title: Protocol for a systematic review and individual participant data meta-analysis of B-type natriuretic peptide-guided therapy for heart failure.
abstract: BACKGROUND
  Several aggregate data meta-analyses suggest that treatment guided by the serum concentration of natriuretic peptides (B-type natriuretic peptide (BNP) or its derivative N-terminal pro-B-type natriuretic peptide (NT-BNP)) reduces all-cause mortality compared with usual care in patients with heart failure (HF). We propose to conduct a meta-analysis using individual participant data (IPD) to estimate the effect of BNP-guided therapy on clinical outcomes, and estimate the extent of effect modification for clinically important subgroups.
  
  
  METHODS
  We will use standard systematic review methods to identify relevant trials and assess study quality. We will include all randomized controlled trials (RCTs) of BNP-guided treatment for HF that report a clinical outcome. The primary outcome will be time to all-cause mortality. We will collate anonymized, individual patient data into a single database, and carry out appropriate data checks. We will use fixed-effects and random-effects meta-analysis methods to combine hazard ratios (HR) estimated within each RCT, across all RCTs. We will also include a meta-analysis and meta-regression analyses based on aggregate data, and combine IPD with aggregate data if we obtain IPD for a subset of trials.
  
  
  CONCLUSIONS
  The IPD meta-analysis will allow us to estimate how patient characteristics modify treatment benefit, and to identify relevant subgroups of patients who are likely to benefit most from BNP-guided therapy. This is important because aggregate meta-analyses have suggested that clinically relevant subgroup effects exist, but these analyses have been unable to quantify the effects reliably or precisely.
  
  
  BACKGROUND
  PROSPERO 2013: CRD42013005335.
authors.affiliation: Clinical Trials and Evaluation Unit, University of Bristol, Level 7, Bristol Royal Infirmary, Queen's Building, Bristol BS2 8HW, UK. maria.pufulete@bristol.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Pufulete
authors.forename: Julian Pt
authors.initials: JP
authors.lastname: Higgins
authors.forename: Chris A
authors.initials: CA
authors.lastname: Rogers
authors.forename: Lucy
authors.initials: L
authors.lastname: Dreyer
authors.forename: William
authors.initials: W
authors.lastname: Hollingworth
authors.forename: Mark
authors.initials: M
authors.lastname: Dayer
authors.forename: Angus
authors.initials: A
authors.lastname: Nightingale
authors.forename: Theresa
authors.initials: T
authors.lastname: McDonagh
authors.forename: Barnaby C
authors.initials: BC
authors.lastname: Reeves
mesh_terms: D054316:Biomarkers, Pharmacological / Q000097:blood; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D000078202:Systematic Reviews as Topic; D015201:Meta-Analysis as Topic
chemical_list: D054316:Biomarkers, Pharmacological; D002316:Cardiotonic Agents; D020097:Natriuretic Peptide, Brain