BACKGROUND AND AIMS:It remains unclear what the safe serum potassium range is in heart failure (HF) and whether it is the same in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS:A patient-level pooled analysis from 12 randomized controlled trials including 32 346 HFrEF and 13 723 HFpEF patients was performed. Baseline serum potassium level was categorized into six groups (<3.5, ≥3.5-<4.0, ≥4.0-<4.5, ≥4.5-<5.0, ≥5.0-<5.5, and ≥5.5 mmol/L) and serum potassium level at baseline was also analysed as a continuous variable using restricted cubic splines. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, sudden death, pump failure death, first HF hospitalization, and composites of HF hospitalization and cardiovascular or all-cause death. RESULTS:The median follow-up was 24.2 and 36.8 months in HFrEF and HFpEF trials, respectively. In HFrEF, serum potassium levels showed a reverse J-shaped association with outcomes. Compared with ≥4.0-4.5 mmol/L (reference), potassium <3.5 mmol/L was associated with higher risks of all-cause mortality (adjusted hazard ratio 1.49; 95% confidence interval, 1.27-1.76), as well as cardiovascular, sudden, and pump failure death. The lowest risk for all outcomes was observed within the baseline serum potassium range of 4.2-5.0 mmol/L, but even 'mild hyperkalaemia' (5.0-5.5 mmol/L) was not associated with worse outcomes in HFrEF. Although the risk curve was U-shaped and flatter in HFpEF, the lowest incidence of all outcomes was observed over the same potassium range as HFrEF. CONCLUSION:In HFrEF, hypokalaemia is strongly associated with worse outcomes and should be avoided. In terms of safety, the optimal serum potassium concentration in both HFrEF and HFpEF appears to be in the range 4.2-5.0 mmol/L.

BACKGROUND:Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells. Increased LDH levels are a nonspecific measure of cellular injury and may be prognostically important in heart failure (HF). OBJECTIVES:This study aims to assess the relationship between LDH and clinical characteristics and outcomes in heart failure and reduced ejection fraction (HFrEF). METHODS:Using data from GALACTIC-HF, a phase 3, randomized, placebo-controlled trial evaluating the efficacy and safety of omecamtiv mecarbil (OM) in patients with HFrEF, the relationship between LDH and clinical outcomes was analyzed. The incremental value of LDH added to a validated prognostic model (PREDICT-HF) was also calculated using Harrell's C statistic, integrated discrimination index (IDI), and net reclassification index (NRI). RESULTS:In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and high-sensitivity troponin I. Compared with patients in the lowest LDH (Q1: 155 U/L [25th-75th percentile: 144-163 U/L]), the HRs for the primary outcome (first HF event or cardiovascular death) were Q2: 183 U/L (25th-75th percentile: 177-188 U/L); HR: 1.15 [95% CI: 1.02-1.31]; Q3: 207 U/L (25th-75th percentile: 201-215 U/L); HR: 1.39 [95% CI: 1.23-1.58]; and Q4: 253 U/L (25th-75th percentile: 236-280 U/L); HR: 1.84 [95% CI: 1.62-2.08], respectively. Even after adjustment, elevated LDH remained independently associated with higher HR. When added to the PREDICT-HF risk model, baseline LDH improved Harrell's C statistic, IDI, and NRI for the primary outcome. CONCLUSIONS:In GALACTIC-HF, higher LDH levels were independently associated with a higher risk of clinical outcomes in HFrEF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329; EudraCT number: 2016-002299-28).

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is characterized by the frequent co-occurrence of obesity, central adiposity, insulin resistance, type 2 diabetes mellitus, and low-grade inflammation. How these exposures sustain myocardial remodeling remains uncertain. One-carbon metabolism provides a plausible biochemical interface between nutrient stress and epigenetic regulation: S-adenosylmethionine (SAM) donates methyl groups, whereas S-adenosylhomocysteine (SAH) inhibits methyltransferases. Altered nicotinamide N-methyltransferase (NNMT) flux, homocysteine-related SAH retention, and metabolic regulation of DNA methyltransferase (DNMT) and ten-eleven translocation (TET) enzymes could therefore reshape DNA methylation and hydroxymethylation. Direct human evidence remains sparse: available HFpEF methylation data are blood-derived rather than myocardial, and cardiac or adjacent models support individual components of the framework but not a continuous disease-specific pathway. We therefore view DNA methylation as a context-dependent regulatory layer that may amplify or stabilize inflammatory, fibrotic, and metabolic programs rather than as a uniform initiating cause. Accordingly, translational studies should prioritize compartment-specific target engagement, reversibility, and biomarker-guided patient selection rather than assume a role for methylation-directed therapy.

