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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 -
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. Renal... May 2022
Topics: Angiotensins; Kidney; Nephrectomy
PubMed: 35343851
DOI: 10.1152/ajprenal.00063.2022 -
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 -
Synergistic actions between angiotensin-converting enzyme inhibitors and statins in atherosclerosis.Nutrition, Metabolism, and... Apr 2022Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and... (Review)
Review
AIMS
Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response.
DATA SYNTHESIS
The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum.
CONCLUSION
Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications.
Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Atherosclerosis; Atorvastatin; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Renin-Angiotensin System
PubMed: 35082055
DOI: 10.1016/j.numecd.2021.11.015 -
Current Cancer Drug Targets May 2011Lung cancer is a leading cause of death in both men and women, with over 1,000,000 new cases diagnosed worldwide annually and a 5-year survival rate of only 14%, a... (Review)
Review
Lung cancer is a leading cause of death in both men and women, with over 1,000,000 new cases diagnosed worldwide annually and a 5-year survival rate of only 14%, a figure that has improved little in the past thirty years. This poor prognosis suggests a need for novel approaches for the treatment and prevention of lung cancer. The renin-angiotensin system is an established, primary regulator of blood pressure, homeostasis, and natriuresis; however, compelling evidence indicates that the angiotensin peptides also play a role in cell proliferation and inflammation. Angiotensin II is a vasoconstrictor, a mitogen, and an angiogenic factor, while angiotensin-(1-7) has vasodilator, anti-proliferative, and anti-angiogenic properties. This review focuses on studies examining the renin-angiotensin system in pulmonary cancers and whether clinical intervention of this pathway may serve as an effective chemotherapeutic and/or chemopreventive modality for lung cancer.
Topics: Angiotensins; Animals; Humans; Lung Neoplasms; Peptide Fragments; Renin-Angiotensin System
PubMed: 21395552
DOI: 10.2174/156800911795538048 -
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 -
JAMA Apr 2023Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II...
Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.
IMPORTANCE
Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.
OBJECTIVE
To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.
DESIGN, SETTING, AND PARTICIPANTS
Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.
INTERVENTIONS
A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.
RESULTS
Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.
CONCLUSIONS AND RELEVANCE
In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04924660.
Topics: Adult; Female; Humans; Male; Middle Aged; Angiotensin II; Angiotensins; COVID-19; Hypoxia; Infusions, Intravenous; Ligands; Oligopeptides; Randomized Controlled Trials as Topic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; SARS-CoV-2; Vasodilator Agents
PubMed: 37039791
DOI: 10.1001/jama.2023.3546