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Background: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline. Methods: Iron deficiency was defined as a ferritin level Results: Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P P -interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo. Conclusions: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

Steroidal mineralocorticoid receptor antagonists (MRAs) form a cornerstone of the management of heart failure (HF), but little is known about the long-term effects of MRA therapy on kidney function. We evaluated acute and chronic estimated glomerular function (eGFR) slopes in the two largest completed trials testing steroidal MRAs in chronic HF.We conducted parallel post hoc eGFR slope analyses in two multinational, double-blind randomized, placebo-controlled trials of steroidal MRAs in chronic HF with reduced ejection fraction (EMPHASIS-HF) and preserved ejection fraction (TOPCAT Americas region). GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Annual slopes of eGFR were assessed by generalized random coefficient models. Least square mean differences in eGFR slopes between steroidal MRA and placebo arms were assessed. Median follow-up was 1.8 years (EMPHASIS-HF) and 3.3 years (TOPCAT Americas). From baseline to month 4-6 ('acute eGFR slope'), compared to placebo, MRA treatment led to an acute decline in eGFR of -2.4 ml/min/1.73 msup2/sup(95% confidence interval [CI] -3.4 to -1.4; p lt; 0.001) and -2.0 ml/min/1.73 msup2/sup(95% CI -3.0 to -1.8; p lt; 0.001) in EMPHASIS-HF and TOPCAT Americas, respectively. From month 4-6 to end of study, there was no difference in 'chronic eGFR slope' between MRA and placebo arms (-0.3 ml/min/1.73 msup2/sup/year [95% CI -1.3 to 0.7; p = 0.53] and 0.1 ml/min/1.73 msup2/sup/year [95% CI -1.4 to 1.7; p = 0.86]) in EMPHASIS-HF and TOPCAT Americas, respectively.Steroidal MRAs result in acute declines in eGFR but do not modify long-term kidney disease trajectories in chronic HF with reduced or preserved ejection fraction.EMPHASIS-HF (ClinicalTrials.gov NCT00232180) and TOPCAT (ClinicalTrials.gov NCT00094302).

Aims: Dapagliflozin resulted in significant and sustained reductions in first and recurrent heart failure (HF) hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied. Methods and results: In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring intensive care unit stay, intravenous vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or mechanical circulatory support were categorized as complicated. The balance was classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 854 (71%) were uncomplicated and 355 (29%) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 453 (57%) were uncomplicated and 346 (43%) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.7% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total ‘uncomplicated’ (DELIVER: rate ratio [RR] 0.67, 95% confidence interval [CI] 0.55–0.82 and DAPA-HF: RR 0.69, 95% CI 0.54–0.87) and ‘complicated’ HF hospitalizations (DELIVER: RR 0.82, 95% CI 0.63–1.06 and DAPA-HF: RR 0.75, 95% CI 0.58–0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS

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

Background: Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real-world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. Methods: We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. Conclusion: Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. Clinicaltrial.gov: NCT03619213. Clinicaltrial.gov: NCT03619213.

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

Background: Insulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. Objectives: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Methods: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. Results: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). Conclusions: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level.

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

Aims: \ud The aim of this study was to examine the association between patient-reported symptoms and the extent of pulmonary congestion in acute heart failure (AHF).\ud \ud Methods and results: \ud In this prospective, observational study, patient-reported symptoms were assessed at baseline using the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) (range 0-100; 0 worst) in patients hospitalized for AHF. In a subset, patient-reported dyspnea at rest and on exertion was examined (range 0-10; 10 worst) at baseline. In addition, 4-zone lung ultrasound (LUS) was performed at baseline at the time of echocardiography. B-lines were quantified offline, blinded to clinical findings, in a core laboratory. Chest x-ray (CXR) and physical examination findings were collected from the medical records.\ud \ud Among 322 patients (mean age 72, 60% men, mean LVEF 39%) with AHF, the median KCCQ-TSS score was 33 [interquartile range 18-48]. Worse KCCQ-TSS was associated with worse NYHA class, dyspnea at rest and on exertion, and peripheral edema (p trend 0.30 for all). Similarly, KCCQ-TSS was not significantly associated with echocardiographic markers of left ventricular filling pressure, pulmonary pressure or with NT-proBNP.\ud \ud Conclusions: \ud Among patients hospitalized for AHF, at baseline, KCCQ-TSS was not associated with pulmonary congestion assessed by LUS, CXR or physical examination. These findings suggest that the profound reduction in KCCQ-TSS in patients with AHF may not be solely explained by pulmonary congestion.