BACKGROUND AND AIMS:The frequency and prognostic significance of abnormalities in serum magnesium concentrations have not been described in a contemporary heart failure (HF) population. The authors evaluated the prognostic significance of magnesium concentrations in patients with HF with reduced ejection fraction (HFrEF) enrolled in GALACTIC-HF trial. METHODS:GALACTIC-HF was a randomized, double-blind, multicentre, event-driven trial that investigated the efficacy and safety of omecamtiv mecarbil compared with placebo in HF patients with left ventricular ejection fraction ≤ 35%. The primary outcome was the composite of a first worsening HF event or cardiovascular death. RESULTS:A total of 6147 outpatients had baseline serum magnesium data. Of these, 1082 (17.6%) had magnesium concentrations below .75 mmol/L, 4410 (71.7%) had concentrations within the normal range, and 655 (10.7%) had concentrations above .95 mmol/L. The incidence rate (per 100 person-years) for the primary composite outcome was highest in patients with hypermagnesaemia (34.9, 95% confidence interval 31.2-39.0), while rates were similar between those with hypomagnesaemia (21.5, 19.4-23.8), and normal magnesium (20.9, 19.9-22.0). Similar trends were observed for the components of the primary outcome and all-cause death. The incidence rate of sudden death and ventricular tachyarrhythmia did not differ among the three magnesium groups, but the risk of death from worsening HF was highest in patients with hypermagnesaemia. CONCLUSIONS:In GALACTIC-HF, 10.7% of outpatients with HFrEF had hypermagnesaemia, which was associated with a higher risk of the primary outcome compared with normal magnesium concentrations. Abnormal magnesium levels were not associated with a higher risk of sudden death or ventricular tachyarrhythmias. These findings do not support routine correction of hypomagnesaemia.

AIMS:Dipstick urine testing is often performed in primary and secondary care, although the results may not be routinely inspected or acted upon. We aimed to examine the prognostic value of semiquantitative urine dipstick proteinuria (DP) assessments in patients with heart failure (HF) and reduced ejection fraction. METHODS:This retrospective analysis utilized data from GALACTIC-HF, a randomized trial that investigated the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil, compared with placebo in patients with HF with reduced ejection fraction. The primary outcome was the composite of a first HF event (hospitalization or urgent visit for HF) or cardiovascular death, and secondary outcomes were a HF event, cardiovascular death, and all-cause death. Cox proportional hazard models were used to examine the relationship between DP levels and clinical outcomes. RESULTS:Baseline DP data were available for 7790 patients, of whom 5910 (75.9%) had a negative test or trace proteinuria, 995 (12.8%) had 1+, and 885 (11.4%) had ≥2+ proteinuria. The incidence rate of the primary outcome (per 100 person-years) increased significantly with increasing DP: negative/trace (21.8, 95% confidence interval 20.8-22.7); 1+ (34.8, 31.8-38.0); and ≥2+ (38.1, 34.7-41.9). Similar trends were observed for the components of the primary outcome and all-cause mortality. The association between greater DP and worse outcomes was stronger in patients with preserved (≥60 ml/min/1.73 m2) estimated glomerular filtration rate compared with reduced estimated glomerular filtration rate (<60 ml/min/1.73 m2). CONCLUSION:In GALACTIC-HF, higher DP levels were independently associated with increased risk of adverse clinical outcomes in patients with reduced ejection fraction. TRIAL REGISTRATION:GALACTIC-HF ClinicalTrials.gov Identifier: NCT02929329; EudraCT number, 2016-002299-28.

