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Journal of the American College of... Jul 2023U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown.
OBJECTIVES
PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event.
METHODS
PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP.
RESULTS
In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95).
CONCLUSIONS
Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).
Topics: Humans; Heart Failure; Neprilysin; Angiotensins; Angiotensin Receptor Antagonists; Stroke Volume; Tetrazoles; Angiotensin-Converting Enzyme Inhibitors; Valsartan; Aminobutyrates; Biphenyl Compounds; Hypotension; Drug Combinations
PubMed: 37212758
DOI: 10.1016/j.jacc.2023.04.019 -
European Journal of Heart Failure Sep 2022Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of...
AIMS
Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin-neprilysin inhibition in a pooled analysis of 13 195 patients with heart failure with reduced and preserved EF.
METHODS AND RESULTS
We combined data from PARADIGM-HF (EF ≤40%; n = 8399) and PARAGON-HF (EF ≥45%; n = 4796) in a pre-specified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in estimated glomerular filtration rate (eGFR), ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 ml/min/1.73 m in PARADIGM-HF and 63 ± 19 ml/min/1.73 m in PARAGON-HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of 6601 patients (1.9%) in the valsartan or enalapril group (hazard ratio 0.56, 95% confidence interval [CI] 0.42-0.75; p < 0.001). The mean eGFR change was -1.8 (95% CI -1.9 to -1.7) ml/min/1.73 m /year for the sacubitril/valsartan group, compared with -2.4 (95% CI -2.5 to -2.2) ml/min/1.73 m /year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (p-interaction = 0.64), but was most pronounced in those with baseline EF between 30% and 60% (p-interaction = 0.001).
CONCLUSIONS
In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Biphenyl Compounds; Drug Combinations; Enalapril; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Neprilysin; Stroke Volume; Tetrazoles; Valsartan
PubMed: 34989105
DOI: 10.1002/ejhf.2421 -
Heart Failure Reviews Sep 2023Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials... (Review)
Review
Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.
Topics: Humans; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Heart Failure; Mineralocorticoid Receptor Antagonists; Neprilysin; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 37311917
DOI: 10.1007/s10741-023-10325-2 -
JAMA Network Open Sep 2022In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).
OBJECTIVE
To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF.
DATA SOURCES
A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021.
STUDY SELECTION
Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF.
DATA EXTRACTION AND SYNTHESIS
Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model.
MAIN OUTCOMES AND MEASURES
The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model.
RESULTS
In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes.
CONCLUSIONS AND RELEVANCE
The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Bayes Theorem; Glucose; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Neprilysin; Receptors, Angiotensin; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 36125813
DOI: 10.1001/jamanetworkopen.2022.31963 -
American Journal of Physiology. Heart... Oct 2023The lymphatic system is an integral part of the circulatory system and plays an important role in the fluid homeostasis of the human body. Accumulating evidence has... (Review)
Review
The lymphatic system is an integral part of the circulatory system and plays an important role in the fluid homeostasis of the human body. Accumulating evidence has recently suggested the involvement of lymphatic dysfunction in the pathogenesis of cardio-reno-vascular (CRV) disease. However, how the sophisticated contractile machinery of lymphatic vessels is modulated and, possibly impaired in CRV disease, remains largely unknown. In particular, little attention has been paid to the effect of the renin-angiotensin-system (RAS) on lymphatics, despite the high concentration of RAS mediators that these tissue-draining vessels are exposed to and the established role of the RAS in the development of classic microvascular dysfunction and overt CRV disease. We herein review recent studies linking RAS to lymphatic function and/or plasticity and further highlight RAS-specific signaling pathways, previously shown to drive adverse arterial remodeling and CRV organ damage that have potential for direct modulation of the lymphatic system.
Topics: Humans; Renin; Renin-Angiotensin System; Kidney; Angiotensins; Lymphatic Vessels
PubMed: 37565265
DOI: 10.1152/ajpheart.00023.2023 -
Muscle & Nerve Oct 2022Prognostic factors in Duchenne muscular dystrophy (DMD) predict the disease course and may help individualize patient care. The aim was to summarize the evidence on... (Meta-Analysis)
Meta-Analysis
INTRODUCTION/AIMS
Prognostic factors in Duchenne muscular dystrophy (DMD) predict the disease course and may help individualize patient care. The aim was to summarize the evidence on prognostic factors that may support treatment decisions.
METHODS
We searched six databases for prospective studies that each included ≥50 DMD patients with a minimum follow-up of 1 y. Primary outcomes were age at loss of ambulation (LoA), pulmonary function (forced vital capacity percent of predicted, FVC%p), and heart failure.