No abstract available.

No abstract available.

Background: \ud Atrial fibrillation (AF) and heart failure (HF) often coexist. We investigated the prognostic impact of biomarkers on the development of HF and death in patients with AF and different left ventricular systolic function considering the influence of competing events.\ud \ud Methods: \ud The study included 11,818 patients with AF from the ARISTOTLE trial who at entry had information on history of HF, an estimate of left ventricular function and plasma samples for determination of biomarkers representing cardiorenal dysfunction (NT-proBNP, troponin T, cystatin C) and inflammation (GDF-15, IL-6, CRP). Patients were categorized into: (I) HF with reduced ejection fraction (HFrEF, n=2,048), (II) HF with preserved ejection fraction (HFpEF, n=2,520), and (III) No HF (n=7,250). Biomarker associations with HF hospitalization and death were analyzed using a multi-state model accounting also for repeated events.\ud \ud Results: \ud Baseline levels of NT-proBNP, troponin T, cystatin C, GDF-15, IL-6, and CRP were highest in HFrEF and lowest in No HF. During median 1.9 years follow-up, 546 patients were hospitalized at least once for HF and 819 died. Higher levels of all investigated biomarkers were associated with both outcomes (all p

Background: \ud Despite renin-angiotensin-aldosterone-system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this pre-specified analysis of DAPA-CKD was to assess efficacy and safety of dapagliflozin in a small subgroup participants with FSGS confirmed by kidney biopsy.\ud \ud Methods: \ud In DAPA-CKD, patients with estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomised to dapagliflozin 10mg once-daily or placebo as an adjunct to standard care, and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥ 50%, end-stage kidney disease (ESKD), or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment).\ud \ud Results: \ud Of 104 participants with biopsy-confirmed FSGS, 45 were randomised to dapagliflozin and 59 to placebo. Mean (SD) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73m2 and median (IQR) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomised to dapagliflozin and placebo, respectively (HR 0.62, 95%CI 0.17–2.17). Dapagliflozin led to a larger acute reduction (SE) in eGFR compared to placebo (−4.5 [95% CI − 5.9-−3.1] vs − 0.9 [−2.1–0.4] mL/min/1.73m2 per 2 wks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were − 1.9 (−3.0-−0.9) and − 4.0 (−4.9-−3.0) mL/min/1.73m2/year, respectively (difference 2.0 [95%CI 0.6–3.5] mL/min/1.73m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin.\ud \ud Conclusion: \ud Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared to placebo, although this difference was not statistically significant.

Background: \ud Recent guidelines support consideration of sodium glucose co-transporter(SGLT)-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of SGLT-2 inhibitors.\ud \ud Objectives: \ud To estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups.\ud \ud Methods: \ud In this pre-specified analysis of DELIVER, we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, LVEF>40%, elevated natriuretic peptide levels, and structural heart disease. For every year between age 55 and 85, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from primary endpoint was estimated based on area under the survival curve in each arm.\ud \ud Results: \ud Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 (95%CI 11.0 to 13.2) years with dapagliflozin and 9.7 (95%CI 8.8 to 10.7) years with placebo, representing a 2.3 (95%CI 0.9 to 3.8) year event-free survival gain(P=0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 (95%CI -0.6 to 4.6) years in a 55-year-old to 1.2 (95%CI -0.1 to 2.4) years in a 75-year-old. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups.\ud \ud Conclusions: \ud Treatment with dapagliflozin is projected to extend event-free survival by up to 2-2.5 years among middle age and older individuals with HF with mildly reduced, preserved, or improved ejection fraction.

