Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Measuring congestion with a non-invasive monitoring device in heart failure and haemodialysis: CONGEST-HF.

AIMS: We examined the effectiveness of a novel cardiopulmonary management wearable sensor (worn for less than 5 mins) at measuring congestion and correlated the device findings with established clinical measures of congestion. METHODS AND RESULTS: We enrolled three cohorts of patients: (1) patients with heart failure (HF) receiving intravenous diuretics in hospital; (2) patients established on haemodialysis, and (3) HF patients undergoing right heart catheterization (RHC). The primary outcomes in the respective cohorts were a Spearman correlation between (1) change in weight and change in thoracic impedance (TI) (from enrolment, 24 h after admission to discharge) in patients hospitalized for HF; (2) lung ultrasound B-lines and volume removed during dialysis with device measured TI, and (3) pulmonary capillary wedge pressure (PCWP) and sub-acoustic diastolic, third heart sound (S3) in the patients undergoing RHC. A total of 66 patients were enrolled. In HF patients (n = 25), change in weight was correlated with both change in device TI (Spearman correlation [rsp] = -0.64, p = 0.002) and change in device S3 (rsp = -0.53, p = 0.014). In the haemodialysis cohort (n = 21), B-lines and TI were strongly correlated before (rsp = -0.71, p < 0.001) and after (rsp = -0.77, p < 0.001) dialysis. Volume of fluid removed by dialysis was correlated with change in device TI (rsp = 0.49, p = 0.024). In the RHC cohort (n = 20), PCWP measured at one time point and device S3 were not significantly correlated (rsp = 0.230, p = 0.204). There were no device-related adverse events. CONCLUSIONS: A non-invasive device was able to detect changes in congestion in patients with HF receiving decongestion therapy and patients having fluid removed at haemodialysis. The cardiopulmonary management device, which measures multiple parameters, is a potentially useful tool to monitor patients with HF to prevent hospitalizations.

Effect of PCI on Health Status in Ischemic Left Ventricular Dysfunction: Insights From REVIVED-BCIS2.

BACKGROUND: In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). OBJECTIVES: This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. METHODS: Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ-Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. RESULTS: A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. CONCLUSIONS: PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048).

Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups. METHODS: In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836. FINDINGS: We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death). INTERPRETATION: SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors. FUNDING: None.

Cardiovascular Eligibility Criteria and Adverse Event Reporting in Combined Immune Checkpoint and VEGF Inhibitor Trials.

Background: Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors (VEGFIs) has improved cancer outcomes and is increasingly used. These drug classes are associated with cardiovascular toxicities when used alone, but heterogeneity in trial design and reporting may limit knowledge of toxicities in patients receiving these in combination. Objectives: The aim of this study was to assess consistency and clarity in definitions and reporting of cardiovascular eligibility criteria, baseline characteristics, and cardiovascular adverse events in ICI and VEGFI combination trials. Methods: A scoping review was conducted of phase 2 to 4 randomized controlled trials of ICI and VEGFI combination therapy for solid tumors. Trial cardiovascular eligibility criteria and baseline cardiovascular characteristic reporting in trial publications was assessed, and cardiovascular adverse event definitions and reporting criteria were also examined. Results: Seventeen trials (N = 10,313; published 2018-2022) were included. There were multiple cardiovascular exclusion criteria in 15 trials. No primary trial publication reported baseline cardiovascular characteristics. Thirteen trials excluded patients with prior heart failure, myocardial infarction, hypertension, or stroke. There was heterogeneity in defining cardiovascular conditions. "Grade 1 to 4" cardiovascular adverse events were reported when incidence was ≥5% to 25% in 15 trials. Incident hypertension was recorded in all trials, but other cardiovascular events were not consistently reported. No trial specifically noted the absence of cardiovascular events. Conclusions: In ICI and VEGFI combination trials, there is heterogeneity in cardiovascular exclusion criteria, reporting of baseline characteristics, and reporting of cardiovascular adverse events. This limits an optimal understanding of the incidence and severity of events relating to these combinations. Better standardization of these elements should be pursued. (Exclusions and Representation of Patients With Kidney Disease and Cardiovascular Disease in Drug Trials of the Novel Systemic Anti-Cancer Therapies VEGF-Signalling Pathway Inhibitors Alone or in Combination With Immune Checkpoint Inhibitors; CRD42022337942).

