice and the use of guideline-recommended therapy.

OBJECTIVE: Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium–glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes. RESULTS: Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79–0.96) without SGLT2i and 0.67 (95% CI 0.42–1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69–0.92) without SGLT2i and 0.42 (95% CI 0.16–1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment. CONCLUSIONS: Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use. [ABSTRACT FROM AUTHOR]

Aims BAY 94-8862 is a novel, non-steroidal, mineralocorticoid receptor antagonist with greater selectivity than spironolactone and stronger mineralocorticoid receptor binding affinity than eplerenone. The aims of the MinerAlocorticoid Receptor Antagonist Tolerability Study (ARTS; NCT01345656) are to evaluate the safety and tolerability of BAY 94-8862 in patients with heart failure associated with a reduced left ventricular ejection fraction (HFREF) and chronic kidney disease (CKD), and to examine the effects on biomarkers of cardiac and renal function. Methods ARTS is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study divided into two parts. In part A, oral BAY 94-8862 [2.5, 5, or 10 mg once daily (o.d.)] is compared with placebo in ∼60 patients with HFREF and mild CKD. Outcome measures include serum potassium concentration, biomarkers of renal injury, estimated glomerular filtration rate (eGFR), and albuminuria. Part B compares BAY 94-8862 (2.5, 5, or 10 mg o.d., or 5 mg twice daily), placebo, and open-label spironolactone (25–50 mg o.d.) in ∼360 patients with HFREF and moderate CKD. Outcome measures include the change in serum potassium concentration with BAY 94-8862 vs. placebo (primary endpoint) and vs. spironolactone, safety and tolerability, biomarkers of cardiac and renal function or injury, eGFR, and albuminuria. BAY 94-8862 pharmacokinetics are also assessed. Perspectives ARTS is the first phase II clinical trial of BAY 94-8862 and is expected to provide a wealth of information on BAY 94-8862 in patients with HFREF and CKD, including the optimal dose range for further studies. [ABSTRACT FROM PUBLISHER]

Aims To test the hypothesis that baseline hypoalbuminaemia is associated with incident heart failure (HF) in community-dwelling older adults. Methods and results Of the 5795 community-dwelling adults aged ≥65 years in the Cardiovascular Health Study, 5450 were free of centrally adjudicated prevalent HF at baseline, and also had data on baseline serum albumin. Of these, 599 (11%) had hypoalbuminaemia, defined as baseline serum albumin levels ≤3.5 mg/dL. Propensity scores for hypoalbuminaemia were calculated for each patient and used to assemble a matched cohort of 582 pairs of participants with and without hypoalbuminaemia, who were well balanced on 58 baseline characteristics. Using Cox regression models, we estimated the association of hypoalbuminaemia with centrally adjudicated incident HF during 9.6 years of median follow-up. Matched participants had a mean (±SD) age of 74 (±6) years, 62% were women, and 16% were African Americans. Incident HF occurred in 25 and 20% of matched participants with and without hypoalbuminaemia, respectively [hazard ratio when hypoalbuminaemia was compared with normoalbuminaemia, 1.40; 95% confidence interval, 1.05–1.85; P = 0.020]. Pre-match unadjusted, multivariable-adjusted, and propensity-adjusted hazard ratios (95% confidence intervals) for incident HF associated with hypoalbuminaemia were 1.33 (1.12–1.58; P = 0.001), 1.33 (1.11–1.60; P = 0.002), and 1.25 (1.04–1.50; P= 0.016), respectively. The combined endpoint of incident HF or all-cause mortality occurred in 59 and 50% of matched participants with and without hypoalbuminaemia, respectively (hazard ratio, 1.33; 95% confidence interval, 1.11–1.61; P= 0.002). Conclusions Among community-dwelling older adults without HF, baseline hypoalbuminaemia was associated with increased risk of incident HF during 10 years of follow-up. [ABSTRACT FROM AUTHOR]

Objectives: We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods: We examined 491 patients with systolic CHF (age: 63±11 years, 91%men, New York Heart Association [NYHA] class [I/ II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay. Results: Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02). Conclusions: Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes. [ABSTRACT FROM AUTHOR]