Background: \ud Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes, compared to sinus rhythm, and may modify the effects of therapy.\ud \ud Objectives: \ud We examined the effects of dapagliflozin according to the presence or not of AF in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial (DELIVER).\ud \ud Methods: \ud A total of 6,263 patients with HF with NYHA functional class II-IV, LVEF >40%, evidence of structural heart disease, and elevated NT-proBNP 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 a worsening HF.\ud \ud Results: \ud Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% paroxysmal AF, and 38.7% 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 (95% CI), 4.5 (4.0-5.1); paroxysmal AF 7.5 (6.4-8.7); persistent/permanent AF 6.4 (5.7-7.1) (P

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, was evaluated in patients with heart failure and reduced ejection fraction (HFrEF) randomized in the Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial. Methods: HFrEF patients with or without type 2 diabetes and an eGFR ≥30 mL/min/1.73m2 were randomized to placebo or dapagliflozin 10mg 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 using repeated measure mixed effect models. Results: The mean change in eGFR between day 0 and 14 was -1.1 ml/min/1.73m2 (95% CI -1.5,-0.7) with placebo and -4.2 ml/min/1.73m2 (-4.6,-3.9) with dapagliflozin, giving a between treatment difference of 3.1 (2.6, 3.7) ml/min/1.73m2. 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), P10% 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), P-interaction 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 starting dapagliflozin was small and associated with better clinical outcomes, compared with a similar decline on placebo in patients with HFrEF. Large declines in eGFR were uncommon with dapagliflozin.

Background: \ud The Heart Failure Collaboratory (HFC) has developed a score integrating classes and doses of guideline-directed medical therapies prescribed for patients with heart failure (HF) and reduced ejection fraction. One potential use of this score is to test whether new treatments demonstrate incremental benefits, even in patients receiving comprehensive guideline-directed medical therapy.\ud \ud Objectives\ud The authors investigated the efficacy of dapagliflozin according to a modified HFC score in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.\ud \ud Methods: \ud In DAPA-HF, 4,744 patients with HF and reduced ejection fraction were randomized to dapagliflozin or placebo. The modified HFC score accounted for race and electrocardiogram rhythm and rate, with a maximum possible score of 100%. The primary outcome was the composite of worsening HF or cardiovascular death.\ud \ud Results: \ud The median modified HFC score was 50% (IQR: 27.5%-62.5%; range 0%-100%). Compared with the lowest tertile, the highest tertile of the treatment score was associated with a lower risk of worsening HF or cardiovascular death (tertile 1, reference; tertile 2, HR: 0.97 [95% CI: 0.82-1.14]; tertile 3, HR: 0.83 [95% CI: 0.70-0.99]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of treatment score (the HRs for dapagliflozin vs placebo from tertile 1 to 3 were: 0.76 [95% CI: 0.61-0.94], 0.76 [95% CI: 0.60-0.97], and 0.71 [95% CI: 0.55-0.90]), respectively; Pinteraction = 0.89). Consistent benefits were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TTS).\ud \ud Conclusions: \ud Dapagliflozin, compared with placebo, improved all outcomes examined, regardless of the modified HFC score. This score can be easily calculated in clinical trials and used to evaluate the incremental effects of new treatments. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

Aims: \ud Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to the HF hospitalization or how this high-risk clinical event impacts renal outcomes.\ud \ud Methods and Results: \ud In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (1) time to ≥50% decline in eGFR ; (2) development of end stage renal disease (ESRD); or (3) death attributable to renal causes. 2,306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan vs. valsartan was similar between patients with (HR 0.43; 95% CI: 0.26 to 0.75) and without (HR 0.63; 95% CI: 0.33 to 1.18; Pinteraction = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (Pinteraction =0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p

No abstract available.