RESULTS
Out of 5074 references, 59 studies were analyzed. Corticosteroid use was associated with a delayed LoA (pooled effect hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.23-0.75, I2 94%), better pulmonary function tests (higher peak FVC%, prolonged time with FVC%p > 50%, and reduced need for assisted ventilation) and delayed cardiomyopathy. Longer corticosteroid treatment was associated with later LoA (>1 y compared to <1 y; pooled HR: 0.50, 95% CI 0.27-0.90) and early treatment start (aged <5 y) may be associated with early cardiomyopathy and higher fracture risk. Genotype appeared to be an independent driver of LoA in some studies. Higher baseline physical function tests (e.g., 6-minute walk test) were associated with delayed LoA. Left ventricular dysfunction and FVC <1 L increased and the use of angiotensin-converting enzyme (ACE) inhibitors reduced the risk of heart failure and death. Fusion surgery in scoliosis may potentially preserve pulmonary function.
DISCUSSION
Prognostic factors that may inform clinical decisions include age at corticosteroid treatment initiation and treatment duration, ACE-inhibitor use, baseline physical function tests, pulmonary function, and cardiac dysfunction.
Topics: Adrenal Cortex Hormones; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Cardiomyopathies; Disease Progression; Heart Failure; Humans; Muscular Dystrophy, Duchenne; Prognosis; Prospective Studies; Treatment Outcome
PubMed: 35860996
DOI: 10.1002/mus.27682 -
Methods in Molecular Biology (Clifton,... 2017The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order... (Review)
Review
The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order to understand the functions of the system, characterization of angiotensin peptides (products and substrates) is important. Radioimmunoassays with the requisite specificity and sensitivity have been developed to allow for the characterization and quantification of circulating and tissue angiotensins. Here, we describe the appropriate methods for collecting the tissue and blood, the extractions steps required to partially purify and remove larger molecular weight-interfering proteins from tissue and plasma, and the radioimmunoassay of three of the peptides of this system (Ang I, Ang II, and Ang-(1-7)), as well as the verification of immunoreactive identity for Ang II and Ang-(1-7) by combined high-performance liquid chromatography-RIA analysis.
Topics: Angiotensin I; Angiotensin II; Animals; Chromatography, High Pressure Liquid; Humans; Peptide Fragments; Radioimmunoassay; Renin-Angiotensin System
PubMed: 28116709
DOI: 10.1007/978-1-4939-6625-7_7 -
Journal of Medicine and Life 2020The role of the renin-angiotensin system in hypertension and end-organ damage has long been recognized. Angiotensin l converting enzyme inhibitors are superior to other... (Review)
Review
The role of the renin-angiotensin system in hypertension and end-organ damage has long been recognized. Angiotensin l converting enzyme inhibitors are superior to other antihypertensive agents in protecting the kidney against progressive deterioration, even in normotensive persons. Likewise, angiotensin II type 1 receptor antagonists improve or even reverse glomerulosclerosis in rat animal models. These findings suggest that Angiotensin II has nonhemodynamic effects in progressive renal disease. The renin-angiotensin system is now recognized to be linked to the induction of plasminogen activator-inhibitor-1, possibly via the AT4 receptor, thus promoting both thrombosis and fibrosis. Interactions of the renin-angiotensin system with aldosterone and bradykinin may impact both blood pressure and tissue injury. The beneficial effect on renal fibrosis of inhibiting the renin-angiotensin system likely reflects the central role that angiotensin has in regulating renal function and structure by its various actions. This article explores the renin-angiotensin-aldosterone system with plasminogen activator-inhibitor-1 interaction and the potential significance of these interactions in the pathogenesis of progressive renal disease and remodeling of renal sclerosis.
Topics: Aging; Aldosterone; Angiotensins; Animals; Humans; Kidney Diseases; Remission Induction; Renin-Angiotensin System
PubMed: 32728402
DOI: 10.25122/jml-2020-0006 -
BMC Nephrology Mar 2023Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the...
BACKGROUND
Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin-angiotensin-aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function.
METHODS
This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years.
RESULTS
Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1-5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77-1.0] vs. 0.63 [95%CI: 0.34-0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB.
CONCLUSIONS
Early use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB.
Topics: Humans; Antihypertensive Agents; Renin; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Retrospective Studies; Emergencies; Kidney; Renin-Angiotensin System; Hypertension
PubMed: 36949416
DOI: 10.1186/s12882-023-03117-1 -
Cells Sep 2022Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular... (Review)
Review
Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin-angiotensin axis or of sodium-glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.
Topics: Albumins; Albuminuria; Angiotensins; Diabetes Mellitus; Diabetic Nephropathies; Glucose; Humans; Proteinuria; Renin; Sodium
PubMed: 36139492
DOI: 10.3390/cells11182917