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ImportanceThe expansion of sodium-glucose cotransporter-2 (SGLT-2) inhibitor use in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) more than 40% following the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) and the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials have major implications in the US.ObjectiveTo quantify the estimated US population-level impact of reducing worsening HF events with SGLT-2 inhibitors in individuals with LVEF more than 40%.Design, Setting, and ParticipantsThis decision analytical model study used self-reported HF data from the National Health and Nutritional Examination Survey from 2015 to 2018, which was weighted across the entire US population and subsequently mapped onto newly eligible LVEF distributions from the Get With The Guidelines–Heart Failure registry. All patients older than 18 years with HF from the National Health and Nutritional Examination Survey were grouped into the following categories: all LVEF and LVEF more than 40%. Numbers needed to treat estimations over 3 years were obtained for outcome measures from the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction), EMPEROR-Preserved, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), and DELIVER trials.Main Outcomes and MeasuresWorsening HF events (unplanned HF hospitalizations, urgent HF visits requiring intravenous therapy, or cardiovascular death).ResultsA projected 4 794 524 (95% CI, 3 997 363-5 591 684) adults (57% male; 67% White; mean age, 66 years) with HF would be eligible for SGLT-2 inhibitors. Of this total population, 2 619 248 (95% CI, 2 183 759-3 054 737) would be estimated as newly eligible with LVEF more than 40%. Based on estimates from the EMPEROR-Reduced/EMPEROR-Preserved and DAPA-HF/DELIVER trials, a projected 624 247 (95% CI, 520 457-728 037) to 627 124 (95% CI, 522 855-731 392) worsening HF events could be prevented across the LVEF spectrum with SGLT-2 inhibitors over 3 years, of which 232 589 (95% CI, 193 918-271 260) to 282 879 (95% CI, 235 846-329 912) events could be prevented in individuals with LVEF more than 40%. Moreover, an estimated 468 904 (95% CI, 390 942-546 867) to 499 110 (95% CI, 416 125-582 094) total HF hospitalizations could be prevented across the LVEF spectrum, of which 172 870 (95% CI, 144 128-201 613) to 231 018 (95% CI, 192 608-269 428) could be prevented in individuals with LVEF more than 40%.Conclusions and RelevanceIn addition to the proven benefit in HF with LVEF of 40% and less, optimal implementation of SGLT-2 inhibitor therapy for HF with LVEF more than 40% can potentially prevent/postpone an additional approximately 250 000 worsening HF events over 3 years in the US.

ImportanceGout is common in patients with heart failure (HF), and sodium-glucose cotransporter 2 inhibitors, a foundational treatment for HF, reduce uric acid levels.ObjectiveTo examine the reported prevalence of gout at baseline, the association between gout and clinical outcomes, and the effect of dapagliflozin in patients with and without gout and the introduction of new uric acid–lowering therapy and colchicine.Design, Setting, and ParticipantsThis post hoc analysis used data from 2 phase 3 randomized clinical trials conducted in 26 countries, DAPA-HF (left ventricular ejection fraction [LVEF] ≤40%) and DELIVER (LVEF >40%). Patients with New York Heart Association functional class II through IV and elevated levels of N-terminal pro–B-type natriuretic peptide were eligible. Data were analyzed between September 2022 and December 2022.InterventionAddition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.Main Outcomes and MeasuresThe primary outcome was the composite of worsening HF or cardiovascular death.ResultsAmong 11 005 patients for whom gout history was available, 1117 patients (10.1%) had a history of gout. The prevalence of gout was 10.3% (488 of 4747 patients) and 10.1% (629 of 6258 patients) in those with an LVEF up to 40% and greater than 40%, respectively. Patients with gout were more often men (897 of 1117 [80.3%]) than those without (6252 of 9888 [63.2%]). The mean (SD) age was similar between groups, 69.6 (9.8) years for patients with gout and 69.3 (10.6) years for those without. Patients with a history of gout had a higher body mass index, more comorbidity, and lower estimated glomerular filtration rate and were more often treated with a loop diuretic. The primary outcome occurred at a rate of 14.7 per 100 person-years (95% CI, 13.0-16.5) in participants with gout compared with 10.5 per 100 person-years (95% CI, 10.1-11.0) in those without (adjusted hazard ratio [HR], 1.15; 95% CI, 1.01-1.31). A history of gout was also associated with a higher risk of the other outcomes examined. Compared with placebo, dapagliflozin reduced the risk of the primary end point to the same extent in patients with (HR, 0.84; 95% CI, 0.66-1.06) and without a history of gout (HR, 0.79; 95% CI, 0.71-0.87; P = .66 for interaction). The effect of dapagliflozin use with other outcomes was consistent in participants with and without gout. Initiation of uric acid–lowering therapy (HR, 0.43; 95% CI, 0.34-0.53) and colchicine (HR, 0.54; 95% CI, 0.37-0.80) was reduced by dapagliflozin compared with placebo.Conclusions and RelevanceThis post hoc analysis of 2 trials found that gout was common in HF and associated with worse outcomes. The benefit of dapagliflozin was consistent in patients with and without gout. Dapagliflozin reduced the initiation of new treatments for hyperuricemia and gout.Trial RegistrationClinicalTrials.gov Identifiers: NCT03036124 and NCT03619213