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.

Sodium Glucose Co-Transporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to not only control blood glucose but to improve cardiovascular and kidney outcomes. Diabetic Ketoacidosis (DKA) is an uncommon but a serious complication of type 2 diabetes which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials (RCTs) in people with type 2 diabetes using SGLT2 inhibitors has been very low, although the relative risk is higher in those assigned to SGLT2i compared with placebo. In those without diabetes prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalised type 2 diabetes patients, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine “sick day” guidance should be re-examined based on current evidence with a call for further research in this area. Further high quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease and trials of continuation of SGLT2 inhibitors in people with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Background: \ud Biomarker-driven prognostic models incorporating NT-proBNP and hs-cTnT in HFpEF are lacking.\ud \ud Aims: \ud To generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved.\ud \ud Methods: \ud Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death (ii) all-cause death (iii) cardiovascular death and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort.\ud \ud Results: \ud NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, NYHA class III or IV, history of COPD, insulin-treated diabetes, low hemoglobin, and a longer time since HF diagnosis were key predictors (8 variables, all P22x higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c=0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, LVEF ≥50%, NYHA class III or IV and insulin-treated diabetes (8 variables, all P

Aims: \ud Data on long-term treatment effects are scarce, despite the intent to use new therapies for many years and the need of patients, physicians and payers to have a better understanding of the lifetime benefits of treatments. The restricted mean or median survival time (RMST) calculated using age instead of time, hypothetically enables estimation of long-term gain in event-free or overall survival from the short-term (within-trial) effects of an intervention, compared with its control. Tha aim of the study is to use trials with long-term follow-up available through extension studies to compare the long-term projections estimated using RMST from within-trial follow-up data with the actual long-term outcomes in the extension studies.\ud \ud Methods and results: \ud We estimated the median long-term survival time using age instead of follow-up time and compared these model-based projections with the actual long-term estimates in the (i) SCD-HeFT trial vs. SCD-HeFT long-term outcomes; (ii) SOLVD trial vs. SOLVD 12 year follow-up; (iii) STICH trial vs. STICHES; and (iv) ACCORD study vs. ACCORDION. In the long-term follow-up of SCD-HeFT, gain in survival with ICD vs. placebo over a median of 11.0 years was +1.4 years of life. The RMST model-derived survival projection from the within-trial data (median follow-up of 3.4 years) gave an estimated survival gain of +1.2 years. In STICHES, over a median follow-up of 9.8 years, coronary artery bypass grafting (CABG) vs. medical care led to a survival extension of +1.4 years in favour of CABG. RMST projections using within-trial data from STICH (median follow-up of 4.9 years), gave an extended survival of +2.4 years in favour of CABG in younger patients. In the long-term follow-up of SOLVD, enalapril vs. placebo led to a survival gain of +0.8 years over a median follow-up of 12.1 years. The RMST projections from the within-trial data (median follow-up of 2.8 years) gave a survival extension of +0.3 years in favour of enalapril. In the long-term follow-up ACCORDION study, with a median follow-up of 8.8 years, intensive vs. a standard anti-hyperglycaemic treatment did not influence long-term survival, which was concordant with the RMST projections from the short-term ACCORD study with median follow-up of 4.9 years.\ud \ud Conclusions: \ud Age-based survival projections using within-trial data generally provided concordant results with the actual survival measured in long-term follow-up extension studies. Our findings suggest that age-based lifetime projections may be used as means to assess the long-term treatment effects.

