Abstract
Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure. The evidence for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in trial design have been highlighted in recent literature, necessitating a thorough review of all evidence for sacubitril/valsartan. Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care, with either an active comparator or placebo as a control.Heart failure of any subtype or NYHA class will be included. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected studies for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the Cochrane Risk of Bias tool (RoB 2). Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes. Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol is registered on PROSPERO (referenceCRD42020162031).
Highlights
Sacubitril/valsartan is a first-in-class angiotensinreceptor neprilysin inhibitor used to treat heart failure
It is a recent addition to the European Society of Cardiology (ESC) and National Institute for Health and Clinical Excellence (NICE) guidelines for the management of heart failure, in those with New York Heart Association (NYHA) class II-IV HFrEF2,9. It was approved by the National Centre for Pharmacoeconomics (NCPE) for reimbursement on the Irish state drug schemes in 2016 for an estimated potential 18,500 patients with HFrEF10
This study showed no significant differences in NYHA class or patient-related quality of life scores using the Kansas City Cardiomyopathy Questionnaire (KCCQ) between intervention and control groups at 12 weeks
Summary
It is a recent addition to the European Society of Cardiology (ESC) and NICE guidelines for the management of heart failure, in those with NYHA class II-IV HFrEF2,9 It was approved by the National Centre for Pharmacoeconomics (NCPE) for reimbursement on the Irish state drug schemes in 2016 for an estimated potential 18,500 patients with HFrEF10. In order to obtain a more complete picture of the evidence base for sacubitril/valsartan, we aim to complete a thorough systematic review and meta-analysis of all available randomised controlled trials (RCTs) for this novel medication, to include both published and unpublished sources. Research question In patients with heart failure taking sacubitril/valsartan, are clinical outcomes improved compared with those on standard therapy when all RCT evidence, including unpublished trial evidence, is considered?. The aim of this systematic review is to explore the evidence for the efficacy and safety of sacubitril/valsartan in patients with heart failure
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