Aims Adrenomedullin (ADM) is a vasodilatory peptide. Its plasma levels or its precursors have not been evaluated in large populations of patients with chronic heart failure (CHF). We sought to explore mid-regional proADM (MR-proADM). Methods and results We assessed MR-proADM in 501 CHF patients [age 63 ± 11 years, New York Heart Association (NYHA) class I/II/III/IV 9/44/39/8%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 878 pg/mL (interquartile range—IQR 348–2480 pg/mL), median left ventricular ejection fraction (LVEF) 31% (IQR 25–37%)]. Mid-regional pro-adrenomedullin levels (median 0.64 nmol/L, IQR 0.49–0.87 nmol/L) increased with NYHA class (P < 0.0001). During 1-year follow-up, 70 patients (14%) died. Increasing MR-proADM was a predictor of poor survival at 12 months (hazard ratio 1.82, 95% confidence interval 1.24–2.66, P = 0.002) after multivariable adjustment. In receiver-operating characteristic curve analysis of 12-month survival, the area under the curve for MR-proADM and NT-proBNP was similar (P = 0.3). Comparison of Cox proportional hazard models using the likelihood ratio χ2 statistic showed that both NT-proBNP and MR-proADM added prognostic value to a base model of LVEF, age, creatinine, and NYHA class. Adding MR-proADM to the base model had stronger prognostic power than adding NT-proBNP (both P < 0.01). Conclusion Mid-regional pro-adrenomedullin is an independent predictor of mortality in CHF patients, which adds prognostic information to NT-proBNP. [ABSTRACT FROM PUBLISHER]

Hospitalizations for acute heart failure syndromes (AHFS) are associated with high post-discharge morbidity and mortality. The potential role of vasopressin antagonists (VA) in AHFS was presented at the 2008 European Society of Cardiology Working Group on Acute Cardiac Care Meeting held in Versailles, France from 25-28 October 2008. This report represents a summary of the presentation at this meeting. [ABSTRACT FROM AUTHOR]

Acute heart failure syndromes (AHFS) resulting in hospitalization are associated with an extremely high post-discharge mortality and readmission rate. There are several important prognostic factors, which includes blood pressure, body weight, renal function, QRS duration, and presence of coronary artery disease. The epidemiology of AHFS, prognostic factors and therapeutic targets were discussed at the 2008 European Society of Cardiology Working Group on Acute Cardiac Care Meeting held in Versailles, France from 25-28 October 2008. This is a brief summary of the lectures presented on these topics at this meeting. [ABSTRACT FROM AUTHOR]

Hypertension is a risk factor for heart failure and stroke. However, the effect of hypertension on stroke in patients with heart failure has not been well studied. In the Digitalis Investigation Group trial, 3,674 (47%) of the 7,788 patients had a history of hypertension. Probability or propensity scores for a history of hypertension were calculated for each patient through use of a multivariable logistic regression model and were then used to match 2,386 pairs of patients with and without a history of hypertension. Kaplan-Meier and matched Cox regression analyses were used to estimate associations of a history of hypertension hospitalization for stroke during 37 months of median follow-up. After matching, patients without and with a history of hypertension had a mean systolic blood pressure of 127 mm Hg. Hospitalization for stroke occurred in 90 patients (rate, 129/10,000 person-years of follow-up) without a history of hypertension and 121 patients (rate, 178/10,000 person-years of follow-up) with a history of hypertension (hazard ratio when hypertension was compared with no hypertension = 1.52; 95% confidence interval = 1.11 to 2.08; p = 0.010). This association was also observed among patients with baseline systolic blood pressure <140 mm Hg (hazard ratio = 1.35; 95% confidence interval =1.01 to 1.81; p = 0.044). In conclusion, a history of hypertension was associated with increased risk of hospitalization for stroke among patients with heart failure who were balanced in all measured baseline covariates, including blood pressure. [Copyright &y& Elsevier]

Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction. [ABSTRACT FROM AUTHOR]

