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Sacubitril/valsartan for heart failure with reduced ejection fraction: A first real-life observational study in Poland.
Lelonek, M, Wiśniowska-Śmiałek, S, Rubiś, P, Nowakowska, I, Pawlak, A
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2021;(1):67-75
Abstract
BACKGROUND Despite the progress in the treatment of heart failure with reduced ejection fraction (HFrEF), the prognosis remains unfavorable. OBJECTIVES To evaluate the effectiveness, tolerance and safety after one-year follow-up of Polish patients with stable chronic HFrEF treated with sacubitril/valsartan. MATERIAL AND METHODS This was an observational multicenter study conducted in 3 centers (Kraków, Łódź and Warszawa) specializing in heart failure (HF). We enrolled 89 HFrEF patients (aged 59.3 ±13.5 years, 82% males) in NYHA class II-IV (ambulatory). Clinical, laboratory and echocardiographic parameters were evaluated at baseline and after a one-year follow-up. The composite endpoint was defined as death or urgent HF hospitalization. RESULTS After 1 year, 80% of patients used 50% or more of the target dose of sacubitril/valsartan. After a year of treatment, there were significant improvements of HF symptoms, N-terminal prohormone B-type natriuretic peptide (NT proBNP), ejection fraction (EF), and distance in six-minute walk test (6MWP) (all p < 0.001). Patients treated with the highest dose of sacubitril/valsartan exhibited the greatest benefits. The safety profile was favorable and consistent with that previously reported; however, therapy discontinuation due to side effects occurred in 11% of patients. The independent predictors for composite endpoint (n = 24, 26.9%) were history of HF hospitalization, tricuspid annular plane systolic excursion (TAPSE) and angiotensin-converting-enzyme inhibitor (ACEI)-naive patients. CONCLUSIONS Treatment of chronic HFrEF patients with sacubitril/valsartan is safe and is associated with significant clinical and objective improvement. The non-survivors had more advanced HF, so the initiation and uptitration of sacubitril/valsartan should be done early.
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Urinary peptidome and diabetic retinopathy in the DIRECT-Protect 1 and 2 trials.
Rotbain Curovic, V, Magalhães, P, He, T, Hansen, TW, Mischak, H, Rossing, P, ,
Diabetic medicine : a journal of the British Diabetic Association. 2021;(9):e14634
Abstract
BACKGROUND Given the association of diabetic retinopathy (DR) and kidney disease, we investigated the urinary peptidome to presence and deterioration of DR in a post hoc analysis of trials investigating the effect of candesartan on progression of DR in type 1 and type 2 diabetes, respectively. METHODS Baseline urinary peptidomic analysis was performed on a random selection of 783 and 792 subjects in two randomized controlled trials, DIRECT-Protect 1 and 2, respectively. End points were two-step (RET2) and three-step (RET3) change in Early Treatment of Diabetic Retinopathy Study protocol (ETDRS) defined level. Peptide levels were correlated to baseline EDTRS level in a discovery set of 2/3 of the participants from DIRECT-Protect 1. The identified peptides were then validated cross-sectionally in the remaining 1/3 from DIRECT-Protect 1. Thereafter, peptides identified in the discovery set were assessed in the entire DIRECT-Protect 1 and 2 cohorts and significant peptides were tested longitudinally. RESULTS Follow-up ranged 4.0-4.7 years. 24 peptides were associated with baseline DR in the discovery set. COL3A1 (seq: NTG~) and COL4A1 (seq: DGA~) were associated with baseline DR in the validation set (Rho: -.223, p < 0.001 and Rho: -.141, p = 0.024). Neither was significantly associated with end points. Assessing the 24 identified peptides in the entire cohorts, several collagen peptides were associated with baseline DR and end points; however, there was no overlap across diabetes types. CONCLUSIONS We identified several urinary peptides (mainly collagen) associated with the presence of DR, however they could not be conclusively associated with worsening of DR.
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Comparison of the Efficacy and Safety of Sacubitril/Valsartan versus Ramipril in Patients With ST-Segment Elevation Myocardial Infarction.
Rezq, A, Saad, M, El Nozahi, M
The American journal of cardiology. 2021;:7-13
Abstract
The role of sacubitril and/or valsartan in patient with heart failure (HF) is established. Whether sacubitril and/or valsartan plays a role in improving outcomes in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. The current study aims to comparing the efficacy and safety of sacubitril and/or valsartan versus ramipril in post-STEMI patients. Patients presenting with STEMI were randomized to receive either sacubitril and/or valsartan or ramipril after primary percutaneous coronary intervention. The main efficacy endpoint was major adverse cardiac events (MACE) at 30 days and 6 months, defined as a composite of cardiac death, myocardial infarction, and HF hospitalizations. Multiple secondary clinical safety and efficacy endpoints were examined. A total of 200 patients were randomized from January 2018 to March 2019, mean age 54.5±10.4, 87% men, 75% presented with anterior wall STEMI. Baseline clinical and echocardiographic characteristics were comparable between groups. The primary endpoint of MACE was similar with sacubitril/valsartan versus ramipril at 30 days (p = 0.18); however, at 6 months, sacubitril/valsartan was associated with significant reduction of MACE (p = 0.005), mainly driven by reduction in HF hospitalizations (18% vs 36%, OR 0.40, 95% 0.22 to 0.75; p = 0.004). At 6 months, LV ejection fraction was higher with sacubitril/valsartan (46.8±12.5% vs 42.09±13.8%; p = 0.012), with improved LV remodelling (LV end diastolic dimension 50.6±3.9 mm vs 53.2±2.7 mm, p = 0.047; and LV end systolic dimension 36.1±3.4 mm versus 39.9±6.3 mm, p = 0.001) compared with ramipril. No difference in other efficacy or safety clinical endpoints was observed. In conclusion, early initiation of sacubitril/valsartan may offer clinical benefit and improvement in myocardial remodelling in post-STEMI patients.