Aims Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful. Methods and results The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes were comprehensively adjusted for other prognostic variables, including natriuretic peptides. An ‘obesity-survival paradox’ related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10 [95% confidence interval (CI) 0.87–1.39]. However, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of the primary outcome and HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (95% CI 1.06–1.81). Conclusion In patients with HFrEF, alternative anthropometric measurements showed no evidence for an ‘obesity-survival paradox’. Newer indices that do not incorporate weight showed that greater adiposity was clearly associated with a higher risk of HF hospitalization.

Aim PARADISE-MI examined the efficacy of sacubitril/valsartan in acute myocardial infarction (AMI) complicated by reduced left ventricular ejection fraction (LVEF), pulmonary congestion, or both. We sought to assess the trajectory of pulmonary congestion using lung ultrasound (LUS) and its association with cardiac structure and function in a pre-specified substudy. Methods and results Patients without prior heart failure (HF) underwent eight-zone LUS and echocardiography at baseline (±2 days of randomization) and after 8 months. B-lines were quantified offline, blinded to treatment, clinical findings, time point, and outcomes. Among 152 patients (median age 65, 32% women, mean LVEF 41%), B-lines were detectable in 87% at baseline [median B-line count: 4 (interquartile range 2–8)]. Among 115 patients with LUS data at baseline and follow-up, B-lines decreased significantly from baseline (mean ± standard deviation: −1.6 ± 7.3; P = 0.018). The proportion of patients without pulmonary congestion at follow-up was significantly higher in those with fewer B-lines at baseline. Adjusted for baseline, B-lines at follow-up were on average 6 (95% confidence interval: 3–9) higher in patients who experienced an intercurrent HF event vs. those who did not (P = 0.001). A greater number of B-lines at baseline was associated with larger left atrial size, higher E/e′ and E/A ratios, greater degree of mitral regurgitation, worse right ventricular systolic function, and higher tricuspid regurgitation velocity (P-trend Conclusion In this AMI cohort, B-lines, indicating pulmonary congestion, were common at baseline and, on average, decreased significantly from baseline to follow-up. Worse pulmonary congestion was associated with prognostically important echocardiographic markers.

