Empagliflozin reduced the combined relative risk of cardiovascular death and hospitalization for heart failure (primary endpoint) by 25 percent in adults with and without diabetes who had heart failure with reduced ejection fraction

Background: Anemia is common and associated with worse outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined: 1) whether dapagliflozin corrected anemia in these patients, and 2) the effect of dapagliflozin on outcomes, in patients with or without anemia, in DAPA-HF. Methods: Anemia was defined as baseline hematocrit <39% in men and <36% in women (WHO). Correction of anemia was defined as two consecutive hematocrit measurements above these thresholds at any time during follow-up (follow-up visits: 2 weeks, 2 and 4 months and 4-monthly thereafter). The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Findings: Of the 4744 patients randomized in DAPA-HF, 4691 had a baseline hematocrit and 1032 were anemic (22.0%). Anemia was corrected in 62% of patients in the dapagliflozin group, compared with 41% of patients in the placebo group (odds ratio 2.37 [95% CI 1.84-3.04]; p<0.001). The effect of dapagliflozin on the primary outcome was consistent in anemic and non-anemic patients (HR 0.68 [95% CI 0.52-0.88] versus 0.76 [0.65-0.89]; P-interaction=0.44) [Figure]. A consistent benefit was also observed for the secondary outcomes, irrespective of anemia status t baseline. Patients with resolution of anemia had better outcomes than those with persisting anemia: rate of primary outcome 9.9 per 100 patient-years (95% CI 8.0-12.4) in those with resolution versus 24.1 per 100 patient-years (20.4-28.3) in those without anemia resolution. Interpretation: Anemia was common in patients in DAPA-HF and associated with worse outcomes. Resolution of anemia was associated with better outcomes than persistence of anemia, regardless of treatment allocation. Although dapagliflozin corrected anemia more often than placebo, treatment with dapagliflozin improved outcomes, irrespective of anemia status.

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Circulating proteomic signature of early death in heart failure patients with reduced ejection fraction

Scientific Reports ◽

10.1038/s41598-019-55727-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Marie Cuvelliez ◽

Vincent Vandewalle ◽

Maxime Brunin ◽

Olivia Beseme ◽

Audrey Hulot ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Plasma Proteins ◽

Early Death ◽

Cardiovascular Death ◽

Wilcoxon Test ◽

Complement C3 ◽

Reduced Ejection Fraction ◽

Matrix Organization ◽

Selection Operator

AbstractHeart failure (HF) remains a main cause of mortality worldwide. Risk stratification of patients with systolic chronic HF is critical to identify those who may benefit from advanced HF therapies. The aim of this study is to identify plasmatic proteins that could predict the early death (within 3 years) of HF patients with reduced ejection fraction hospitalized in CHRU de Lille. The subproteome targeted by an aptamer-based technology, the Slow Off-rate Modified Aptamer (SOMA) scan assay of 1310 proteins, was profiled in blood samples from 168 HF patients, and 203 proteins were significantly modulated between patients who died of cardiovascular death and patients who were alive after 3 years of HF evaluation (Wilcoxon test, FDR 5%). A molecular network was built using these 203 proteins, and the resulting network contained 2281 molecules assigned to 34 clusters annotated to biological pathways by Gene Ontology. This network model highlighted extracellular matrix organization as the main mechanism involved in early death in HF patients. In parallel, an adaptive Least Absolute Shrinkage and Selection Operator (LASSO) was performed on these 203 proteins, and six proteins were selected as candidates to predict early death in HF patients: complement C3, cathepsin S and F107B were decreased and MAPK5, MMP1 and MMP7 increased in patients who died of cardiovascular causes compared with patients living 3 years after HF evaluation. This proteomic signature of 6 circulating plasma proteins allows the identification of systolic HF patients with a risk of early death.

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Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM‐HF

Journal of the American Heart Association ◽

10.1161/jaha.120.019238 ◽

2021 ◽

Vol 10 (4) ◽

Author(s):

Solmaz Ehteshami‐Afshar ◽

Leanne Mooney ◽

Pooja Dewan ◽

Akshay S. Desai ◽

Ninian N. Lang ◽

...

Keyword(s):

Heart Failure ◽

Chronic Obstructive Pulmonary Disease ◽

Ejection Fraction ◽

Pulmonary Disease ◽

Cardiovascular Death ◽

Chronic Obstructive ◽

Heart Failure Hospitalization ◽

Obstructive Pulmonary Disease ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor Blocker–Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non‐COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P <0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P <0.001) and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (73 versus 81; P <0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta‐blockade (87% versus 94%; P <0.001) and diuretics (85% versus 80%; P <0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13–1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05–1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94–1.30), or all‐cause mortality (HR, 1.14; 95% CI, 0.99–1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05–1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29–1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM‐HF, COPD was associated with lower use of beta‐blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high‐risk subgroup. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01035255.

