A. To estimate the effect of treatment guided by serial BNP monitoring on clinical outcomes compared with standard care (symptom-based therapy).
B. To estimate the extent of effect modification for clinically important subgroups (e.g. age, gender, type of HF, severity of HF, baseline BNP levels, etc.).
C. To quantify the extent to which improved outcomes are explained by up-titration of medication and/or reduction in BNP levels (if data describing titration of medication are available).
D. To pool adverse event and discontinuation data to describe the safety of BNP-guided therapy in patients with HF.
We initially used published systematic reviews to identify relevant trials. We will supplement these with additional searches of MEDLINE, EMBASE, The Cochrane Library and ISI Web of Science (Citations Index and Conference Proceedings). A search strategy has been developed. We will search the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; http://apps.who.int/trialsearch/) and Current Controlled Trials (http://www.controlled-trials.com) to identify trials in progress. We will also review the reference of all full text papers and correspond with all trial authors to identify any trials that we may have missed.
We propose to conduct an IPD meta-analysis to determine whether BNP-guided therapy improves outcomes in patients with heart failure.
All patients >18 years who are being treated for HF in primary or secondary care.
Treatment guided by serial BNP measurements (BNP-guided therapy).
Treatment guided by clinical assessment (standard care).
Primary and secondary care.
Time to all-cause mortality.
Death related to heart failure; All-cause hospital admission; Hospital admission for heart failure; Adverse events; Quality of life.
Data extraction, (selection and coding)
Two members of the review team (not authors on any of the included trials) will independently review the titles and abstracts to remove those that are clearly inappropriate. The remaining papers will have clear inclusion criteria applied to them. Disagreements about study inclusion will be resolved by discussion with a third review author. RCT authors will be contacted, if necessary, to clarify details such as allocation concealment. Adequate allocation procedures include centralised randomisation or use of consecutively numbered, opaque sealed envelopes containing the allocation information kept by a person otherwise not involved in the study and not made available to the person recruiting a participant until a participant has been shown to be eligible and has given informed consent. All trials excluded from the review will be given reasons for exclusion as follows: not a randomised trial, allocation unclear or inadequate, no clinical outcome, inappropriate control.
Risk of bias (quality) assessment
Contributors will be expected to provide their study protocol to assist the risk of bias assessment. Two members of the review team will independently assess the risk of bias in each included study using the domain-based evaluation tool described in the Cochrane Handbook for Systematic Reviews of Interventions. Disagreements will be resolved by discussion with a third review author. We will assess the following domains as low risk of bias, unclear or high risk of bias. Where the risk of bias for a domain remains unclear, contributors will be asked to provide additional information to resolve the uncertainty.
Generation of allocation sequence (selection bias)
Allocation concealment (selection bias)
Blinding of participants, personnel and outcome assessors (performance bias)
Incomplete outcome data (attrition bias)*
Selective reporting (reporting bias)*
Other sources of bias
* These assessments will only be used for the aggregate data meta-analysis. Detection bias is not on the list because the primary outcome is all cause mortality (which is objective).
Strategy for data synthesis
We plan to obtain individual participant data. We will use standard meta-analysis methods incorporating all available IPD. All analyses will be performed on an intention-to-treat basis. The primary outcome will be time to all-cause mortality, defined as the time from randomisation to death from any cause, which will be analysed by survival methods. Hazard ratios (HR) will be estimated using Cox regression models within each trial. The estimated log HRs will be combined across studies using standard fixed-effect and random-effects meta-analysis methods as above.
Sensitivity analysis: We plan to conduct a sensitivity analysis on trials classified as having low risk of bias overall versus those classified as having a high risk of bias overall. We will also conduct a sensitivity analysis based on allocation concealment (good allocation concealment versus poor allocation concealment), since this has been shown to be the most important source of bias in RCTs.
Analysis of subgroups or subsets
Subgroup effects (including age, gender, baseline BNP level, NYHA class, presence of co-morbidities) will be estimated by treatment-by-covariate interaction terms within studies and combining these across studies in the same way. Other sub-groups will investigate study-level variables such as BNP-guided intervention characteristics (comparisons to be specified when study level data have been extracted). Forest plots will be produced for overall effects and for interaction effects. Interaction effects will be interpreted by applying them to meta-analyses of the participants in a reference subgroup (for example, when looking at the effect in males vs females, the meta-analytic interaction coefficient will be added to the result of a meta-analysis of HRs among females only to obtain an estimate HR for among males). As above, we intend to present random-effects estimates, along with prediction intervals to represent heterogeneity.
Findings from both meta-analyses will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We will also adhere to additional reporting guidelines recommended for IPD meta-analysis.
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.