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Aims Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF. Methods and results The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92 and 0.74, 95% CI 0.62-0.88, respectively; p for interaction = 0.88]. Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86, 95% CI 0.60-1.22). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF. Conclusions Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF. [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]

Background The primary end point in most heart failure (HF) trials is a composite of time to a first worsening HF event or cardiovascular death. Prevention of recurrent events and improvements in symptoms/quality of life are also important for patients but are usually analyzed separately. Win statistics can integrate all these outcomes into a single composite end point, which is analyzed in hierarchical order, reflecting the clinical importance of each component. Methods The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF, n=4744) and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER, n=6263) trials enrolled patients with New York Heart Association class II, III, or IV HF, elevated natriuretic peptides, and either an ejection fraction of 40% or less (DAPA-HF) or greater than 40% and left atrial enlargement/left ventricular hypertrophy (DELIVER). We examined the effects of dapagliflozin compared with placebo on a hierarchical composite outcome, including cardiovascular death, total (first and recurrent) HF hospitalizations, total urgent HF visits, and improvement/deterioration in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS; range from 0 to 100, with a higher score indicating fewer symptoms and physical limitations) at 8 months.Results For this composite outcome, the win ratio was 1.30 (95% confidence interval [CI], 1.23 to 1.36) in the pooled cohort, 1.33 (95% CI, 1.23 to 1.43) in the DAPA-HF trial, and 1.27 (95% CI, 1.18 to 1.36) in the DELIVER trial. Win odds and net benefit in overall patients were 1.19 (95% CI, 1.14 to 1.24) and 8.7% (95% CI, 6.6 to 10.9%), respectively. In the overall pooled cohort, the majority of wins and losses were accounted for by KCCQ-TSS; 52.4% were settled by the KCCQ-TSS tier in the pooled cohort. Conclusions In both the DAPA-HF and DELIVER trials, dapagliflozin led to a significant improvement in composite outcomes that incorporated patient-reported outcomes along with total HF events, as well as cardiovascular deaths. These analyses provided a comprehensive presentation of win statistics and illustrated the utility and flexibility of win statistics in describing the effects of dapagliflozin in two recent clinical trials in patients with HF. (Funded by British Heart Foundation Centre of Research Excellence and others; clinical trial registration numbers, NCT03036124 and NCT03619213.) [ABSTRACT FROM AUTHOR]

Aim: To determine whether initiation of antibiotic therapy (ABX) by procalcitonin (PCT) within 8 h of admission in patients presenting to the emergency department with symptoms and signs of acute heart failure (AHF) and elevated natriuretic peptides would improve clinical outcomes.Methods and Results: The study was a randomized multicentre clinical trial conducted at 16 sites in Europe. Patients were randomized to either a PCT-guided strategy or standard care. Patients with PCT-guided strategy (n = 370) had ABX initiated if PCT was > 0.2 μg/L. Patients with standard care (n = 372) had AHF care in accordance with published guidelines without PCT. The primary endpoint was 90-day all-cause mortality. Pre-specified secondary endpoints included 30-day all-cause mortality and readmission and rate of pneumonia. The Data Safety and Review Committee recommended stopping the study for futility when 762 of the planned 792 patients had been enrolled. A total of 742 patients could be analysed. Patients were elderly (median age: 77 years), 38% were women, and had typical signs and symptoms of AHF. All-cause mortality at 90 days was 10.3% in the PCT-guided group vs. 8.2% in standard care (P = 0.316). Thirty-day readmission was significantly higher in the PCT-guided group vs. standard care but the difference vanished until day 90. The rate of pneumonia was overall low (7.5%) and not different between groups.Conclusions: In patients with AHF, a strategy of PCT-guided initiation of ABX was not more effective than a standard care strategy in improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF. Methods and results The biological variability of established biomarkers [NT-proBNP and high-sensitivity troponin T (hsTnT)], novel biomarkers [galectin-3, suppression of tumorigenicity 2 (ST2), and growth differentiation factor 15 (GDF-15)], and renal/neurohormonal biomarkers (aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) was determined in 28 healthy subjects and 83 HF patients, over a period of 4 months and 6 weeks, respectively. The analytical (CVa), intraindividual (CVi), and interindividual (CVg) variations were calculated, as well as the reference change value (RCV), which reflects the percentage of change that may indicate a 'relevant' change. All crude biomarker levels were significantly increased or decreased in HF patients compared with controls (all P < 0.01). Variation indices were comparable in healthy individuals and HF patients. CVi was not influenced by the individual levels of the biomarker itself. NT-proBNP and GDF-15 had relatively high CVi (21.8% and 16.6%) and RCV (61.7% and 64.3%), whereas ST2 (CVi, 15.0; RCV, 42.9%), hsTnT (CVi, 11.1; RCV, 31.4%), and galectin-3 (CVi, 8.1; RCV, 25.0%) had lower indices of variation. Conclusion Biological variation indices are comparable between healthy subjects and HF patients for a broad spectrum of biomarkers. NT-proBNP and GDF-15 have substantial variation, with lower variation for ST2, hsTnT, and galectin-3. These data are instrumental in proper interpretation of biomarker levels in HF patients. [ABSTRACT FROM AUTHOR]

