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1.
Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.
Mann, DL, Givertz, MM, Vader, JM, Starling, RC, Shah, P, McNulty, SE, Anstrom, KJ, Margulies, KB, Kiernan, MS, Mahr, C, et al
JAMA cardiology. 2022;(1):17-25
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Abstract
IMPORTANCE The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. OBJECTIVE To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. DESIGN, SETTING, AND PARTICIPANTS A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. INTERVENTION Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. MAIN OUTCOMES AND MEASURES The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. RESULTS Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. CONCLUSIONS AND RELEVANCE The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02816736.
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The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review.
Zhang, R, Sun, X, Li, Y, He, W, Zhu, H, Liu, B, Zhang, A
Journal of cardiovascular pharmacology and therapeutics. 2022;:10742484211058681
Abstract
Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.
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Association between ethnicity and degree of improvement in cardiac function following initiation of sacubitril/valsartan.
Holm, N, Bromage, DI, Cannata, A, DeCourcey, J, Bhatti, P, Huang, M, McDonagh, TA
Journal of cardiovascular medicine (Hagerstown, Md.). 2022;(1):37-41
Abstract
AIMS: The aim of this study was to determine the degree of short-term improvement in left ventricular ejection fraction (LVEF), haemodynamics, NT-proBNP and quality of life following initiation of sacubitril/valsartan in black patients when compared with white patients. METHODS This was a retrospective, observational, single-centre, hypothesis-generating study of patients with symptomatic heart failure and reduced ejection fraction (HFrEF) treated with guideline recommended therapy, who were transitioned from an ACE inhibitor (ACE-I) or angiotensin receptor blocker (ARB) to sacubitril/valsartan. RESULTS Our analysis included 83 patients (mean age 57 years) with echocardiography performed before and after transition from ACE-I/ARB to sacubitril/valsartan, after excluding patients with concomitant Cardiac resynchronization therapy implantation. Overall, sacubitril/valsartan was associated with LVEF improvement from 28.8% ± 0.7 to 32.0% ± 1.1% (P = 0.0002), but no reverse remodelling was observed. The association with LVEF improvement was only observed in white patients (n = 46, P = 0.0006), but not in black patients (n = 37, P = 0.1728), and appeared to be associated with reduced blood pressure (baseline vs. 2-week blood pressure 116.5 ± 13.9 vs. 109.4 ± 14.3 mmHg, respectively, in white patients, P = 0.0449). Fifteen patients (18.1%) became ineligible for primary prevention Implantable cardioverter defibrillator implantation. CONCLUSION Sacubitril/valsartan was associated with improved LVEF, NT-proBNP concentrations and quality of life in patients with symptomatic HFrEF on guideline recommended therapy. However, in our cohort, improvement of LVEF and quality of life might be attenuated in black patients, which warrants further investigation.
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Role of sacubitril-valsartan in the prevention of atrial fibrillation occurrence in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials.
Liu, X, Liu, H, Wang, L, Zhang, L, Xu, Q
PloS one. 2022;(1):e0263131
Abstract
OBJECTIVE Heart failure (HF) and atrial fibrillation (AF) are often coexisting. They have common risk factors and pathophysiologic mechanisms. Sacubitril/valsartan has shown efficacy and tolerability in patients with HF. Thus, the study was performed to evaluate the impact of sacubitril/valsartan on AF occurrence in patients with HF. METHODS The Embase and PubMed were searched from their inception date to June 2021 for all relevant randomized controlled trials (RCTs) evaluating the efficacy of sacubitril/valsartan in HF. The outcome of interest was the AF occurrence during the follow-up. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS Six trials involving a total of 15,512 patients were included (7,750 randomized to sacubitril/valsartan and 7,762 to control). All trials were randomized, double-blind, and active-control. There was no significant difference in the prevention of AF occurrence between the sacubitril/valsartan group and the control group (enalapril or valsartan) in patients with HF (RR 1.07, 95%CI 0.95 to 1.19; I2 4%). CONCLUSIONS Sacubitril/valsartan was similar to either enalapril or valsartan in preventing the occurrence of AF in patients with HF.
