scholarly journals Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (13) ◽  
pp. 1236-1245 ◽  
Author(s):  
Finnian R. Mc Causland ◽  
Martin P. Lefkowitz ◽  
Brian Claggett ◽  
Nagesh S. Anavekar ◽  
Michele Senni ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Renal Outcome ◽  
Preserved Ejection Fraction ◽  
Double Blind ◽  
Prospective Comparison ◽  
Patients With Heart Failure ◽  
Neprilysin Inhibition

Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). Methods: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 mL·min –1 ·1.73 m – 2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33–0.77]; P =0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min –1 ·1.73 m –2 ( P -interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (–2.0 [95% CI, –2.2 to –1.9] versus –2.7 [95% CI, –2.8 to –2.5] mL·min –1 ·1.73 m –2 per year). Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

Association between use of beta-blockers and mortality/morbidity in patients with heart failure with reduced, midrange or preserved ejection fraction and advanced chronic kidney disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Fu ◽  
A Uijl ◽  
F.W Dekker ◽  
L.H Lund ◽  
G Savarese ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Beta Blocker ◽  
Beta Blockers ◽  
Preserved Ejection Fraction ◽  
Advanced Chronic Kidney Disease ◽  
Patients With Heart Failure ◽  
All Cause Mortality

Abstract Background Beta-blockers reduce mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, patients with advanced chronic kidney disease (CKD) were underrepresented in landmark trials. Purpose We evaluated if beta-blockers are associated with improved survival and cardiovascular outcomes in patients with HFrEF and advanced CKD, and if potential benefits of beta-blockers would extend also to HFpEF and HFmrEF with advanced CKD. Methods We identified 3906 persons with an ejection fraction &lt;40% and advanced CKD (eGFR &lt;30 mL/min/1.73m2) enrolled in the Swedish Heart Failure Registry during 2001–2016. We did not exclude patients with atrial fibrillation. The associations between beta-blocker use, 5-year all-cause mortality, and the composite of time to cardiovascular (CV) mortality/first HF hospitalization were assessed by multivariable Cox regression. Analyses were adjusted for 36 variables, including demographics, laboratory measures, comorbidities, medication use, medical procedures, and socioeconomic status. To assess consistency, the same analyses were performed in a positive control cohort of 12,673 patients with moderate CKD (eGFR &lt;60–30 mL/min/1.73m2). Analyses were repeated in individuals with HF with preserved ejection fraction (HFpEF; EF ≥50%) or midrange ejection fraction (HFmrEF; EF 40–49%). Results In HFrEF and advanced CKD, 89% received beta-blockers. Overall, median (IQR) age was 81 (74–86) years, 36% were women and median eGFR was 26 (20–28) ml/min/1.73m2. During a median of 1.3 years follow-up, 2086 (53.4%) individuals had a subsequent HF hospitalization, and 2954 (75.6%) individuals died, of which 2089 (70.1%) due to cardiovascular causes. Beta-blocker use was associated with a significant reduction in 5-year all-cause mortality [adjusted hazard ratio (HR) 0.86; 95% confidence interval (CI) 0.76–0.96)] and CV mortality/HF hospitalization (HR 0.87; 95% CI 0.77–0.98). The magnitude of the associations between beta-blocker use and outcomes was similar to that observed for HFrEF patients with mild/moderate CKD [all-cause mortality: 0.85 (95% CI 0.78–0.91); CV mortality/HF hospitalization: 0.88 (95% CI 0.82–0.96)]. Adjusted HRs were 0.88 (95% CI 0.77–1.02) and 1.07 (95% CI 0.92–1.24) for individuals with HFpEF and advanced CKD and 0.95 (95% CI 0.80–1.13) and 1.13 (95% CI 0.94–1.36) for individuals with HFmrEF and advanced CKD, for all-cause mortality and CV mortality/HF hospitalization, respectively. Conclusion Despite lack of trial evidence, the use of beta-blockers in patients with HFrEF and advanced CKD was high in routine Swedish care, and was independently associated with reduced mortality to the same degree as HFrEF with moderate CKD. However, these benefits were not observed in patients with HFpEF or HFmrEF with severe CKD. Funding Acknowledgement Type of funding source: None