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EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction

Global Cardiology Science and Practice ◽

10.21542/gcsp.2021.17 ◽

2021 ◽

Vol 2021 (3) ◽

Author(s):

Kerolos Wagdy ◽

Sherif Nagy

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Complex Disease ◽

Hospital Admissions ◽

Sglt2 Inhibitor ◽

Cardiovascular Death ◽

Sglt2 Inhibitors ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Sglt2 Inhibition

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease which accounts for more than half of all HF hospital admissions with high prevalence and lack of effective evidence-based management. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new antidiabetic drug that recently gained a new role in the management of heart failure with reduced ejection fraction but its role in HFpEF had yet to be studied.Study and results: EMPEROR-Preserved trial set out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with HFpEF. The patients were randomized in a 1:1 fashion into two groups; to receive either empagliflozin 10 mg per day (n = 2,997) or placebo (n = 2,991) in addition to usual therapy. Empagliflozin led to a 21% risk reduction of the composite of cardiovascular death or hospitalization for heart failure, which was mainly related to a 29% lower risk of hospitalization for heart failure rather than effect on cardiovascular death empagliflozin. The effects SGLT2 inhibitors were consistent in all patients.

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Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.636152 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qingchun Zeng ◽

Qing Zhou ◽

Weitao Liu ◽

Yutong Wang ◽

Xingbo Xu ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Large Scale ◽

Heart Diseases ◽

Cardiovascular Death ◽

Serum Glucose ◽

Clinical Syndrome ◽

Sglt2 Inhibitors ◽

Reduced Ejection Fraction ◽

Beneficial Effects

Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.

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Plasma Proteomic Profile Predicts Survival in Heart Failure with Reduced Ejection Fraction

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003140 ◽

2021 ◽

Author(s):

Hongsheng Gui ◽

Ruicong She ◽

Jasmine Luzum ◽

Jia Li ◽

Timothy D. Bryson ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Risk Stratification ◽

Risk Score ◽

Cox Regression ◽

Clinical Score ◽

Cardiovascular Death ◽

Reduced Ejection Fraction ◽

C Statistic ◽

Kaplan Meier

Background - It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score for survival in HFrEF patients (HFrEF-PRS). Methods - Patients meeting Framingham criteria for HF with EF<50% were enrolled (n=1017) and plasma underwent SOMAscan® profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and N-Terminal pro-B-Type Natriuretic Peptide (NTproBNP), then was tested in the validation cohort. Risk stratification improvement was evaluated by C-statistic, integrated discrimination index (IDI), continuous net reclassification index (NRI), and median improvement in risk score (MIRS) for 1-year and 3-year mortality. Results - Participants' mean age was 68 years, 48% identified as African American, 35% were female and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio (HR) =2.27 [95% Confidence interval (95%CI) 1.84-2.82], p =6.3x10 -14 ), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles ( p =2.2x10 -6 ), and it remained significant after adjustment for clinical score and NTproBNP (HR=1.37, 95%CI 1.05-1.79, p =0.021). The HFrEF-PRS improved metrics of risk stratification (C-statistic change=0.009, p =0.612; IDI=0.041, p =0.010; NRI=0.391, p =0.078; MIRS=0.039, p =0.016) and associated with cardiovascular death and HF phenotypes (e.g. 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. Conclusions - A plasma multi-protein score improved risk stratification in HFrEF patients and identified novel candidates.

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Abstract P164: Urban-rural Disparities Amongst Heart Failure Patients With Reduced Ejection Fraction

Circulation ◽

10.1161/circ.141.suppl_1.p164 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Sherrie Khadanga ◽

Daniel N Silverman ◽

Timothy B Plante ◽

Charles Cubberly ◽

Johannes Steiner

Keyword(s):