Background: Published work suggests that some types of endothelial cells undergo apoptosis in response to ligation of the receptor Fas (CD95, APO1) but other types are resistant. Because heterogeneity among endothelial cells from different tissues, has been demonstrated, the purpose of this study was to determine, if Fas ligation and/or activation by human Fas ligand induces apoptosis and caspase activities, in cultured human coronary artery endothelial cells, and the differences between TNF-a and FAS induced apoptosis in these cells. Results: Cultured human coronary artery endothelial cells (HCAEC) were exposed to the monoclonal Fas-activating antibody CH-11, to purified recombinant human Fas ligand, to the Fas-neutralizing antibody ZB4, or to purified recombinant human TNF-α. Apoptosis was detected by assessment of chromatin condensation and nuclear fragmentation and by assay of the enzymatic activities of Caspase 1 and Caspase 3 with membrane-permeable substrates applied to intact cells. Fas protein was detected by immunoblotting of HCAEC lysates. Apoptosis was induced in HCAEC by purified Fas ligand or by the monoclonal activating antibody CH-11 at concentrations of 25 or 200 ng/ml, but not by nonspecific isotype-matched immunoglobulins. The apoptotic index elicited by either Fas activator was equal to that induced by TNF-a (3.0-3.6-fold versus control, p < 0.01). The Fas-neutralizing antibody ZB4 abrogated HCAEC apoptosis induced by CH-11, but had no inhibitory effect on apoptosis in response to TNF-a. Fas ligation significantly increased the activities of both Caspase 1 and Caspase 3 at 20 hours of stimulation (1.7- and 2.0-fold versus control, both p < 0.05); in contrast, purified TNF-a increased the activity of Caspase 3 but not Caspase 1 (2.1-fold, p < 0.05). Western blotting of HCAEC lysates with antibody CH-11 identified a single immunoreactive protein of 90 kDa. Conclusions: Cultured human coronary artery endothelial cells express functional Fas capable of inducing apoptosis in response to either purified Fas ligand or receptor-activating monoclonal antibodies, at levels equal to those inducible by purified TNF-α. Immunologic studies and differential kinetics of caspase activation suggest that Fas and TNF-α induce apoptosis in HCAEC by signaling pathways that are distinct but equal in potency. [ABSTRACT FROM AUTHOR]

Apoptosis has been found in skeletal muscles of patients with chronic heart failure (CHF) and has been associated with exercise intolerance. In CHF, cachexia is characterized by neurohormonal activation and muscle wasting. Neurohormonal activation can lead to cell death and fibrosis. The purpose of the study was to determine the severity of apoptosis and fibrosis in skeletal muscles of patients with CHF and cachexia and its relationship to exercise intolerance in these patients. Skeletal muscle biopsies of 21 patients with CHF (eight with cachexia) and four healthy controls of similar age have been studied by in situ end labeling (ISEL) for apoptosis and by the Picrosirius Red technique for collagen. Apoptosis in skeletal muscles was detected by ISEL in 52% of the patients with CHF (11 out of 21) and in none of the controls. CHF patients with apoptosis-positive skeletal muscles had impaired exercise tolerance (peak oxygen consumption 11.4±5.7 vs. 16.91±6.6, P=0.029). Increased collagen was detected by Picrosirius Red in eight out of 21 patients with CHF and in none of the controls. Increased collagen (fibrosis) was detected in six out of eight patients with cachexia and in two out of 13 patients without cachexia (P=0.01). Peak oxygen consumption and apoptosis were similar in cachectic and non-cachectic patients. Thus, the skeletal musculature of patients with cardiac cachexia is characterised by the presence of fibrosis. Apoptosis was not found to be more frequent in cachectic CHF patients. Our data support the hypothesis that cachexia contributes by a different mechanism to skeletal muscle myopathy of CHF patients and different mechanisms are implicated in deterioration of exercise tolerance and progression to cardiac cachexia. [Copyright &y& Elsevier]

Recent investigations have shown that, in addition to neurohormonal system overactivation, another class of biologically active molecules, termed cytokines, is also overexpressed in the setting of chronic heart failure and participates actively in the progression of the syndrome. In this article, we present recent experimental and clinical data describing the pathophysiological role of cytokines in left ventricular remodeling, endothelial dysfunction, and peripheral myopathy characterizing the progression of chronic heart failure, as well as novel therapeutic approaches aimed at attenuating the deleterious effects of cytokines on the cardiovascular system. [Copyright &y& Elsevier]

Examines the roles of vasoactive peptides in the regulation of apoptosis. Description of endothelin-1 (ET-1); Role of ET-1 in the pathophysiology of cancers; Discussion on atrial natriuretic peptide; Role of adrenomedullin in some biological processes; Evidence showing whether apoptosis is a pathogenic mechanism in the models of lung injury.

Examines apoptosis regulation by vasoactive peptides. Physiological role of vasoactive peptides; Regulation of cell proliferation in a variety of cell types of tissues; Role of ET-1 vasoconstrictor and growth factor in cancer pathophysiology.