Age-specific mortality trends in heart failure over 25 years: a retrospective Danish nationwide cohort study.

BACKGROUND: Despite advances in heart failure care reducing mortality in clinical trials, it remains unclear whether real-life cohorts have had similar improvements in life expectancy across the age spectrum. We aimed to investigate how mortality trends changed in patients with heart failure over the past 25 years, stratified by age groups. METHODS: Using Danish nationwide registries, we identified patients with new-onset heart failure aged 18-95 years. The 5-year all-cause mortality risk and the absolute risk difference of mortality between patients with heart failure and age-matched and sex-matched heart failure-free controls were assessed using Kaplan-Meier estimates and multivariable Cox regression models. Mortality trends were analysed across five calendar periods (1996-2000, 2001-05, 2006-10, 2011-15, and 2016-20) and three age groups (<65 years, 65-79 years, and ≥80 years). FINDINGS: 194 997 patients with heart failure were included. Mortality significantly decreased from 1996-2000 (66% [95% CI 65·5-66·4]) to 2016-20 (43% [42·1-43·4]), with similar results shown in all age groups (<65 years: 35% [33·9-36·1] to 15% [14·6-16·3]; 65-79 years: 64% [63·1-64·5] to 39% [37·6-39·6]; and ≥80 years: 84% [83·1-84·3] to 73% [71·7-73·9]). Adjusted mortality rates supported these associations. The absolute risk difference declined notably in younger age groups (<65 years: 29·9% [28·8-31·0] to 12·7% [12·0-13·4] and 65-79 years: 41·1% [40·3-41·9] to 25·1% [24·4-25·8]), remaining relatively stable in those aged 80 years or older (30·6% [29·9-31·3] to 28% [27·2-28·8]). INTERPRETATION: Over 25 years, there has been a consistent decrease in mortality among patients with heart failure across age groups, albeit less prominently in patients aged 80 years or older. Further insight is needed to identify effective strategies for improving disease burden in older patients with heart failure. FUNDING: None. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Use of medical therapy and risk of clinical events according to frailty in heart failure patients - A real-life cohort study.

AIMS: Although recent randomized clinical trials have demonstrated the advantages of heart failure (HF) therapy in both frail and not frail patients, there is insufficient information on the use of HF therapy based on frailty status in a real-world setting. The aim was to examine how frailty status in HF patients associates with use of HF therapy and with clinical outcomes. METHODS AND RESULTS: Patients with new-onset HF between 2014 and 2021 were identified using the nationwide Danish registers. Patients across the entire range of ejection fraction were included. The associations between frailty status (using the Hospital Frailty Risk Score) and use of HF therapy and clinical outcomes (all-cause mortality, HF hospitalization, and non-HF hospitalization) were evaluated using multivariable-adjusted Cox models adjusting for age, sex, diagnostic setting, calendar year, comorbidities, pharmacotherapy, and socioeconomic status. Of 35 999 participants (mean age 69.1 years), 68% were not frail, 26% were moderately frail, and 6% were severely frail. The use of HF therapy was significantly lower in frailer patients. The hazard ratio (HR) for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation was 0.74 (95% confidence interval 0.70-0.77) and 0.48 (0.43-0.53) for moderate frailty and severe frailty, respectively. For beta-blockers, the corresponding HRs were 0.74 (0.71-0.78) and 0.51 (0.46-0.56), respectively, and for mineralocorticoid receptor antagonists, 0.83 (0.80-0.87) and 0.58 (0.53-0.64), respectively. The prevalence of death and non-HF hospitalization increased with frailty status. The HR for death was 1.55 (1.47-1.63) and 2.32 (2.16-2.49) for moderate and severe frailty, respectively, and the HR for non-HF hospitalization was 1.37 (1.32-1.41) and 1.82 (1.72-1.92), respectively. The association between frailty status and HF hospitalization was not significant (HR 1.08 [1.02-1.14] and 1.08 [0.97-1.20], respectively). CONCLUSION: In real-world HF patients, frailty was associated with lower HF therapy use and with a higher incidence of clinical outcomes including mortality and non-HF hospitalization.