Heart Failure ◽

Relative Risk ◽

Ejection Fraction ◽

New England ◽

Urban Areas ◽

Care Delivery ◽

Smoking Status ◽

Medical Center ◽

Reduced Ejection Fraction ◽

Urban Rural

Intro: Differences in health care delivery between urban and rural populations have been described, but the extent to which this impacts treatment and outcomes in patients with heart failure with reduced ejection fraction (HFrEF) within a large, rural HF referral network has not been evaluated to date. Objective: To describe differences in guideline directed medical therapy (GDMT) usage and cardiovascular (CV) mortality in urban vs rural dwelling individuals with HFrEF in Vermont. Methods: A retrospective analysis was performed on adult HFrEF patients residing in Vermont referred to University of Vermont Medical Center between January 1, 2015-2017. The study included all patients with a documented EF < 35% on echo. Demographics, risk factors, use of GDMT, and all-cause CV mortality were obtained. Urban and rural designations were based on the ZIP code version of the Rural-Urban Commuting Area (RUCA) classification system. Poisson regression analysis was used to compare the relative risk for mortality and use of GDMT by rurality. Results: 838 patients were identified (mean age 71.4 + 12.9 years old; 66.5% male) and divided into 3 RUCA groups (urban, rural, isolated). Adjusting for age, sex, hypertension, diabetes mellitus, atrial fibrillation and smoking status, no difference was seen in GDMT (table 1) between urban and rural patients (relative risk [RR], 1.03; 95% CI, 0.64-1.67). Urban patients were less likely than isolated patients to use GDT (RR, 0.75; 95% CI 0.52-1.08). There was a CV mortality benefit for those in rural (RR, 0.50; 95% CI 0.34-0.73) or isolated areas (RR, 0.74; 95% CI 0.62-0.89) compared to those in urban areas. Conclusion: While GDMT reduces morbidity and mortality in HFrEF patients, it was underutilized throughout Vermont. Findings from this state-wide cohort of decreased CV mortality in rural and isolated areas are contrary to prior studies. This finding highlights the unique socioeconomic environment of Northern New England and has important implications for CHF management and resource allocation.

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LCZ696, an Angiotensin–neprilysin Inhibitor Versus Enalapril in Heart Failure – Summary of PARADIGM-HF Results

European Journal of Arrhythmia & Electrophysiology ◽

10.17925/ejae.2016.02.01.14 ◽

2016 ◽

Vol 02 (01) ◽

pp. 14 ◽

Cited By ~ 2

Author(s):

José Silva Cardoso ◽

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiovascular Death ◽

Reduced Ejection Fraction ◽

Neprilysin Inhibitor ◽

Patients With Heart Failure

This editorial summarises important findings from the PARADIGM-HF study. PARADIGM-HF indicated that the angiotensin receptorneprilysin inhibitor, LCZ696, is superior to enalapril in reducing the risks of cardiovascular death and of hospitalisation for heart failure in patients with heart failure and reduced ejection fraction.

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Association of admission and discharge anemia status with outcomes in patients hospitalized for acute decompensated heart failure: Differences between patients with preserved and reduced ejection fraction

European Heart Journal Acute Cardiovascular Care ◽

10.1177/2048872617730039 ◽

2017 ◽

Vol 8 (7) ◽

pp. 606-614 ◽

Cited By ~ 1

Author(s):

Katsuya Kajimoto ◽

Yuichiro Minami ◽

Shigeru Otsubo ◽

Naoki Sato

Keyword(s):

Heart Failure ◽

Confidence Interval ◽

Ejection Fraction ◽

Primary Endpoint ◽

Acute Decompensated Heart Failure ◽

Decompensated Heart Failure ◽

Hazard Ratio ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Heart Failure Patients

Background: In acute decompensated heart failure patients with a preserved or reduced ejection fraction, the association of admission and discharge anemia status with outcomes remains unclear. Methods and results: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4433 patients (2017 with a preserved and 2416 with a reduced ejection fraction) were examined to investigate associations among the anemia status at admission and discharge (no anemia, developed anemia, resolved anemia, or persistent anemia), a preserved or reduced ejection fraction and the primary endpoint (all-cause death and readmission for heart failure). In the preserved ejection fraction group, adjusted analysis showed that either developed or persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.53; 95% confidence interval (CI): 1.11–2.11; p=0.009 and hazard ratio: 1.60; 95% CI: 1.26–2.04; p<0.001, respectively), but there was no association between resolved anemia and the primary endpoint (hazard ratio: 0.98; 95% CI: 0.67–1.45; p=0.937). In the reduced ejection fraction group, either developed or resolved anemia was associated with a tendency toward higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.29; 95% CI: 0.95–1.62; p=0.089, and hazard ratio: 1.31; 95% CI: 0.96–1.77; p=0.085, respectively), while persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.36; 95% CI: 1.12–1.65; p=0.002). Conclusions: In acute decompensated heart failure patients, the association of admission and discharge anemia status with outcomes differs markedly between patients with a preserved or reduced ejection fraction.

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