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Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond.

ABSTRACT: Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction.

SUBMITTER: Singh JS

PROVIDER: S-EPMC4459540 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond.

Singh Jagdeep S S JS Lang Chim C CC

Vascular health and risk management 20150601

Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechani ...[more]

PMID: 26082640

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Project description:BACKGROUND:There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS:Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end-diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS:Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.

Project description:BackgroundData regarding using angiotensin receptor-neprilysin inhibitor (ARNI) in patients with both heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease (CKD) are limited.Methods and resultsBetween January 2016 and December 2018, patients with HFrEF and advanced CKD (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min/1.73 m2) were identified from a multi-institutional database in Taiwan. Patients who had never been prescribed with an ARNI, angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB) were excluded. We used inverse probability of treatment weighting (IPTW) to balance baseline covariates, and compared outcomes between ARNI and ACEI/ARB users. There were 206 patients in the ARNI group and 833 patients in the ACEI/ARB group. After IPTW adjustment, the mean ages (65.1 vs. 66.6 years), male patients (68.3 vs. 67.9%), left ventricular ejection fraction (30.5 vs.31.2%), eGFR (20.9 vs. 20.3 mL/min/1.73 m2) were comparable in the ARNI and ACEI/ARB groups. Over 85% of the patients had beta-blockers prescriptions in both groups (86.2 vs. 85.5%). After IPTW adjustment, the mean follow-up durations were 7.3 months and 6.6 months in the ARNI and ACEI/ARB groups, respectively. ARNI and ACEI/ARB users had a comparable risk of the composite clinical event (all-cause mortality or heart failure hospitalization) (hazard ratio [HR], 1.31; 95% confidence interval (CI) 0.91-1.88) and progression to dialysis (HR 1.04; 95% CI 0.54-2.03). In subgroup analysis, dialysis patients who used ARNIs were associated with higher incidence of heart failure hospitalization (subdistribution HR, 1.97; 95% CI 1.36-2.85).ConclusionsCompared with ACEIs or ARBs, ARNIs were associated with comparable clinical and renal outcomes in patients with HFrEF and advanced CKD (eGFR ≤ 30 mL/min/1.73 m2). In short-term, HF hospitalization may occur more frequently among ARNI users, especially in patients on dialysis.

Project description:AimsThe clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi.MethodsSeventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up.ResultsFollowing ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition.ConclusionThe significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.

Project description:BackgroundAngiotensin receptor-neprilysin inhibitor (ARNI) prescription in the United States remains suboptimal despite strong evidence for efficacy and value in heart failure with reduced ejection fraction. Factors responsible for under prescription are not completely understood. Economic limitations may play a disproportionate role in reduced access for some patients.MethodsThis is an analysis of the Get With The Guidelines-Heart Failure registry, supplemented with data from the Distressed Community Index. Data were fit to a mixed-effects regression model to investigate clinical and socioeconomic factors associated with ARNI prescription at hospital discharge. Missing data were handled by multilevel multiple imputation.ResultsOf the 136 144 patients included in analysis, 12.6% were prescribed an ARNI at discharge. The dominant determinants of ARNI prescription were ARNI use while inpatient (odds ratio [OR], 72 [95% CI, 58-89]; P<0.001) and taking an ARNI before hospitalization (OR 9 [95% CI, 7-13]; P<0.001). Having an ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB)/ARNI contraindication was associated with lower likelihood of ARNI prescription at discharge (OR, 0.11 [95% CI, 0.10-0.12]; P<0.001). Socioeconomic factors associated with lower likelihood of ARNI prescription included having no insurance (OR, 0.60 [95% CI, 0.50-0.72]; P<0.001) and living in a ZIP Code identified as distressed (OR, 0.81 [95% CI, 0.70-0.93]; P=0.010). The rate of ARNI prescription is increasing with time (OR, 2 [95% CI, 1.8-2.3]; P<0.001 for patients discharged in 2020 as opposed to 2017), but the disparity in prescription rates between distressed and prosperous communities appears to be increasing.ConclusionsMultiple medical and socioeconomic factors contribute to low rates of ARNI prescription at hospital discharge. Potential targets for improving ARNI prescription rates include initiating ARNIs during hospitalization and aggressively addressing patients' access barriers with the support of inpatient social services and pharmacists.

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Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond.

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Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond.

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