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Meta-Analysis of Dedicated Heart Failure Trials Evaluating the Effect of Sacubitril/Valsartan on Major Cardiac Rhythm Disorders.
Patoulias, D, Papadopoulos, C, Toumpourleka, M, Tranidou, A, Boulmpou, A, Doumas, M
The American journal of cardiology. 2021;:120-122
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Eligibility for sacubitril/valsartan in heart failure across the ejection fraction spectrum: real-world data from the Swedish Heart Failure Registry.
Savarese, G, Hage, C, Benson, L, Schrage, B, Thorvaldsen, T, Lundberg, A, Fudim, M, Linde, C, Dahlström, U, Rosano, GMC, et al
Journal of internal medicine. 2021;(3):369-384
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Abstract
BACKGROUND Randomized controlled trials (RCT) generalizability may be limited due to strict patient selection. OBJECTIVE In a real-world heart failure (HF) population, we assessed eligibility for sacubitril/valsartan based on PARADIGM-HF (sacubitril/valsartan effective)/PARAGON-HF [sacubitril/valsartan effective in mildly reduced ejection fraction (EF)]. METHODS Outpatients from the Swedish HF Registry (SwedeHF) were analysed. In SwedeHF, EF is recorded as <30, 30-39, 40-49 and ≥50%. In PARAGON-HF, sacubitril/valsartan was effective with EF ≤ 57% (i.e. median). We defined reduced EF/PARADIGM-HF as EF < 40%, mildly reduced EF/PARAGON-HF ≤ median as EF 40-49%, and normal EF/PARAGON-HF > median as EF ≥ 50%. We assessed 2 scenarios: (i) criteria likely to influence treatment decisions (pragmatic scenario); (ii) all criteria (literal scenario). RESULTS Of 37 790 outpatients, 57% had EF < 40%, 24% EF 40-49% and 19% EF ≥ 50%. In the pragmatic scenario, 63% were eligible in EF < 50% (67% for EF < 40% and 52% for 40-49%) and 52% in EF ≥ 40% (52% for EF ≥ 50%). For the literal scenario, 32% were eligible in EF < 50% (38% of EF < 40%, 20% of EF 40-49%) and 22% in EF ≥ 40% (25% for EF ≥ 50%). Eligible vs. noneligible patients had more severe HF, more comorbidities and overall worse outcomes. CONCLUSION In a real-world HF outpatient cohort, 81% of patients had EF < 50%, with 63% eligible for sacubitril/valsartan based on pragmatic criteria and 32% eligible based on literal trial criteria. Similar eligibility was observed for EF 40-49% and ≥50%, suggesting that our estimates for EF < 50% may be reproduced whether or not a higher cut-off for EF is considered.
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Association of Sacubitril/Valsartan with Metabolic Parameters in Patients with Reduced Ejection Fraction Heart Failure at a Multidisciplinary Clinic.
Ryu, R, Tran, H, Bahjri, K
Metabolic syndrome and related disorders. 2021;(2):115-118
Abstract
Background: Sacubitril/valsartan was approved for New York Heart Association (NYHA) class II-IV heart failure with reduced ejection fraction (HFrEF) in 2015, based on the results of the PARADIGM-HF trial, which showed a reduction in cardiovascular (CV) death and heart failure hospitalization, compared with enalapril. A subsequent subgroup analysis of the trial showed glycemic improvement for patients on sacubitril/valsartan compared with those on enalapril. Methods: This was a retrospective observational study at the Loma Linda University (LLU) International Heart Institute (IHI). The aim was to evaluate the association of sacubitril/valsartan with glycemic index and other metabolic parameters, including change in hemoglobin A1C (HbA1C), blood pressure (BP), ejection fraction (EF), body weight, and lipid profile from baseline and at 3, 6, and 12 months. The rates of CV-related hospitalizations and total hospitalizations were also assessed. Results: The change in mean HbA1C from baseline was not significantly different at 1 year (P = 0.993). The mean EF was significantly higher and the mean diastolic BP was significantly lowered. Body weight and lipid parameters remained unchanged. Both the rates of CV-related hospitalizations and total hospitalizations were significantly lowered. For the prespecified subgroup analysis of diabetic HFrEF patients, the mean HbA1C was nonsignificant at 12 months (mean difference -0.48, P = 0.993). Conclusion: A non-significant reduction in HbA1C was associated in HFrEF patients with diabetes mellitus. Large randomized trials are needed to confirm our findings regarding the potential metabolic benefits of sacubitril/valsartan.
