Background
Description of the condition
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Heart failure with an LVEF of 40% or less is named heart failure with reduced ejection fraction (HFrEF).
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Heart failure with an LVEF of 50% or more is named heart failure with preserved ejection fraction (HFpEF).
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Heart failure with LVEF between 41 and 49% is named heart failure with mid-range ejection fraction (HFmrEF).
Description of the intervention
Treatment of heart failure (usual care)
Angiotensin receptor blocker neprilysin inhibitor
Why is it important to do this review
Methods
Criteria for considering studies for this review
Types of studies
Types of participants
Types of interventions
Types of outcomes
Primary outcomes
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All-cause mortality.
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Serious adverse events. We will define a serious adverse event as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalisation or prolongation of existing hospitalisation, and resulted in persistent or significant disability or jeopardised the patient [42] (dichotomous outcome).
Secondary outcomes
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Myocardial infarction (dichotomous outcome)
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Quality of life measured on any valid scale (continuous outcome)
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Non-serious adverse events (dichotomous outcome) (please see above)
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Hospitalisation during follow-up (dichotomous outcome)
Exploratory outcomes
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Cardiovascular mortality
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Ejection fraction (continuous outcome)
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Six minutes of walking distance (continuous outcome)
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NT-proBNP (continuous outcome)
Search methods
Electronic searches
Searching other resources
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Google Scholar (https://scholar.google.dk/)
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The Turning Research into Practice (TRIP) Database (https://www.tripdatabase.com)
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European Medicines Agency (EMA) (https://www.ema.europa.eu/ema/)
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US Food and Drug Administration (FDA) (www.fda.gov)
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China Food and Drug Administration (CFDA) (http://eng.sfda.gov.cn/WS03/CL0755/)
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Medicines and Healthcare products Regulatory Agency (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency)
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The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch)
Data collection and analysis
Selection of studies
Data extraction and management
Trial characteristics
Participant characteristics and diagnosis
ARNI strategy characteristics
Co-intervention characteristics
Notes
Assessment of risk of bias in included studies
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Random sequence generation
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Allocation concealment
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Blinding of participants and treatment providers
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Blinding of outcome assessment
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Incomplete outcome data
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Selective outcome reporting
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For profit bias
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Other risks of bias
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Overall risk of bias
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Low risk: if sequence generation was achieved using a computer random number generator or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were also considered adequate if performed by an independent adjudicator.
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Unclear risk: if the method of randomisation was not specified, but the trial was still presented as being randomised.
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High risk: if the allocation sequence is not randomised or only quasi-randomised. These trials will be excluded.
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Low risk: if the allocation of patients was performed by a central independent unit, on-site locked computer, identical-looking numbered sealed envelopes, drug bottles, or containers prepared by an independent pharmacist or investigator
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Uncertain risk: if the trial was classified as randomised but the allocation concealment process was not described
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High risk: if the allocation sequence was familiar to the investigators who assigned the participants
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Low risk: if the participants and the treatment providers were blinded to the intervention allocation and this was described
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Uncertain risk: if the procedure of blinding was insufficiently described
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High risk: if the blinding of the participants and the treatment providers was not performed
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Low risk of bias: if it was mentioned that outcome assessors were blinded, and this was described
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Uncertain risk of bias: if it was not mentioned if the outcome assessors in the trial were blinded or the extent of blinding was insufficiently described
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High risk of bias: if no blinding or incomplete blinding of outcome assessors was performed
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Low risk of bias: if missing data were unlikely to make treatment effects depart from plausible values. This could be either (1) there were no drop-outs or withdrawals for all outcomes or (2) the numbers and reasons for the withdrawals and drop-outs for all outcomes were clearly stated and could be described as being similar to both groups. Generally, the trial is judged as at a low risk of bias due to incomplete outcome data if drop-outs are less than 5%. However, the 5% cut-off is not definitive.
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Uncertain risk of bias: if there was insufficient information to assess whether missing data were likely to induce bias on the results.
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High risk of bias: if the results were likely to be biassed due to missing data either because the pattern of drop-outs could be described as being different in the two intervention groups or the trial used improper methods in dealing with the missing data (e.g. last observation carried forward).
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Low risk of bias: if a protocol was published before or at the time the trial was begun, and the outcomes specified in the protocol were reported on. If there is no protocol or the protocol was published after the trial has begun, reporting of all-cause mortality and all serious adverse events will grant the trial a grade of low risk of bias.
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Uncertain risk of bias: if no protocol was published and the outcome all-cause mortality and serious adverse events were not reported on.
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High risk of bias: if the outcomes in the protocol were not reported on.
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Low risk of bias: if the trial is not financed by a company that might have an interest in a given result
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Uncertain risk of bias: if there is no description of how the trial is financed
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High risk of bias: if the trial is financed by a company that might have an interest in a given result
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Low risk of bias: if the trial appears to be free of other components (for example, academic bias) that could put it at risk of bias
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Unclear risk of bias: if the trial may or may not be free of other components that could put it at risk of bias
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High risk of bias: if there are other factors in the trial that could put it at risk of bias (for example, academic bias)
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Low risk of bias: the trial will be classified as overall ‘low risk of bias’ only if all of the bias domains described in the above paragraphs are classified as ‘low risk of bias’.
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High risk of bias: the trial will be classified as ‘high risk of bias’ if any of the bias risk domains described in the above are classified as ‘unclear’ or ‘high risk of bias’.
Measures of treatment effect
Dichotomous outcomes
Continuous outcomes
Dealing with missing data
Dichotomous outcomes
Continuous outcomes
Assessment of heterogeneity
Assessment of reporting biases
Unit of analysis issues
Data synthesis
Meta-analysis
Trial sequential analysis
Subgroup analysis and investigation of heterogeneity
Subgroup analysis
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Trials at high risk of bias compared to trials at low risk of bias
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Participants with HFrEF, HFmrEF, and HFpEF
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Participants with acute decompensated heart failure compared to chronic heart failure
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Participants with NYHA 1 and 2, compared to NYHA 3 and 4
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Trials sponsored by the industry compared to trials not sponsored by the industry
Sensitivity analysis
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‘Best-worst-case’ scenario: we will assume that all participants lost to follow-up in the ARNI group have survived, had no serious adverse events, had no myocardial infarction, had a higher quality of life (see paragraph below), and had no adverse events. We will assume the opposite for all participants lost to follow-up in the control group.
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‘Worst-base-case’ scenario: we will assume that all participants lost to follow-up in the ARNI group have not survived, had serious adverse events, had a myocardial infarction, had a lower quality of life (see paragraph below), and had adverse events. We will assume the opposite for all participants lost to follow-up in the control group.