AIMS:Given the emerging role of transcatheter valve repair in HFrEF patients with moderate/severe secondary mitral regurgitation (MR), we evaluated the prevalence and outcomes related to MR in the GALACTIC-HF trial. METHODS:The randomized GALACTIC-HF trial compared the efficacy and safety of omecamtiv mecarbil to placebo in 8232 patients with HFrEF, with a primary composite outcome of a first HF event or cardiovascular death. RESULTS:Of 7998 patients (97.2%) with baseline data on MR, 5782 (72.3%) had no MR, 970 (12.1%) had mild MR, and 1221 (15.3%) had moderate MR (only 25 had severe MR). Patients with moderate MR had a higher risk of the primary outcome than those without MR (adjusted HR 1.11; 95% CI 1.01-1.23); risk was not higher in patients with mild MR. The association between moderate MR and the primary outcome was most prominent in patients with less severe HF (milder NYHA class, higher LVEF, and lower N-terminal pro-B-type natriuretic peptide) compared to more severe HF. In adjusted analyses, MR was not associated with mortality, and the results of all analyses remained consistent after including patients with severe MR. The beneficial treatment effect of omecamtiv mecarbil versus placebo on clinical outcomes was not modified by MR. Over 80% of patients with moderate/severe MR fulfilled the broad inclusion criteria for COAPT and RESHAPE-HF2. CONCLUSIONS:In GALACTIC-HF, almost 15% of patients with heart failure and reduced ejection fraction had moderate MR, which was associated with a higher risk of the primary outcome.

Accurately identifying coronary vulnerable plaque that would cause major adverse clinical events based on morphological characteristics remains a major clinical challenge. Plaque biomechanics are closely associated with plaque rupture and could assist in rupture risk stratification to identify high-risk coronary plaques for potential intervention. In vivo optical coherence tomography images of 40 coronary plaques from 40 patients with coronary artery disease were acquired and categorized into three groups according to their morphological characteristics: stable, vulnerable, and ruptured plaques. Finite element analysis was performed to obtain the peak stress value over the fibrous cap and shoulder region denoted as critical plaque wall stress (CPWS). A rupture risk stratification scheme was proposed based on the CPWS value to classify three plaque groups from biomechanical perspective, and its agreement rate with morphological classification was calculated. Ruptured and vulnerable plaques exhibited significant higher CPWS values than stable ones while no significant difference was found between ruptured and vulnerable plaques. The biomechanical risk stratification scheme was formed using 150 kPa and 230 kPa as threshold values for CPWS to classify three types of plaques, and its agreement rates with morphological classification were 17/20, 5/10, and 7/10 for stable, vulnerable, and ruptured plaques, respectively. This biomechanical scheme holds the potential to accurately stratify the rupture risk of coronary plaques as demonstrated by reasonable concordance with morphological classification. Discrepancy between two classifications highlights the unique value of biomechanical scheme, when integrated with morphological classification, in preventing unnecessary interventions and detecting rupture-prone plaques.

BackgroundDiabetic Cardiac Autonomic Neuropathy (DCAN), a critical yet frequently underdiagnosed microvascular complication, is associated with increased mortality. Standard cardiovascular autonomic reflex tests (CARTs) are complex and time-consuming, hindering their widespread use in routine screening in clinical settings. This study aimed to develop and validate a predictive nomogram for DCAN in patients with diabetes using readily available clinical variables.MethodsWe retrospectively analyzed the clinical data of 453 patients with type 1 or type 2 diabetes hospitalized at Shenzhen People’s Hospital between February 2022 and December 2025. The dataset was randomly divided into training (70%) and validation (30%) cohorts. Key predictors were identified using a rigorous selection strategy that combined univariate analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate logistic regression. Four candidate prediction models (Logistic Regression (LR), Random Forest, Extreme Gradient Boosting (XGBoost), and Light Gradient Boosting Machine (LightGBM) were constructed and evaluated for discrimination, calibration, and clinical utility. The optimal model was visualized as a nomogram and interactive web calculator.ResultsThe prevalence of DCAN in the study population was 45.0% (204/453). The following seven independent predictors were identified: a history of diabetic retinopathy (DR) or diabetic kidney disease (DKD), diabetes duration, age, heart rate (HR), fasting plasma glucose (FPG), and HbA1c. Among the algorithms tested, the LR model exhibited the most balanced performance in the validation cohort (area under the curve (AUC) = 0.838) with the highest sensitivity (77.0%) and was thus selected as the optimal prediction tool. Consequently, the LR model was transformed into a predictive nomogram. This nomogram demonstrated good calibration and potential clinical utility for individualized risk assessment.ConclusionWe successfully developed and validated a high-sensitivity prediction model for DCAN applicable to type 1 and type 2 diabetes. The developed visual nomogram and interactive web-based tool are cost-effective and user-friendly instruments that can facilitate early risk assessment and personalized clinical management.