Empagliflozin to prevent progressive adverse remodelling after myocardial infarction (EMPRESS-MI): rationale and design.

AIMS: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. METHODS AND RESULTS: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) is a randomized, double-blind, placebo-controlled, multi-centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end-systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. CONCLUSIONS: EMPRESS-MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI.

Impact of Anatomical and Viability-guided Completeness of Revascularization on Clinical Outcomes in Ischemic Cardiomyopathy.

BACKGROUND: Complete revascularization of coronary disease has been linked to improved outcomes in patients with preserved left ventricular (LV) function. OBJECTIVES: To identify the impact of complete revascularization in patients with severe LV dysfunction. METHODS: Patients enrolled in the REVIVED-BCIS2 trial were eligible if baseline/procedural angiograms and viability studies were available for analysis by independent core laboratories. Anatomical and viability-guided completeness of revascularization were measured by the coronary and myocardial revascularization indices (RIcoro and RImyo) respectively, where RIcoro=[change in BCIS Jeopardy Score (BCIS-JS)] / [baseline BCIS-JS] and RImyo=[number of revascularized viable segments] / [ number of viable segments supplied by diseased vessels]. The PCI group was classified as having complete or incomplete revascularization by median RIcoro and RImyo. The primary outcome was death or hospitalization for heart failure. RESULTS: Of 700 randomized patients, 670 were included. The baseline BCIS-JS and SYNTAX scores were 8 (6 to 10) and 22 (15 to 29) respectively. In those assigned to PCI, median RIcoro and RImyo values were 67% and 85%. Compared to the group assigned to optimal medical therapy alone, there was no difference in the likelihood of the primary outcome in those receiving complete anatomical or viability-guided revascularization (HR 0.90, 95% CI 0.62-1.32 and HR 0.95, 95% CI 0.66-1.35 respectively). A sensitivity analysis by residual SYNTAX score showed no association with outcome. CONCLUSIONS: In patients with severe left ventricular dysfunction, neither complete anatomical nor viability-guided revascularization were associated with improved event-free survival compared to incomplete revascularization or treatment with medical therapy alone.

Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.

Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). OBJECTIVES: This study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI. METHODS: In the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months. RESULTS: Among 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. CONCLUSIONS: In patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674).

Empagliflozin after Acute Myocardial Infarction.

BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction.

AIMS: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. METHODS AND RESULTS: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation <20% or ferritin <100 µg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between-group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between-group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow-up (defined as haemoglobin >16.5 g/dL [men] or >16 g/dL [women]). CONCLUSIONS: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron-deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one.

Temporal Trends in the Initiation of Dialysis Among Patients With Heart Failure With or Without Diabetes: A Nationwide Study From 2002 to 2016.