Abstract 471: Combination of Allogeneic Mesenchymal and Kidney Stem Cells Ameliorates Chronic Kidney Disease Induced Heart Failure With Preserved Ejection Fraction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Angela C Castellanos ◽  
Bryon A Tompkins ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
Monisha Banerjee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Stem Cells ◽  
Stem Cell ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Cell Therapy ◽  
Renal Artery ◽  
Preserved Ejection Fraction ◽  
Kidney Stem Cells

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition involving multiple comorbidities. Phenotypic classification of HFpEF associated with chronic kidney disease (CKD) manifests worse outcomes, compared to other HFpEF phenotypes. Few treatments improve morbidity and mortality in HFpEF. Stem cell therapy promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that allogeneic stem cell treatment ameliorates HFpEF in a large animal model of CKD. Methods: Yorkshire pigs (n=26) underwent 5/6 embolization-mediated nephrectomy and 4-weeks later received either: allogeneic mesenchymal stem cells (MSCs) (10х10 6 ), Kidney stem cells (KSC; 10х10 6 ), combination (ACCT; MSC+KSC; 1:1 ratio [5х10 6 each]), or placebo (n=6-7/ group). Cell therapy was delivered via the patent renal artery of the remnant kidney. RNAsec analysis compared placebo and ACCT groups. Results: Mean arterial pressure increased significantly in the placebo- (21.89±6.05 mmHg, p<0.0001) compared to the ACCT-group (p=0.04) at 12 weeks. Glomerular filtration rate improved significantly in the ACCT group (p=0.002). RNAseq analysis revealed a significant decrease in genes normally increased during kidney transplant rejection (q<10 -6 , NES = -2.32) in ACCT. Consistent with these results, there was a downregulation of canonical drivers of tubular damage and regeneration, including SOX9 (-2.39 fold, p=0.0004) and apoptosis of kidney cell types (-24.89 fold, p=0.004), including podocytes (-2.065 fold, p=0.04) with ACCT. ACCT administration also downregulated genes related to oxidative stress (-4.6 fold, p<0.0001), fibrosis, inflammatory response (-4.760 fold, p=<0.05), and renin-angiotensin signaling (-3.162 fold, p=0.024), which are related to cardiac hypertrophy pathways (-7.23, fold, p<0.0001). EDPVR improved in with ACCT (p=0.003), indicating decreased ventricular stiffness. Ejection fraction, relative wall thickness, and left ventricular mass did not differ between groups at 12 weeks. Conclusion: Intra-renal artery allogeneic cell therapy was safe. Beneficial effects were observed in the ACCT and MSC groups in the kidney and heart. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

scholarly journals SO057BETA-BLOCKERS ARE ASSOCIATED WITH REDUCED MORTALITY IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION AND ADVANCED CHRONIC KIDNEY DISEASE: COHORT STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Edouard L Fu ◽  
Alicia Uijl ◽  
Friedo W Dekker ◽  
Lars H Lund ◽  
Gianluigi Savarese ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Beta Blocker ◽  
Beta Blockers ◽  
Advanced Chronic Kidney Disease ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
All Cause Mortality

