Effects of Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction in Patients Undergoing Peritoneal Dialysis.
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SUBMITTER: Fu S
PROVIDER: S-EPMC8255468 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsRed cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON-HF.Methods and resultsPARAGON-HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5-15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT-proBNP concentration, more advanced New York Heart Association class, and worse Kansas City Cardiomyopathy Questionnaire scores. There was a graded relationship between quartiles of RDW at randomization and the primary endpoint, with a significantly higher risk associated with increasing RDW, even after adjustment for NT-proBNP and other prognostic variables {Quartile 1, reference; Quartile 2, rate ratio 1.03 [95% confidence interval (CI) 0.83 to 1.28]; Quartile 3, 1.25 [1.01 to 1.54]; Quartile 4, 1.70 [1.39 to 2.08]}. This association was seen for each of the secondary outcomes, including cardiovascular and all-cause death. Compared with valsartan, sacubitril/valsartan reduced RDW at 48 weeks [mean change -0.09 (95% CI -0.15 to -0.02)]. The effect of sacubitril/valsartan vs. valsartan was not significantly modified by RDW levels at randomization.ConclusionsRDW, a routinely available and inexpensive biomarker, provides incremental prognostic information when added to established predictors. Compared with valsartan, sacubitril/valsartan led to a small reduction in RDW.
| S-EPMC10804200 | biostudies-literature
Project description:Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical condition characterized by large pathophysiology heterogeneity with lack of effective therapies as proven by the disappointing results generated by randomized controlled trials. The innovative therapeutic concept provided by sacubitril-valsartan, a molecule combining angiotensin receptor blocking agent and neprilysin inhibitor has suggested the hypothesis it would have led to a reduced risk of hospitalization for HF or death from cardiovascular causes among patients with HF and preserved ejection fraction. The PARAGON-HF (ClinicalTrials.gov number, NCT01920711) investigated HF subjects class II to IV HF, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97?mg of sacubitril with 103?mg of valsartan twice daily) or valsartan (target dose, 160?mg twice daily). The trial missed the primary outcome of cardiovascular death and HF hospitalization (HFH) in the overall study population. A subgroup analysis addressed significant decrease of HFH in subjects with left ventricular ejection fraction below the median 57% value in the study. The data were consistent with previous post hoc analysis performed in studies where candesartan and spironolactone were investigated in HFpEF. Those results open the door to investigate angiotensin aldosterone and peptidases inhibition efficacy in the unexplored HF middle range ejection fraction, currently lacking of valid evidence.
| S-EPMC7944492 | biostudies-literature
Project description:Background Dyslipidemia is common in heart failure with preserved ejection fraction. Sacubitril/valsartan improves glycemic control and augments natriuretic peptide signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4774 participants from PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate/creatinine [a biomarker of natriuretic peptide activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (95% CI, -6.6% to -3.5%), increased high-density lipoprotein cholesterol +2.6% (95% CI, +1.7% to +3.4%), and increased low-density lipoprotein cholesterol +1.7% (95% CI, +0.4% to +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (P-interaction<0.001), and at 16 weeks by -13.0% (95% CI, -18.1% to -7.6%), or -29.9 (95% CI, -44.3 to -15.5) mg/dL, in this group. Adjusting for the change in urinary cyclic guanosine monophosphate/creatinine significantly attenuated treatment effects on triglycerides and high-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was nearly threefold stronger in those with elevated baseline triglycerides. Modest increases in high-density lipoprotein cholesterol and low-density lipoprotein cholesterol cholesterol were also observed with therapy. The underlying mechanism(s) of changes in high-density lipoprotein cholesterol and triglycerides are related to sacubitril/valsartan's effects on natriuretic peptide activity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
| S-EPMC8649234 | biostudies-literature
Project description:BackgroundGuidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.ObjectivesThis study sought to determine the optimal achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.MethodsUsing 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.ResultsAverage age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.ConclusionsBaseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
| S-EPMC8109279 | biostudies-literature
Project description:BackgroundThe impact of sacubitril-valsartan on heart failure (HF) patients with preserved ejection fractions (HFpEF) is uncertain. The purpose of this meta-analysis was to explore the clinical advantages and safety of sacubitril-valsartan in patients with HFpEF.MethodsPubMed and Web of Science were searched without any restrictions from inception to 8 May 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed.ResultsFour trials, with a total of 7008 patients were included. Compared with valsartan, sacubitril-valsartan significantly reduced the rate of HF decompensation and of the combined end point of HF decompensation and all-cause mortality. All-cause mortality, New York Heart Association class improvement and rate of hyperkalemia were not significantly different between the two groups. Regarding safety, sacubitril-valsartan was more likely to increase the risk of hypotension.ConclusionThis meta-analysis suggests that sacubitril-valsartan may be an effective strategy to reduce HF decompensation events in patients with HFpEF.Systematic Review registration: CRD42022336077.
| S-EPMC9794138 | biostudies-literature
Project description:The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
| S-EPMC6554586 | biostudies-literature
Project description:The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF.
| S-EPMC6267534 | biostudies-literature
Project description:AimsPatients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan.Methods and resultsIn this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89).ConclusionSacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.Clinical trial registrationPARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.
| S-EPMC8455346 | biostudies-literature
Project description:BackgroundCirculating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%.MethodsConsecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used.ResultssNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16-1.61] vs. 1.04 [0.97-1.11]) and the secondary (HR 1.38 [1.21-1.55] vs. 1.11 [1.04-1.18]) composite endpoints.ConclusionssNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.
| S-EPMC8121351 | biostudies-literature
Project description:AimsIn the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON-HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios.Methods and resultsEligibility was assessed in the Karolinska-Rennes study (acute HFpEF, LVEF ≥ 45%, and N-terminal pro-B-type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (<54% in women and <52% in men); and (iv) LVEF below mean of normal range (<64% in women and <62% in men). Among 425 patients [age 78 (72-83) years, 57% women, 28% LVEF ≤ 57% (median in PARAGON-HF), the trial scenario, identified 34% as eligible. Left atrial enlargement and/or left ventricular hypertrophy were present in 99%. Inclusion criteria not met were diuretic treatment and New York Heart Association class. Important exclusion criteria were estimated glomerular filtration rate <30 mL/min/1.73 m2 , haemoglobin <10 g/day, and cancer. In the pragmatic scenario, 63% were eligible. In LVEF below lower limit of normal range, 5.4% were eligible, and in LVEF below mean of normal range, 41% were eligible. In patients with LVEF ≤ 57%, eligibility was 42%, 69%, 21%, and 91% according to the trial scenario, pragmatic scenario, LVEF below lower limit of normal range, and LVEF below mean of normal range, respectively.ConclusionsIn real-world HFpEF (LVEF ≥ 45%) with N-terminal pro-B-type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON-HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria.
| S-EPMC8788030 | biostudies-literature