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10.1136/bmjopen-2024-088744
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Cardiovascular Medicine
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Comparative effects of sacubitril/valsartan and ACEI/ARB on endothelial function and arterial stiffness in patients with heart failure: a protocol for systematic review and meta-analysis
Ma Zhiyong 1zhiyongma@yeah.net

Fu Zhijie 2fuzhijie104@126.com

Li Na 1lnsduvip@126.com

Huang Shanying 1huangshy2002@163.com

http://orcid.org/0000-0002-1727-0125
Chi Lingyi 313573148930@139.com

1 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
2 Department of Otorhinolaryngology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
3 Department of Neurosurgery, Shandong University, Jinan, Shandong, China
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

None declared.

Dr; 13573148930@139.com
2024
6 9 2024
14 9 e08874414 5 2024
13 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Introduction

Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF.

Methods and analysis

Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China’s National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg’s and Egger’s tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation.

Ethics and dissemination

This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal.

PROSPERO registration number

CRD42024538148.

Heart failure
Meta-Analysis
Medicine
Protocols & guidelines
the Shandong Province Science and Technology Research Program ZR2020MH038 http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81470558 81700891 The sponsor has not taken part in study design, data collection and analysis, decision to publish or manuscript preparation.
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pmcStrengths and limitations of this study

This systematic review and meta-analysis will assess the effect of sacubitril/valsartan on endothelial function and arterial stiffness in heart failure.

Eligible studies will be selected using strict inclusion and exclusion criteria.

The risk of bias and the evidence quality will be evaluated by the Cochrane guidelines and the Grading of Recommendations Assessment, Development, and Evaluation methodology.

The clinical heterogeneity due to different treatment frequency and language bias due to the inclusion of both English and Chinese literature may be the limitations.

Introduction

Heart failure (HF) is a complex syndrome that affects millions of people worldwide and often leads to significant morbidity and mortality.13 There are more than 64 million patients worldwide with a 1–3% incidence of HF in Europe/America and a 1.3% incidence in China, which has become a serious public health issue.1 3 4 The pathophysiology of HF involves multiple mechanisms, of which vascular dysfunction plays an important role in regulating the preload and afterload of the heart and coronary circulation.58 Increasing data revealed that endothelial function and arterial stiffness are important markers of vascular function and independent predictors of the prognosis of HF.8 9 Flow-mediated dilation (FMD) and pulse wave velocity (PWV) have been widely used to assess endothelial function and arterial stiffness. In clinical studies, every 1% increase in FMD is associated with an 8–13% lower risk of fatal and nonfatal cardiovascular (CV) events and/or deaths from all causes.10 11 Similarly, a 1 m/s increase in PWV has been associated with a 15% increase in CV mortality and all-cause mortality.12 13 Therefore, therapeutic strategies targeting endothelial function and arterial stiffness are crucial to improve outcomes in patients with HF.

Among the various pharmacological agents used in HF, ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have long been the mainstay of treatment.1314 These drugs work primarily by blocking the renin–angiotensin–aldosterone system, a key hormonal pathway involved in the pathophysiology of HF.15 In recent years, sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an ARB, has become one of the first-line drugs for the treatment of HF.16 The core clinical trial, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure, revealed that sacubitril/valsartan reduced all-cause mortality by 16% and CV disease mortality by 20% and decreased the rate of hospitalisations related to HF by 21% compared with standard ACEI enalapril therapy in patients with HF with reduced ejection fraction (EF).17 Even in patients with pre-HF with preserved EF, the Patients With Natriuretic Peptide Elevation trial showed that sacubitril/valsartan versus valsartan resulted in a greater increase in the left atrial volume index and a decrease in the N-terminal pro-brain natriuretic peptide (BNP).18 Furthermore, sacubitril/valsartan significantly reduces BNP levels and improves quality of life and ventricular remodelling in patients with HF more than ACEI/ARB.19 Therefore, sacubitril/valsartan has significant protective effects on the CV system compared with traditional ACEI/ARB medications.

Previous studies have found that ACEI/ARB or sacubitril/valsartan can increase FMD and reduce PWV.2022 Sacubitril/valsartan improved endothelial dysfunction and arterial stiffness in patients with chronic HF probably related to reduced oxidative stress, platelet activation and circulating inflammation biomarkers, without adverse effects.23 24 Surprisingly, there is no comprehensive review on the different effects of sacubitril/valsartan and ACEI/ARB on endothelial function and arterial stiffness of HF patients. Therefore, we conducted an exhaustive systematic review and meta-analysis to explore whether sacubitril/valsartan can provide further improvements in endothelial function and arterial stiffness compared with traditional ACEI and ARB agents.

Objectives

The purpose of this systematic review and meta-analysis is to evaluate the comparative effectiveness in endothelial function and arterial stiffness between sacubitril/valsartan and ACEI/ARB in the management of HF from clinical randomised controlled trials (RCTs).