Abstract Background and Aims Beta-blockers reduce mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, patients with advanced chronic kidney disease (CKD) were underrepresented in landmark trials. We evaluated if beta-blockers are associated with improved survival in patients with HFrEF and advanced CKD. Method We identified 3906 persons with an ejection fraction &lt;40% and advanced CKD (eGFR &lt;30 mL/min/1.73m2) enrolled in the Swedish Heart Failure Registry during 2001-2016. The associations between beta-blocker use, 5-year all-cause mortality, and the composite of time to cardiovascular (CV) mortality/first HF hospitalization were assessed by multivariable Cox regression. Analyses were adjusted for 36 variables, including demographics, laboratory measures, comorbidities, medication use, medical procedures, and socioeconomic status. To assess consistency, the same analyses were performed in a positive control cohort of 12,673 patients with moderate CKD (eGFR &lt;60-30 mL/min/1.73m2). Results The majority (89%) of individuals with HFrEF and advanced CKD received treatment with beta-blockers. Median (IQR) age was 81 (74-86) years, 36% were women and median eGFR was 26 (20-28) mL/min/173m2. During 5 years of follow-up, 2086 (53.4%) individuals had a subsequent HF hospitalization, and 2954 (75.6%) individuals died, of which 2089 (70.1%) due to cardiovascular causes. Beta-blocker use was associated with a significant reduction in 5-year all-cause mortality [adjusted hazard ratio (HR) 0.86; 95% confidence interval (CI) 0.76-0.96)] and CV mortality/HF hospitalization (HR 0.87; 95% CI 0.77-0.98). The magnitude of the associations between beta-blocker use and outcomes was similar to that observed for HFrEF patients with mild/moderate CKD, with adjusted HRs for all-cause mortality and CV mortality/HF hospitalization of 0.85 (95% CI 0.78-0.91) and 0.88 (95% CI 0.82-0.96), respectively. Conclusion Despite lack of trial evidence, the use of beta-blockers in patients with HFrEF and advanced CKD was high in routine Swedish care, and was independently associated with reduced mortality to the same degree as HFrEF with moderate CKD.

scholarly journals A Randomized Double-Blind Trial of Enalapril in Older Patients With Heart Failure and Preserved Ejection Fraction

2010 ◽  
Vol 3 (4) ◽  
pp. 477-485 ◽  
Author(s):  
Dalane W. Kitzman ◽  
W. Gregory Hundley ◽  
Peter H. Brubaker ◽  
Timothy M. Morgan ◽  
J. Brian Moore ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Older Patients ◽  
Preserved Ejection Fraction ◽  
Double Blind Trial ◽  
Double Blind ◽  
Blind Trial ◽  
Patients With Heart Failure

Abstract 17063: Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Finnian R Mc Causland ◽  
Marty Lefkowitz ◽  
Brian Claggett ◽  
Nagesh Anavekar ◽  
MICHELE SENNI ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Pooled Analysis ◽  
Renal Outcome ◽  
Patients With Heart Failure ◽  
Neprilysin Inhibition ◽  
Valsartan Group ◽  
Stage Renal Disease ◽  
End Stage ◽  
Enalapril Group

Background: In patients with heart failure, chronic kidney disease (CKD) is associated with a higher risk of renal events than in patients without CKD, irrespective of the ejection fraction. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure in a pooled analysis of 13,195 patients with reduced and preserved ejection fraction. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8,399) and PARAGON-HF (LVEF eligibility≥45%; n=4,796) in a prespecified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan compared with enalapril or valsartan) on the renal composite outcome, defined as the time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes. We also assessed the influence of therapy on eGFR slope. Results: At randomization, eGFR was 68±20 ml/min/1.73m 2 in PARADIGM-HF and 63±19 ml/min/1.73m 2 in PARAGON-HF. The composite renal outcome occurred in 70 of the 6594 patients (1.1%) in the sacubitril/valsartan group and 123 of the 6601 patients (1.9%) in the valsartan or enalapril group, with a risk reduction of 44% (HR 0.56, 95%CI 0.42-0.75; P<0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m 2 ; P-interaction=0.46) or baseline ejection fraction (P-interaction=0.35). From randomization, the mean decline in eGFR was -1.8 (95%CI -1.9 to -1.7) ml/min/1.73 m 2 per year for the sacubitril/valsartan group, compared with -2.4 (95%CI -2.5 to -2.2) ml/min/1.73 m 2 per year for the valsartan or enalapril group, with an adjusted mean difference of 0.6 (95%CI 0.4 to 0.7; P<0.001) ml/min/1.73 m 2 per year. Conclusions: In patients with heart failure, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan or enalapril, across the spectrum of ejection fraction.

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