AimsFew reports have examined the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) or their relationship with mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF).Methods and resultsData from the PARAGON-HF, TOPCAT, I-Preserve, and CHARM-Preserved trials were merged. VT/VF, reported as adverse events, were identified. Patients who experienced VT/VF were compared with patients who did not. The relationship between VT/VF and mortality was examined in time-updated Cox proportional hazard regression models. Variables associated with VT/VF were examined in Cox proportional hazard regression models. The rate of VT/VF in patients with HFmrEF compared with patients with HFpEF was examined in a Cox proportional hazards regression model. Of 13 609 patients, over a median follow-up of 1170 days (interquartile range: 966–1451), 146 (1.1%) experienced an investigator-reported VT/VF (incidence rate 0.3 per 100 person-years). Patients who experienced VT/VF were more likely to be male, have had a myocardial infarction, poorer renal function, more adverse left ventricular remodelling, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) than patients who did not. Occurrence of VT/VF was associated with NT-proBNP, history of atrial fibrillation/flutter, male sex, lower ejection fraction, and history of hypertension. VT/VF was associated with all-cause death [adjusted hazard ratio (HR): 3.95, 95% confidence interval (CI): 2.80–5.57; P < 0.001] and cardiovascular death, driven by death from heart failure and not sudden death. Patients with HFmrEF had a higher rate of VT/VF than patients with HFpEF (adjusted HR: 2.19, 95% CI: 1.77–2.71).ConclusionVT/VF was uncommon in patients with HFmrEF and HFpEF. However, such events were strongly associated with mortality and appear to be a marker of disease severity rather than risk of sudden death.Clinical trial registrationClinicalTrials.gov unique identifier: NCT01920711(PARAGON-HF); NCT00094302 (TOPCAT); NCT00095238 (I-Preserve); NCT00634712 (CHARM-Preserved)

Few people now reach old age without taking multiple drugs, often attending various clinics, and undergoing secondary or tertiary investigations. Most chronic conditions are, to differing extents, caused or exacerbated by excess adiposity, but weight management is rarely discussed or attempted for patients. Furthermore, progressive symptoms usually attributed to ageing (eg, musculoskeletal pains, fatigue, and breathlessness), and which create considerable health-care demands, can also be attributed to the accumulation of body fat over time. For many symptoms and diseases that are more frequently reported in people with excess adiposity (such as depression), there exist potentially multidirectional, causal relationships that generate a cycle of clinical and social deterioration. There is insufficient research on the effects of effective weight management on these clinically demanding, age and weight-mediated symptoms. Based on current evidence, we suggest that policy makers need to be more proactive in obesity prevention and effective weight management should receive research funding to match the search for novel therapeutics for secondary chronic diseases.

With modern treatments for heart failure with reduced ejection fraction (EF), indicative of impaired cardiac systolic function, patients may exhibit an increase in EF. Limited data are available regarding the clinical management of this growing population, categorized as heart failure with improved EF (HFimpEF), which has a high event rate and has been excluded from virtually all prior heart failure outcomes trials. In a prespecified analysis of the DELIVER trial (NCT03619213), of a total of 6,263 participants with symptomatic heart failure and a left ventricular EF >40%, 1,151 (18%) had HFimpEF, defined as patients whose EF improved from ≤40% to >40%. Participants were randomized to 10 mg dapagliflozin or placebo daily and the primary outcome of the trial was a composite of cardiovascular death or worsening heart failure (heart failure hospitalization or an urgent heart failure visit). Participants with HFimpEF had similar event rates to those with an EF consistently >40%. In participants with HFimpEF, dapagliflozin reduced the primary composite outcome (hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.56–0.97), first worsening heart failure events (HR = 0.84, 95% CI = 0.61–1.14), cardiovascular death (HR = 0.62, 95% CI = 0.41–0.96) and total worsening heart failure events (rate ratio = 0.68, 95% CI = 0.50–0.94) to a similar extent as for individuals with an EF consistently >40%. These data suggest that patients with HFimpEF who are symptomatic may benefit from the addition of a sodium/glucose cotransporter 2 inhibitor to previously instituted guideline-directed medical therapy to further reduce morbidity and mortality.

Background: \ud Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.\ud \ud Methods: \ud We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.\ud \ud Results: \ud Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but 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 hospitalized patients with type 2 diabetes, 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. Furthermore, 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.

Aims Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. Methods and results In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of 40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55–0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86–1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of −6.5% (95% CI: −9.4 to −3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of −2.5 mg/year; 95% CI: −1.5, −3.7, P < 0.001). Conclusion In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.