Objectives: \ud The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict heart failure (HF) risk.\ud \ud Background: \ud The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of HF hospitalization.\ud \ud Methods: \ud Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.\ud \ud Results: \ud Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).\ud \ud Conclusions: \ud In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

Background Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P interaction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan. Conclusions Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711

In this review, we discuss what is meant by "foundational" therapy for patients with heart failure and reduced ejection fraction (HFrEF) and the evidence supporting the use of the five agents that comprise this group of drugs i.e., sacubitril/valsartan, a beta-blocker, an aldosterone or mineralocorticoid receptor antagonist (MRA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor. We review the conventional approach to sequencing these therapies in HFrEF and proposed new rapid sequencing strategies. We review a recent modelling study suggesting the optimal sequence of treatment includes a sodium-glucose cotransporter 2 inhibition and an MRA as the first two therapies. Finally, we review the important opportunity offered by hospitalization for worsening heart failure to initiate and optimize foundational therapies in patients at high risk of early adverse outcomes.

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.\ud \ud Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.\ud \ud Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.\ud \ud Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa.\ud \ud Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, −0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.\ud \ud Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of −0.10 g/dL (95% CI, −0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, –11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.\ud \ud Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.\ud \ud Trial Registration: ClinicalTrials.gov Identifier: NCT03029208

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium–glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. Methods and results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (2), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06–1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI −0.93 to −0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. Conclusion: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.

Aims: \ud To examine clinical and social correlates of health-related quality of life (HRQL), in patients with heart failure (HF) from high- (HIC), upper middle- (UMIC), lower middle-(LMIC) and low-income (LIC) countries.\ud \ud Methods and Results: \ud Between 2017 and 2020, we enrolled 23,292 patients with HF (32% inpatients, 61% men) from 40 countries in the Global Congestive Heart Failure Study. We recorded HRQL at baseline using Kansas City Cardiomyopathy Questionnaire (KCCQ)-12. In a cross-sectional analysis, we compared age- and sex-adjusted mean KCCQ-12 summary scores (SS: 0-100, higher=better) between patients from different country income levels. We used multivariable linear regression examining correlations (estimated coefficients) of KCCQ-12-SS with sociodemographic-, comorbidity-, treatment- and symptom-covariates. The adjusted model (37 covariates) was informed by univariable findings, clinical importance and backward selection. Mean age was 63 years and 40% were in NYHA class III-IV. Average HRQL was 55±0.5. It was 62.5 (95% CI 62.0-63.1) in HIC, 56.8 (56.1-57.4) in UMIC, 48.6 (48.0-49.3) in LMIC, and 38.5 (37.3-39.7) in LICs (p

Background: \ud The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety.\ud \ud Methods: \ud We report the trial design, key demographic, clinical, and laboratory findings, and baseline therapies of 2964 patients randomised in the open-label (sponsor-blinded) active-controlled, parallel-group, randomised ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large cardiovascular outcome trials (CVOTs) and in the most relevant registries.\ud \ud Results: \ud The median age of patients was 58 years, 43% were female; 67% were white and 16% were black. The median haemoglobin at baseline was 10.4 g/dL. Among randomised patients, 89% were receiving haemodialysis and 11% peritoneal dialysis. Among key co-morbidities, 42% reported a history of diabetes mellitus, and 45% a history of cardiovascular disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron use was noted in 64% and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.\ud \ud Conclusion: \ud ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anaemia with CKD G5D.

Objectives: \ud This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.\ud \ud Background: \ud Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain.\ud \ud Methods: \ud We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed 1) whether baseline serum sodium modified the treatment effect of dapagliflozin, and 2) the effect of dapagliflozin on serum sodium.\ud \ud Results: \ud Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 (95% CI: 0.63-0.84], respectively, P-interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P-interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003).\ud \ud Conclusions: \ud Baseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. [Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF): NCT03036124].