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Effect of Sacubitril/Valsartan on circulating catecholamine levels during a 6-month follow-up in heart failure patients. Timeo Danaos et dona ferentes?
Chalikias, G, Kikas, P, Thomaidis, A, Rigopoulos, P, Pistola, A, Lantzouraki, A, Zisimopoulos, A, Tziakas, D
Acta cardiologica. 2021;(4):396-401
Abstract
We assessed the effect of Sacubitril/Valsartan on circulating catecholamine levels in patients with HF in an observational cohort study. We included 108 consecutive HF patients attending our HF Outpatients Clinic who were eligible to Sacubitril/Valsartan according to the PARADIGM-HF inclusion and exclusion criteria. We furthermore included 58 stable HF patients under optimal medical therapy as a control group. Norepinephrine and epinephrine were measured with immunoradiometric assays at baseline, at 3- and at 6-month time follow-up. Compared to baseline levels there was no change at three months in epinephrine (p = 0.177) or norepinephrine (p = 0.815) concentrations. At 6 months norepinephrine remained unchanged (p = 0.359). However, at 6 months we observed a significant increase in epinephrine levels compared to baseline [66 pg/mL (37-93) vs 38 pg/mL (18-74), p < 0.001]. In the control group no change was observed in epinephrine levels compared to baseline (p = 0.838). This study is the first to report on the effect of the new drug Sacubitril/Valsartan on circulating catecholamine levels in HF patients. Our data show a significant increase in epinephrine levels during a 6 month follow up in stable HF patients.
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The AWAKE-HF Study: Sacubitril/Valsartan Impact on Daily Physical Activity and Sleep in Heart Failure.
Khandwalla, RM, Grant, D, Birkeland, K, Heywood, JT, Fombu, E, Owens, RL, Steinhubl, SR, ,
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2021;(2):241-254
Abstract
BACKGROUND AWAKE-HF evaluated the effect of the initiation of sacubitril/valsartan versus enalapril on activity and sleep using actigraphy in patients who have heart failure with reduced ejection fraction (HFrEF). METHODS In this randomized, double-blind study, patients with HFrEF (n = 140) were randomly assigned to sacubitril/valsartan or enalapril for 8 weeks, followed by an 8-week open-label phase with sacubitril/valsartan. Primary endpoint was change from baseline in mean activity counts during the most active 30 min/day at week 8. The key secondary endpoint was change in mean nightly activity counts/minute from baseline to week 8. Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) was an exploratory endpoint. RESULTS There were no detectable differences between groups in geometric mean ratio of activity counts during the most active 30 min/day at week 8 compared with baseline (0.9456 [sacubitril/valsartan:enalapril]; 95% confidence interval [CI] 0.8863-1.0088; P = 0.0895) or in mean change from baseline in activity during sleep (difference: 2.038 counts/min; 95% CI - 0.062 to 4.138; P = 0.0570). Change from baseline to week 8 in KCCQ-23 was 2.89 for sacubitril/valsartan and 4.19 for enalapril, both nonsignificant. CONCLUSIONS In AWAKE-HF, no detectable differences in activity and sleep were observed when comparing sacubitril/valsartan with enalapril in patients with HFrEF using a wearable biosensor. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02970669.
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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.