Background and Aims To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier NCT04860011

ImportanceDapagliflozin has been shown to improve overall health status based on aggregate summary scores of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure (HF) with mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. A comprehensive understanding of the responsiveness of individual KCCQ items would allow clinicians to better inform patients on expected changes in daily living with treatment.ObjectiveTo examine the association of dapagliflozin treatment with changes in individual components of the KCCQ.Design, Setting, and ParticipantsThis is a post hoc exploratory analysis of DELIVER, a randomized double-blind placebo-controlled trial conducted at 353 centers in 20 countries from August 2018 to March 2022. KCCQ was administered at randomization and 1, 4, and 8 months. Scores of individual KCCQ components were scaled from 0 to 100. Eligibility criteria included symptomatic HF with left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. Data were analyzed from November 2022 to February 2023.Main Outcomes and MeasuresChanges in the 23 individual KCCQ components at 8 months.InterventionsDapagliflozin, 10 mg, once daily or placebo.ResultsBaseline KCCQ data were available for 5795 of 6263 randomized patients (92.5%) (mean [SD] age, 71.5 [9.5] years; 3344 male [57.7%] and 2451 female [42.3%]). Dapagliflozin was associated with larger improvements in almost all KCCQ components at 8 months compared with placebo. The most significant improvements with dapagliflozin were observed in frequency of lower limb edema (difference, 3.2; 95% CI, 1.6-4.8; P P P Conclusions and RelevanceIn this study of patients with HF with mildly reduced or preserved ejection fraction, dapagliflozin was associated with improvement in a broad range of individual KCCQ components, with the greatest benefits in domains related to symptom frequency and physical limitations. Potential improvements in specific symptoms and activities of daily living might be more readily recognizable and easily communicated to patients.Trial RegistrationClinicalTrials.gov Identifier: NCT03619213

Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined.At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002).Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.

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

ImportanceIn the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF).ObjectiveTo evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population.Design, Setting, and ParticipantsIn this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death. Several subgroups were examined to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. Participants were enrolled from August 2018 to December 2020, and data were analyzed from August to October 2022.InterventionsDapagliflozin, 10 mg, once daily or matching placebo.Main Outcomes and MeasuresThe outcome was total episodes of worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death.ResultsOf 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. There were 1057 HF events and cardiovascular deaths in the placebo group compared with 815 in the dapagliflozin group. Patients with more HF events had features of more severe HF, such as higher N-terminal pro–B-type natriuretic peptide level, worse kidney function, more prior HF hospitalizations, and longer duration of HF, although EF was similar to those with no HF events. In the LWYY model, the rate ratio for total HF events and cardiovascular death for dapagliflozin compared with placebo was 0.77 (95% CI, 0.67-0.89; P P P P = .14) for cardiovascular death. The results were similar for total HF hospitalizations (without urgent HF visits) and cardiovascular death and in all subgroups, including those defined by EF.Conclusions and RelevanceIn the DELIVER trial, dapagliflozin reduced the rate of total HF events (first and subsequent HF hospitalizations and urgent HF visits) and cardiovascular death regardless of patient characteristics, including EF.Trial RegistrationClinicalTrials.gov Identifier: NCT03619213

Aims The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation. Methods and results CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (−10 and 10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was −0.7 (−6.4–4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C. Conclusion The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients. Clinical Trial Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.