BACKGROUND:Epicardial adipose tissue (EpAT), particularly pericoronary adipose tissue (PCAT), plays a crucial role in diabetes mellitus (DM)-aggravated coronary artery disease (CAD). Emerging evidence suggests that dysfunction of the arterial lymphatic network contributes to atherosclerosis progression. Our study aimed to investigate whether lymphatic vessel impairment in PCAT (a type of EpAT) is involved in DM-related CAD and to explore its underlying molecular mechanisms. METHODS:We prospectively enrolled patients undergoing heart valve surgery (control [CTRL] group) and coronary artery bypass grafting surgery (CAD group) between February 2024 and March 2025. EpAT volume (EpATv) and SYNTAX scores were assessed, and human PCAT samples were performed with pathological staining. Single-nucleus RNA sequencing (snRNA-seq) was employed to characterize intercellular communication between epicardial adipocytes and lymphatic endothelial cells (LECs). In vitro diabetic models of human adipocytes and LECs were established using palmitic acid (PA) and high concentration glucose (HG) to verify intercellular signaling. RESULTS:Of a total of 160 patients enrolled (113 males), 48 were controls and 112 were CAD patients (44 with DM). CAD patients, particularly those with DM, showed increased EpATv, adipocyte size, macrophage infiltration, and reduced lymphatic vessel density. Lymphatic vessel density was inversely correlated with both adipocyte size and CAD severity. CAD patients with DM also had worse prognosis and higher readmission rates. snRNA-seq analysis revealed significantly attenuated IGF1-IGF1R signaling between epicardial adipocytes and LECs in the PCAT of CAD patients with DM. Recombinant IGF1 effectively enhanced LEC proliferation, migration, and tube formation under diabetic conditions, whereas the IGF1R antagonist impeded these protective effects. CONCLUSIONS:Our findings demonstrate that attenuated IGF1-IGF1R signaling between epicardial adipocytes and LECs may contribute to lymphatic impairment in PCAT, which is associated with CAD progression in DM. Our work may represent a novel potential therapeutic target for CAD patients with DM. RESEARCH INSIGHTS:What is currently known about this topic? Lymphatic vessels play a crucial role in mediating the progression of atherosclerosis. Epicardial adipose tissue (EpAT) acts as critical anatomical and functional link coupling diabetes mellitus (DM) and coronary artery disease (CAD). Adipocytes are involved in the regulation of lymphatic endothelial cell proliferation and lymphangiogenesis. What is the key research question? Whether impaired lymphatic vessels in pericoronary adipose tissue (PCAT, a type of EpAT) were involved in the pathological development of DM-related CAD. What is new? DM-aggravated CAD is associated with reduced lymphatic vessel density within PCAT. It identifies a novel intercellular signaling interaction between epicardial adipocytes and lymphatic endothelial cells in modulating lymphangiogenesis. How might this study influence clinical practice? Enhancing lymphangiogenesis through modulation of IGF1-IGF1R signaling pathway may offer new strategies for improving cardiovascular outcomes. Additionally, lymphatic vessel density in PCAT may serve as a biomarker for CAD severity and progression. This work highlights a novel potential therapeutic target for CAD patients with DM.