Aim: Traditionally, risk stratification in heart failure (HF) emphasizes assessment of high risk. We aimed to determine if biomarkers could identify patients with HF at low risk for death or HF rehospitalization.Methods and Results: This analysis was a substudy of The Coordinating Study Evaluating Outcomes of Advising and Counselling in Heart Failure (COACH) trial. Enrolment of HF patients occurred before discharge. We defined low risk as the absence of death and/or HF rehospitalizations at 180 days. We tested a diverse group of 29 biomarkers on top of a clinical risk model, with and without N-terminal pro-B-type natriuretic peptide (NT-proBNP), and defined the low risk biomarker cut-off at the 10th percentile associated with high positive predictive value. The best performing biomarkers together with NT-proBNP and cardiac troponin I (cTnI) were re-evaluated in a validation cohort of 285 HF patients. Of 592 eligible COACH patients, the mean (± SD) age was 71 (± 11) years and median (IQR) NT-proBNP was 2521 (1301-5634) pg/mL. Logistic regression analysis showed that only galectin-3, fully adjusted, was significantly associated with the absence of events at 180 days (OR 8.1, 95% confidence interval 1.06-50.0, P = 0.039). Galectin-3, showed incremental value when added to the clinical risk model without NT-proBNP (increase in area under the curve from 0.712 to 0.745, P = 0.04). However, no biomarker showed significant improvement by net reclassification improvement on top of the clinical risk model, with or without NT-proBNP. We confirmed our results regarding galectin-3, NT-proBNP, and cTnI in the independent validation cohort.Conclusion: We describe the value of various biomarkers to define low risk, and demonstrate that galectin-3 identifies HF patients at (very) low risk for 30-day and 180-day mortality and HF rehospitalizations after an episode of acute HF. Such patients might be safely discharged. [ABSTRACT FROM AUTHOR]

Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). Methods and results We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 % ) ARVC patients and in 39 (15 % ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del– DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 % ) R14del+ ARVC samples, but in only one of nine (11 % ) R14del+ DCM samples (P = 0.03). Conclusions The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of ‘arrhythmogenic cardiomyopathy’. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor alpha (LXR(alpha)) and LXR(beta) in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXR(alpha) functioned as a cAMP-activated factor, LXR(beta) was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXR(alpha) was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXR(alpha) to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXR(alpha) mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXR(beta) mice exhibited reduced kidney renin mRNA levels compared with controls. LXR(alpha)LXR(beta) mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXR(alpha) and LXR(beta) regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXR(alpha) signaling pathway is required for the adrenergic control of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Background: The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant.Aims: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers.Methods: We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes.Results: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL.Conclusion: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism. [ABSTRACT FROM AUTHOR]

Background: Obese subjects have lower natriuretic peptide levels, but males and females have different anthropometric characteristics and fat distribution. Whether obesity-associated lowering of natriuretic peptides differs among males and females is unknown. Therefore, we investigated sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels among adults in the general population.Methods and Results: Using 8260 participants (50.1% females) from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, we evaluated the relationship of NT-proBNP levels with obesity-associated parameters, i.e. waist circumference (WC), body mass index (BMI) and body weight in the overall population, and in males and females separately. NT-proBNP levels were higher in females (median, interquartile range: 50.5, 28.2-87.0 ng/L) than in males (24.3, 10.1-54.6 ng/L; P < 0.001). In the overall population, NT-proBNP levels were significantly lower in heavier individuals and displayed a 'U-shaped' relationship with increasing WC, but were not associated with BMI. After sex stratification, there was no significant association between NT-proBNP concentrations and anthropometric measures in females. However, in males increasing WC and BMI were associated with higher NT-proBNP levels (P < 0.05) while increasing body weight was associated with slightly lower NT-proBNP levels (P < 0.05). Age strongly confounded the association of NT-proBNP levels with obesity, and age-associated increases in NT-proBNP were significantly higher in males than in females (P < 0.001). In multivariable adjusted analyses, the inverse association of obesity and NT-proBNP levels was also significantly modified by sex: NT-proBNP levels were lower with increasing WC, BMI and body weight among females compared with males (Pinteraction  < 0.05). After also accounting for BMI, abdominal obesity was associated with lower NT-proBNP levels in females, but not in males (Pinteraction  < 0.001).Conclusions: Natriuretic peptide deficiency in obesity mostly pertains to females with abdominal obesity, whereas the relationship between obesity and natriuretic peptides appears to be more complex in males. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy.Objectives: This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial.Methods: A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction >40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF.Results: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P < 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ-TSS.Conclusions: In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213). [ABSTRACT FROM AUTHOR]