Aims Hypertensive heart disease (HHD) is recognized as a key clinical precursor to heart failure with preserved ejection fraction (HFPEF). However, pathophysiological transition from HHD to HFPEF is not well understood. We sought determine whether regional differences in impaired myocardial function may underlie the greater mechanical dysfunction seen in HFPEF compared to HHD. Methods and results We used standardized echocardiography to assess regional myocardial deformation in a cohort of n = 327 adults with preserved left ventricular (LV) ejection fraction (≥45%), including: n = 129 with HFPEF, n = 158 with HHD and no heart failure, and n = 40 normotensive controls. From detailed measurements of LV systolic strain performed in multiple views, we derived and then compared regional measures of basal, mid-ventricular, and apical longitudinal strains. In models adjusting for clinical covariates, basal and mid-ventricular LV myocardial deformation was more impaired in HHD than in controls (P ≤ 0.003), whereas apical deformation was more impaired in HFPEF than in HHD (P = 0.005). In multivariable-adjusted analyses, only apical strain remained independently associated with HFPEF vs. HHD status [odds ratio 1.18 (1.02–1.37), P = 0.030 per 1% decrease in apical strain]. Compared to other regional strains, apical longitudinal strain optimally differentiated HFPEF from HHD (area under the receiver operating curve: apical longitudinal strain = 0.67; mid-ventricular longitudinal strain = 0.59; basal longitudinal strain = 0.60). Conclusion We found that while apical mechanical function is preserved in HHD, it was impaired in HFPEF and may contribute to the transition from an asymptomatic heart disease to a symptomatic heart disease.

Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias.Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (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/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. 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 (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 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 the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020).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.

Aim: 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.Methods and results: 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, Conclusion: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

Document Reviewers: Rudolf A. de Boer (CPG Review Coordinator) (Netherlands), P. Christian Schulze (CPG Review Coordinator) (Germany), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Elena Arbelo (Spain), Riccardo Asteggiano (Italy), Johann Bauersachs (Germany), Antoni Bayes-Genis (Spain), Michael A. Borger (Germany), Werner Budts (Belgium), Maja Cikes (Croatia), Kevin Damman (Netherlands), Victoria Delgado (Netherlands), Paul Dendale (Belgium), Polychronis Dilaveris (Greece), Heinz Drexel (Austria), Justin Ezekowitz (Canada), Volkmar Falk (Germany), Laurent Fauchier (France), Gerasimos Filippatos (Greece), Alan Fraser (United Kingdom), Norbert Frey (Germany), Chris P. Gale (United Kingdom), Finn Gustafsson (Denmark), Julie Harris (United Kingdom), Bernard Iung (France), Stefan Janssens (Belgium), Mariell Jessup (United States of America), Aleksandra Konradi (Russia), Dipak Kotecha (United Kingdom), Ekaterini Lambrinou (Cyprus), Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany), Christophe Leclercq (France), Basil S. Lewis (Israel), Francisco Leyva (United Kingdom), AleVs Linhart (Czech Republic), Maja-Lisa Løchen (Norway), Lars H. Lund (Sweden), Donna Mancini (United States of America), Josep Masip (Spain), Davor Milicic (Croatia), Christian Mueller (Switzerland), Holger Nef (Germany), Jens-Cosedis Nielsen (Denmark), Lis Neubeck (United Kingdom), Michel Noutsias (Germany), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Dimitrios J. Richter (Greece), Evgeny Schlyakhto (Russia), Petar Seferovic (Serbia), Michele Senni (Italy), Marta Sitges (Spain), Miguel Sousa-Uva (Portugal), Carlo G. Tocchetti (Italy), Rhian M. Touyz (United Kingdom), Carsten Tschoepe (Germany), Johannes Waltenberger (Germany/Switzerland) All experts involved in the development of these guidelines have submitted declarations of interest. These have been compiled in a report and published in a supplementary document simultaneously to the guidelines. The report is also available on the ESC website www.escardio.org/guidelines For the Supplementary Data which include background information and detailed discussion of the data that have provided the basis for the guidelines see European Heart Journal online.

Background Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. Methods The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3–5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8–10 g/dL or receiving ESAs with screening Hb of 8–12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28–52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. Results Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin–angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.

Background The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305). Methods ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study). Results In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined. Conclusions Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat. Trial registration The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

ImportanceIn 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes.ObjectiveTo examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF.Design, Setting, and ParticipantsThis was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment.InterventionDapagliflozin vs placebo.Main Outcomes and MeasuresThe mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression.ResultsOf 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI.Conclusions and RelevanceIn a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF.Trial RegistrationClinicalTrials.gov Identifier: NCT03036124, NCT03619213