Aims: \ud The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF).\ud \ud Methods and results: \ud A total of 43,138 ambulatory patients with HFrEF from 12 clinical trials were included (mean age 64.3 years; 9,580 (22.2%) women). Mean eGFR was 67 (SD 21) ml/min/1.73m2 and 70 (SD 21) ml/min/1.73m2 using the original and new CKD-EPI equations, respectively (mean difference 3.20 [95%CI, 3.17-3.23] ml/min/1.73m2, P

Background: Patients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure). Methods: The total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable Lei-Wei-Yang-Ying model. Results: Of 2371 participants randomly assigned to placebo, 318 experienced 469 hospitalizations for HF; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model, factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. In the Lei-Wei-Yang-Ying model, the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or cardiovascular death was 0.75 (95% CI, 0.65–0.88), P=0.0002. In the joint frailty model, the rate ratio for total HF hospitalizations was 0.71 (95% CI, 0.61–0.82), P

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

Aim:\ud There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF.\ud \ud Methods and results:\ud Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c

Objectives: \ud This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials.\ud \ud Background: \ud The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter–2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF).\ud \ud Methods: \ud Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo.\ud \ud Results: \ud A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m2; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF.\ud \ud Conclusions: \ud DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213]).

Background:\ud Sudden death is a leading cause of mortality in HFrEF. In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyze the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias.\ud \ud Methods:\ud Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analyzed: ventricular arrhythmias and the composite of a ventricular arrhythmia, ICD shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/CRT-D use, and the effect of sacubitril/valsartan was analyzed.\ud \ud Results:\ud Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia [HR 0.76 (0.62–0.95); p = 0.015] and the composite arrhythmia outcome [HR 0.79 (0.65–0.97); p = 0.025]. The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (0.71–1.21) versus 0.53 (0.37–0.78) in those without an ischaemic aetiology (p for interaction = 0.020).\ud \ud Conclusions:\ud Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology.

No abstract available.

With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The HeartFailure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF withreduced ejection fraction.

Supplemental Digital Content is available in the text., 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

Objectives: \ud In this study, we sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial.\ud \ud Background: \ud Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes.\ud \ud Methods: \ud A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death.\ud \ud Results: \ud History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan.\ud \ud Conclusions: \ud History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

The FREEDOM studies evaluated exenatide delivered via an implanted minipump in patients with type 2 diabetes; the final study evaluated cardiovascular outcomes but offers up more questions than answers.

Background: \ud Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials.\ud \ud Methods: \ud This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment.\ud \ud Findings: \ud 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of −0·01% [95% CI −0·03 to 0·01], −0·1 mmol/mol [95% CI −0·3 to 0·1] at 12 months).\ud \ud Interpretation: \ud Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c.\ud \ud Funding: \ud AstraZeneca.

Aims: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: A total of 43 138 ambulatory patients with HFrEF from 12 clinical trials were included (mean age 64.3 years; 9580 [22.2%] women). Mean eGFR was 67 (standard deviation [SD] 21) ml/min/1.73 m2 and 70 (SD 21) ml/min/1.73 m2 using the original and new CKD-EPI equations, respectively (mean difference 3.20 ml/min/1.73 m2, 95% confidence interval [CI] 3.17–3.23, p < 0.001). Of the 935 patients with chronic kidney disease (CKD) stages 4 or 5, identified using the original equation, 309 (33.0%) were reclassified to CKD stages 1–3 (eGFR ≥30 ml/min/1.73 m2) with the new equation. However, the opposite was observed among the 2521 Black patients (5.8%) included, with a reduction in mean eGFR from 75 to 68 ml/min/1.73 m2 using the original and new equations, respectively (mean difference 6.94 ml/min/1.73 m2, [95% CI 6.82–7.06], p < 0.001). The number of Black patients with an eGFR 2 increased from 49 (1.9%) using the original equation to 71 (2.8%) with the new equation. Conclusions: The new CKD-EPI creatinine equation reclassified CKD stage in a large proportion of patients with HFrEF enrolled in clinical trials. As eGFR is an essential determinant of eligibility for several key pharmacological therapies in HFrEF, this reclassification could result in a substantial change in the proportion of patients considered eligible for such therapies and reduce the proportion of eligible Black patients.