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

Background: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.Objectives: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.Methods: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.Results: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.Conclusions: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction.Methods: We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527.Findings: Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73-0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77-1·00]) and first hospitalisation for heart failure (0·74 [0·67-0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72-0·82]), cardiovascular death (0·87 [0·79-0·95]), first hospitalisation for heart failure (0·72 [0·67-0·78]), and all-cause mortality (0·92 [0·86-0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction.Interpretation: SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting.Funding: None. [ABSTRACT FROM AUTHOR]

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

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events.Methods: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction ≤40% and elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide), were eligible. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or an urgent HF visit requiring intravenous therapy) or cardiovascular death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to the initiation of new, or the augmentation of existing, oral treatment.Results: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65-0.82]; P<0.0001). Each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat with dapagliflozin to prevent 1 experiencing an episode of fatal or nonfatal worsening was 16. Among the 4744 randomly assigned patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with intravenous therapy in 20 (0.4%), HF hospitalization in 489 (10.3%), and cardiovascular death in 295 (6.2%). The adjusted risk of death from any cause (in comparison with no event) after an outpatient worsening was hazard ratio, 2.67 (95% CI, 2.03-3.52); after an urgent HF visit, the adjusted risk of death was hazard ratio, 3.00 (95% CI, 1.39-6.48); and after a HF hospitalization, the adjusted risk of death was hazard ratio, 6.21 (95% CI, 5.07-7.62).Conclusion: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo.Methods: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms.Results: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.Conclusions: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Classification of the total sample (n=156) according to the HFA-PEFF algorithm (A) and the H 2 FPEF score (B), along with corresponding rates of invasively defined heart failure with preserved ejection fraction (HFpEF inv). Sources of Funding This work was supported by grants from the National Institutes of Health (R01HL134893, R01-HL140224, and K24 HL153669 to Dr Ho, R01-HL142809 to Dr Malhotra, K23-HL138260 to Dr Nayor, and R01-HL131029 to Dr Lewis) and the American Heart Association (15GPSGC24800006 to Dr Lewis). Pulmonary capillary wedge pressure patterns during exercise predict exercise capacity and incident heart failure. [Extracted from the article]

Cardiovascular disease (CVD) often goes unrecognized, despite symptoms frequently being present. Proactive screening for symptoms might improve early recognition and prevent disease progression or acute cardiovascular events. We studied the diagnostic value of symptoms for the detection of unrecognized atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) and developed a corresponding screening questionnaire. We included 100,311 participants (mean age 52 ± 9 years, 58% women) from the population-based Lifelines Cohort Study. For each outcome (unrecognized AF/HF/CAD), we built a multivariable model containing demographics and symptoms. These models were combined into one 'three-disease' diagnostic model and questionnaire for all three outcomes. Results were validated in Lifelines participants with chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM). Unrecognized CVD was identified in 1325 participants (1.3%): AF in 131 (0.1%), HF in 599 (0.6%), and CAD in 687 (0.7%). Added to age, sex, and body mass index, palpitations were independent predictors for unrecognized AF; palpitations, chest pain, dyspnea, exercise intolerance, health-related stress, and self-expected health worsening for unrecognized HF; smoking, chest pain, exercise intolerance, and claudication for unrecognized CAD. Area under the curve for the combined diagnostic model was 0.752 (95% CI 0.737-0.766) in the total population and 0.757 (95% CI 0.734-0.781) in participants with COPD and DM. At the chosen threshold, the questionnaire had low specificity, but high sensitivity. In conclusion, a short questionnaire about demographics and symptoms can improve early detection of CVD and help pre-select people who should or should not undergo further screening for CVD. [ABSTRACT FROM AUTHOR]