Methods and analysis

Patient and public involvement

Patient and public are not involved in the design or conduct of the study.

Eligibility criteria

Types of studies

RCTs investigating the effect of sacubitril/valsartan, ACEI and/or ARB on endothelial function/FMD and arterial stiffness/PWV in patients with HF will be included. Cross-sectional studies, non-RCTs, case series, case reports, reviews, commentaries and animal studies will be excluded.

Types of participants

The patients were diagnosed with acute or chronic HF according to the ‘ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure’ or the ‘ACCF/AHA guideline for the treatment of heart failure’ or the ‘Guidelines for the Diagnosis and Treatment of Heart Failure in China’.13 Patients with acute coronary syndrome, cancer, pregnancy, rheumatic disease and systemic infection diseases were excluded.

Type of interventions and comparisons

Conventional treatment for HF plus sacubitril/valsartan versus conventional treatment for HF including ACEI and/or ARB was included. Conventional treatment for HF includes diuretic, β-blocker, mineralocorticoid receptor antagonist and/or cardiotonic and/or vasodilator.

Outcomes

The outcomes of interest are changes in endothelial function assessed by FMD (%) and changes in arterial stiffness assessed by PWV (m/s). The basic effects of sacubitril/valsartan on all-cause and CV disease mortality, the rate of HF-related rehospitalisations and the EF are also analysed.

Methods of obtaining and analysing data

Literature search and study selection

Two authors carried out independent searches of databases including PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Internet (CNKI) database up to January 2024. The search strategy combined medical subject headings and free text terms such as the following: ‘HF’ OR ‘chronic heart failure (CHF)’ AND ‘sacubitril / valsartan’ OR ‘angiotensin converting enzyme inhibitor (ACEI, including enalapril, ramipril, captopril, lisinopril or trandolapril)’ OR ‘angiotensin receptor blocker (ARB, including valsartan, candesartan or losartan)’ AND ‘endothelial function’ OR ‘flow-mediated dilation (FMD)’ OR ‘arterial stiffness, OR ‘pulse wave velocity (PWV)’. In addition, other resources from Google Scholar, Baidu Scholar, Clinical Trials.Gov and Chinese Clinical Trial Registry were also searched to avoid grey/unpublished trials. We also manually searched the reference lists of the enrolled studies to find studies relevant to the study topic. The search strategy is shown in online supplemental additional file 1. Only RCTs in English or Chinese were included in the analysis, and there was no restriction on the publication year. The literature selection based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses25 is shown in figure 1.

Figure 1 PRISMA flow chart for the study selection process. CNKI, China National Knowledge Infrastructure; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Assessment of risk of bias and data extraction

The risk of bias was evaluated by two authors using the revised Cochrane risk of bias tool for randomised trials (RoB2.0) .26 The potential types of bias included the following: randomisation bias, deviation bias for the intended intervention, bias from missing data, bias from outcome measurements and bias due to the selection of reported data. The Review Manager (RevMan) V.5.3 was used to generate bias graphs and summary of risk of bias. Reporting bias of the studies will be evaluated by the funnel plot, in which the symmetry will be evaluated using Begg’s and Egger’s tests.27

A standard form was used for data extraction that included information on study characteristics (title, first author, publication year and study design), demographic data of participants (inclusion criteria, sample size, sex, age and baseline status), treatment details (name of the drug, dose and duration of treatment) and results related to endothelial function and arterial stiffness. We excluded studies without sufficient information. Disagreements were resolved by consensus.

Data analysis

RevMan V.5.3 software developed by the Cochrane Collaboration was used to compare the effects of different treatment strategies on endothelial function and arterial stiffness. All outcomes will be continuous variables and were expressed as weighted mean differences with 95% CI. Statistical heterogeneity between selected articles was tested using χ2 test and I2 test. An I2 value of >50% indicates statistically significant heterogeneity in the selected studies.28All analyses were initially done using a fixed-effects model, and if heterogeneity between studies was observed, the analysis was repeated using a random-effects model, which includes a measure of variance in the calculation of the pooled results. To establish the effect of clinical heterogeneity of the included studies on the results of the meta-analysis, a subgroup analysis was performed. P < 0.05 was considered statistically significant.

Quality of evidence

The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation.29 The limitations of the study, inconsistencies of method and results, indirect evidence, inaccuracy and publication bias will be assessed. Evidence will be categorised into four levels: high, moderate, low or very low.

Ethics and dissemination

This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal.

supplementary material

10.1136/bmjopen-2024-088744 online supplemental table 1

Review Process File
6 9 2024

Funding: This work was supported by the Shandong Province Science and Technology Research Program (No. ZR2020MH038) and the National Natural Science Foundation of China (Nos. 81700891 and 81470558).

Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-088744).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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