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Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF.
Cunningham, JW, Claggett, BL, O'Meara, E, Prescott, MF, Pfeffer, MA, Shah, SJ, Redfield, MM, Zannad, F, Chiang, LM, Rizkala, AR, et al
Journal of the American College of Cardiology. 2020;(5):503-514
Abstract
BACKGROUND Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone. OBJECTIVES This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death). METHODS N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint. RESULTS At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates. CONCLUSIONS Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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Effects of Sacubitril/Valsartan on N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction.
Cunningham, JW, Vaduganathan, M, Claggett, BL, Zile, MR, Anand, IS, Packer, M, Zannad, F, Lam, CSP, Janssens, S, Jhund, PS, et al
JACC. Heart failure. 2020;(5):372-381
Abstract
OBJECTIVES The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. BACKGROUND Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). METHODS In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. RESULTS Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p < 0.001). This relationship was stronger in patients with atrial fibrillation (adjusted RR: 2.33 [95% CI: 1.89 to 2.87] vs. 1.58 [95% CI: 1.42 to 1.75] in patients without atrial fibrillation; p interaction <0.001) and weaker in obese patients (adjusted RR: 1.50 [95% CI: 1.31 to 1.71] vs. 1.92 [95% CI: 1.70 to 2.17] in nonobese patients; p interaction <0.001). Screening NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p interaction = 0.96). Sacubitril/valsartan reduced NT-proBNP by 19% (95% CI: 14% to 23%; p < 0.001) compared with valsartan 16 weeks post-randomization, with similar reductions in men (20%) and women (18%), and in patients with left ventricular EF ≤57% (20%) and >57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. CONCLUSIONS Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.
Lyle, MA, Iyer, SR, Redfield, MM, Reddy, YNV, Felker, GM, Cappola, TP, Hernandez, AF, Scott, CG, Burnett, JC, Pereira, NL
JACC. Heart failure. 2020;(1):70-80
Abstract
BACKGROUND In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival. OBJECTIVES This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in patients with HFpEF with normal controls. METHODS A case-control study was performed in 242 symptomatic patients with HFpEF previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates's Effect on Activity Tolerance in Heart Failure With Preserved Ejection (NEAT-HFpEF) clinical trials and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography) who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects. RESULTS Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 9.7]; p = 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history, and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02). CONCLUSIONS Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF.
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Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial.
DeVore, AD, Braunwald, E, Morrow, DA, Duffy, CI, Ambrosy, AP, Chakraborty, H, McCague, K, Rocha, R, Velazquez, EJ, ,
JAMA cardiology. 2020;(2):202-207
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Abstract
IMPORTANCE In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan. OBJECTIVE To describe changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase. INTERVENTIONS Sacubitril/valsartan titrated to 97/103 mg twice daily. DESIGN, SETTING, AND PARTICIPANTS The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 and May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study. MAIN OUTCOMES AND MEASURES Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12. RESULTS Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined -17.2% (95% CI, -3.2 to -29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (-37.4%; 95% CI, -28.1 to -45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97). CONCLUSIONS AND RELEVANCE Switching patients' treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02554890.
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Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial.
Morrow, DA, Velazquez, EJ, DeVore, AD, Desai, AS, Duffy, CI, Ambrosy, AP, Gurmu, Y, McCague, K, Rocha, R, Braunwald, E
Circulation. 2019;(19):2285-2288
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Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction.
Shah, AM, Cikes, M, Prasad, N, Li, G, Getchevski, S, Claggett, B, Rizkala, A, Lukashevich, I, O'Meara, E, Ryan, JJ, et al
Journal of the American College of Cardiology. 2019;(23):2858-2873
Abstract
BACKGROUND The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity. OBJECTIVES The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies. METHODS Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors. RESULTS Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m2; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm2; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e' ratio, pulmonary artery systolic pressure, and event rates. CONCLUSIONS Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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A Drug Utilization Study of Sacubitril/Valsartan in Catalonia.
Molina, A, Vicente, M, Gasol, M, Carbonell, P, López, P, Pontes, C
Revista espanola de cardiologia (English ed.). 2019;(7):593-595