Aims: \ud To investigate the effect of high-dose iron vs. low-dose intravenous (IV) iron on myocardial infarction (MI) in patients on maintenance haemodialysis.\ud \ud Methods and results: \ud This was a pre-specified analysis of secondary endpoints of the Proactive IV Iron Therapy in Hemodialysis Patients trial (PIVOTAL) randomized, controlled clinical trial. Adults who had started haemodialysis within the previous year, who had a ferritin concentration

Aims: \ud The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result.\ud \ud Methods and Results: \ud We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, noncompletion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower hemoglobin, lower estimated glomerular filtration rate, higher NT-proBNP, higher NYHA functional class, prior HF hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio, 0.86; 95% confidence interval, 0.74–1.00).\ud \ud Conclusion: \ud Patients with more advanced heart failure were at higher risk for noncompletion of the run-in period in PARAGON-HF. Reanalysis of study outcomes accounting for the effect of run-in noncompletion did not alter the estimated treatment effects of sacubitril/valsartan vs valsartan.

No abstract available.

Background: \ud In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.\ud \ud Methods: \ud The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and Machine Learning algorithms.\ud \ud Results: \ud The mean age was 66 years and 30% of the patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses: HR (95%CI) comparing high- vs- low-dose losartan for the composite outcome of all-cause death or all-cause hospitalisation was 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women, interaction P=0.018. Female sex clustered along with older age, ischemic HF, NYHA III/IV, and eGFR

Background: \ud Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy (GDMT) for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and MRA use and dosing in a large randomized clinical trial.\ud \ud Methods: \ud Patients with full data on medication/dose use were included. We examined β-blocker and MRA use/dose in patients randomized to sacubitril/valsartan versus enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups.\ud \ud Results: \ud Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87.1% and 55%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-months and 12-months follow-up. New initiations through 12-months follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers (37 [9.0%] vs. 42 [10.2%], p = 0.56) and MRA (127 [7.6%] vs. 143 [9.2%], p = 0.10). Among patients on MRA therapy at baseline (n = 4634), there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12-months (125 [6.2%] vs. 187 [9.0%], p = 0.001). Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs 2.6%, p = 0.26).\ud \ud Conclusions: \ud Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose downtitrations of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.

Background: \ud Patients with heart failure with reduced ejection fraction (HFrEF) in Asia exhibit many differences from those in other parts of the world.\ud \ud Objectives: \ud This study sought to investigate the efficacy and safety of dapagliflozin, compared with placebo, in HFrEF patients in Asia, compared with those elsewhere, enrolled in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial.\ud \ud Methods: \ud Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and elevated N-terminal pro–B-type natriuretic peptide were eligible for the DAPA-HF trial. The primary outcome in the DAPA-HF trial was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.\ud \ud Results: \ud Of the 4,744 patients in the DAPA-HF trial, 1,096 (23.1%) were enrolled in Asia; 721 (15.2% overall, 65.8% of patients in Asia) were enrolled in East Asia (237 in China, 343 in Japan, and 141 in Taiwan), 138 (2.9% overall, 12.6% in Asia) in South-East Asia (Vietnam), and 237 (5.0% overall, 21.6% in Asia) in South Asia (India). Patients from Asia had similar rates of worsening HF events and mortality compared with patients elsewhere. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients from Asia (HR: 0.65; 95% CI: 0.49 to 0.87) as elsewhere (HR: 0.77; 95% CI: 0.66 to 0.89) (P for interaction = 0.32). Consistent benefits were observed for the other prespecified outcomes and among the regions of Asia. Study drug discontinuation and prespecified adverse events did not differ between regions.\ud \ud Conclusions: \ud Dapagliflozin, compared with placebo, reduced the risk of worsening HF events and cardiovascular death to the same extent in Asian patients as elsewhere. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).