BACKGROUND: The incidence and distribution of acute and chronic dialysis among patients with heart failure (HF), stratified by diabetes, remain uncertain. We hypothesized that with improved survival and rising comorbidities, the demand for dialysis would increase over time. METHODS AND RESULTS: Patients with incident HF, aged 18 to 100 years, between 2002 and 2016, were identified using Danish nationwide registers. Primary outcomes included acute and chronic dialysis initiation, HF-related hospitalization, and all-cause mortality. These outcomes were assessed in 2002 to 2006, 2007 to 2011, and 2012 to 2016, stratified by diabetes. We calculated incidence rates (IRs) per 1000 person-years and hazard ratios (HR) using multivariable Cox regression. Of 115 533 patients with HF, 2734 patients received acute dialysis and 1193 patients received chronic dialysis. The IR was 8.0 per 1000 and 3.5 per 1000 person-years for acute and chronic dialysis, respectively. Acute dialysis rates increased significantly among patients with diabetes over time, while no significant changes occurred in those without diabetes, chronic dialysis, HF-related hospitalization, or overall mortality. Diabetes was associated with significantly higher HRs of acute and chronic dialysis, respectively, compared with patients without diabetes (HR, 2.07 [95% CI, 1.80-2.39] and 2.93 [95% CI, 2.40-3.58] in 2002 to 2006; HR, 2.45 [95% CI, 2.14-2.80] and 2.86 [95% CI, 2.32-3.52] in 2007 to 2011; and 2.69 [95% CI, 2.33-3.10] and 3.30 [95% CI, 2.69-4.06] in 2012 to 2016). CONCLUSIONS: The IR of acute and chronic dialysis remained low compared with HF-related hospitalizations and mortality. Acute dialysis rates increased significantly over time, contrasting no significant trends in other outcomes. Diabetes exhibited over 2-fold increased rates of the outcomes. These findings emphasize the importance of continued monitoring and renal care in patients with HF, especially with diabetes, to optimize outcomes and prevent adverse events.

Physician perceptions, attitudes, and strategies towards implementing guideline-directed medical therapy in heart failure with reduced ejection fraction. A survey of the Heart Failure Association of the ESC and the ESC Council for Cardiology Practice.

27 March 2024: This article published in Early View in error. The article is under embargo and will republish after 11th May 2024.

Impact of Residential Social Deprivation on Prediction of Heart Failure in Patients With Type 2 Diabetes: External Validation and Recalibration of the WATCH-DM Score Using Real World Data.

BACKGROUND: Patients with type 2 diabetes are at risk of heart failure hospitalization. As social determinants of health are rarely included in risk models, we validated and recalibrated the WATCH-DM score in a diverse patient-group using their social deprivation index (SDI). METHODS: We identified US Veterans with type 2 diabetes without heart failure that received outpatient care during 2010 at Veterans Affairs medical centers nationwide, linked them to their SDI using residential ZIP codes and grouped them as SDI <20%, 21% to 40%, 41% to 60%, 61% to 80%, and >80% (higher values represent increased deprivation). Accounting for all-cause mortality, we obtained the incidence for heart failure hospitalization at 5 years follow-up; overall and in each SDI group. We evaluated the WATCH-DM score using the C statistic, the Greenwood Nam D'Agostino test χ2 test and calibration plots and further recalibrated the WATCH-DM score for each SDI group using a statistical correction factor. RESULTS: In 1 065 691 studied patients (mean age 67 years, 25% Black and 6% Hispanic patients), the 5-year incidence of heart failure hospitalization was 5.39%. In SDI group 1 (least deprived) and 5 (most deprived), the 5-year heart failure hospitalization was 3.18% and 11%, respectively. The score C statistic was 0.62; WATCH-DM systematically overestimated heart failure risk in SDI groups 1 to 2 (expected/observed ratios, 1.38 and 1.36, respectively) and underestimated the heart failure risk in groups 4 to 5 (expected/observed ratios, 0.95 and 0.80, respectively). Graphical evaluation demonstrated that the recalibration of WATCH-DM using an SDI group-based correction factor improved predictive capabilities as supported by reduction in the χ2 test results (801-27 in SDI groups I; 623-23 in SDI group V). CONCLUSIONS: Including social determinants of health to recalibrate the WATCH-DM score improved risk prediction highlighting the importance of including social determinants in future clinical risk prediction models.