Background The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death.Methods and Results Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20-12.54) compared with 7.09 (6.17-8.14) per 100 person-years in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI.Conclusions Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months' follow-up. Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (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; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

IMPORTANCE Given their kidney actions, it is important to evaluate the efficacy and safety of mineralocorticoid receptor antagonists when combined with other diuretics and whether they have a so-called diuretic-sparing effect in patients with heart failure (HF). OBJECTIVE To examine the efficacy and tolerability of finerenone related to background diuretic treatment in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). DESIGN, SETTING, AND PARTICIPANTS This study is a prespecified secondary analysis of the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) randomized clinical trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with HFmrEF/HFpEF, who were randomized between September 2020 and January 2023. Data analysis was conducted from December 1, 2024, to January 30, 2025. INTERVENTION Finerenone (titrated to 20 mg or 40 mg) or placebo. MAIN OUTCOMES AND MEASURES The primary outcome was the composite of total HF events and cardiovascular death. Outcomes were compared between finerenone and placebo according to the following baseline diuretic categories: only a nonloop diuretic (thiazide or thiazide-like); loop diuretic (<= 40 mg vs >40 mg furosemide-equivalent dose); and combined nonloop and loop diuretic use. RESULTS Among 5438 patients, 2496 (45.9%) were female, and mean (SD) age was 72.1 (9.6) years. A total of 684 patients (12.6%) were receiving a nonloop diuretic, 3040 (55.9%) less than or equal to 40 mg furosemide equivalent, 1145 (21.1%) 40 mg or greater furosemide equivalent, and 569 (10.5%) both nonloop and loop diuretics. Compared with placebo, finerenone reduced the risk of the primary end point across all diuretic subgroups: rate ratios were 0.84 (95% CI, 0.47-1.51), 0.86 (95% CI, 0.72-1.02), 0.98 (95% CI, 0.78-1.24), and 0.54 (95% CI, 0.35-0.83) for patients in the nonloop, 40 mg or less loop, more than 40 mg loop, and combined nonloop and loop categories, respectively (P for interaction = .18). Compared with placebo, finerenone reduced loop diuretic dose and dose intensification, but not loop diuretic initiation. Safety was consistent across diuretic categories. CONCLUSIONS AND RELEVANCE In this secondary analysis of the FINEARTS-HF randomized clinical trial, the efficacy and safety of finerenone were consistent across all diuretic subgroups. Compared with placebo, finerenone reduced the use of diuretics in patients with HFmrEF/HFpEF; however, finerenone did not reduce the initiation of new loop diuretic in participants not receiving a loop diuretic at baseline.

Background The collection of race and ethnicity data in clinical trials using standardized categories is recommended by the US Food and Drug Administration, although this is primarily for domestic reasons. The applicability and understanding of the categories in multinational trials are uncertain. Methods We analyzed patient‐level data from 13 major heart failure trials, examining race and ethnicity data recorded by country, as recommended by the Food and Drug Administration: “American Indian or Alaska Native,” “Asian,” “Black or African American,” “Native Hawaiian or Other Pacific Islander,” and “White” for race and “Hispanic or Latino” as a minimum for ethnicity (with an expanded list of ethnicities available). Results Of the 54 087 patients studied, approximately 32.3% were women. In the United States, 77% of patients were reported to be of White race and 19% of Black race with very few assigned to another race category (1% Asian, 0.7% Native American, 0.2% Native Hawaiian or other Pacific islander, and 1.4% “other”). In Europe, race was almost uniformly reported as White, and a similar racial homogeneity was reported in Asia (Asian race). Conversely, in Latin America, 8.9% of patients were described as “American Indian or Alaska Native,” with a very high proportion in specific countries (eg, 36% in Guatemala and 21% in Mexico). In the United States, 6.2% of participants were reported to have Hispanic/Latino ethnicity but most patients in Latin America were reported to have this ethnicity; conversely, few patients had this ethnicity reported outside the Americas, including in Spain and Portugal. Among patients designated as Asian race, specific ethnicities (eg, Indian, Japanese etc) almost completely overlapped with the country of origin. Conclusions This study highlights the challenges of applying standardized race and, particularly, ethnicity categories in global clinical trials. A multistakeholder approach is needed to improve the collection of race and ethnicity data in clinical trials.

BACKGROUND:The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. OBJECTIVES:In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. METHODS:Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months' follow-up. RESULTS:Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). CONCLUSIONS:The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (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; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).