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Table 1 Characteristics of included studies and studies eligible for inclusion

From: B-type natriuretic peptide-guided therapy for heart failure (HF): a systematic review and meta-analysis of individual participant data (IPD) and aggregate data

Study Country Study period Setting Duration of follow-up Follow-up schedule BNP/NT-proBNP target Clinical target Primary endpoint Treatment algorithm
Studies that provided IPD
Anguita [20] Spain 2006–2008 HF clinic 18 months 1, 2, 3, 6, 12, and 18 months BNP level < 100 pg/ml Framingham HF score of < 2 Composite of all-cause mortality and cardiovascular hospital admission BNP group: therapy intensified to achieve target BNP
Control group: therapy intensified to achieve target congestion score.
Northstar [27] Denmark 2005–2009 HF clinic 2.5 years Every 1–3 months at the discretion of the investigator No set target Clinical assessment Composite of all-cause mortality and cardiovascular hospital admission BNP group: checklist to evaluate need for further investigation or intensification of therapy when NT-BNP was > 30% from randomisation visit
Control group: therapy evaluated and intensified at clinician discretion
Shochat [32]
Published as abstract only
Israel 2007–2010 HF clinic Median 11 months (IQR 3–22) Every 1–2 months No set target Not known All-cause mortality BNP group: therapy intensified if NT-BNP was higher by > 30% from previous clinic visit
Control group: not stated in abstract
Starbrite [31] USA 2003–2005 HF clinic 4 months Week 1 and then 1, 2, 3, and 4 months Individual BNP at discharge Individual congestion score Composite of 90-day survival and hospital-free survival BNP group: therapy intensified if BNP levels were 2 times greater than or less than the target BNP
Control group: therapy intensified to achieve target congestion score
Upstep [24] Sweden and Norway 2006–2009 HF clinic ≥ 12 months Weeks 2, 6, 10, 16, 24, 36, 48, and then every 6 months < 75 years: BNP level < 150 pg/ml
≥ 75 years: BNP level < 300 pg/ml
Clinical assessment Composite of all-cause mortality, hospitalisation and worsening HF BNP group: therapy intensified according to stepwise algorithm to achieve maximally tolerated or guideline recommended target doses
Control group: therapy intensified at clinician discretion
Studies that provided aggregate data [33]
Christchurch Pilot [29] New Zealand 1998–1999 HF clinic 9.5 months Every 3 months unless treatment targets not met NT-proBNP level < 1700 pg/ml Framingham HF score of < 2 Total cardiovascular events (mortality, hospital admission, new HF-related outpatient episode) BNP group: therapy intensified according to stepwise algorithm to achieve target NT-BNP
Control group: therapy intensified according to stepwise algorithm to achieve target HF score
Time-CHF*[26, 33] Switzerland and Germany 2003–2006 HF clinic 18 months 1, 3, 6, 12, and 18 months NT-proBNP less than 2× upper limit of normal: (< 400 pg/ml for patients < 75 yrs.; < 800 pg/ml for patients > = 75 years) NYHA ≤II Hospital-free survival BNP group: therapy intensified according to stepwise algorithm to achieve target NT-BNP
Control group: therapy intensified according to stepwise algorithm to achieve NYHA ≤II
Berger [21] Austria 2003–2004 HF clinic 15 months 2 weekly, then 1, 3, 6, and 12 months NT-proBNP < 2200 pg/L Clinical assessment Composite of all-cause mortality and HF re-hospitalisation BNP group: therapy intensified according to set protocol to maintain target NT-BNP
Control group: therapy intensified at clinician discretion
Prima [22] Netherlands 2004–2007 HF clinic 24 months 2 weeks, 1 month, then 3 monthly for 2 years Individual NT-proBNP level (lowest level at discharge or at 2 weeks follow-up) Clinical assessment Survival and hospital-free survival BNP group: therapy intensified according to clinical guidelines to maintain target NT-BNP
Control group: therapy intensified at clinician discretion
Signal-HF [25] Sweden 2006–2009 Primary care 9 months 1, 3, 6, and 9 months Individual NT-proBNP level (reduction of 50% from baseline) Clinical assessment Composite of survival, hospital-free survival and symptoms score BNP group: stepwise algorithm to increase therapy to achieve target NT-BNP
Control group: therapy intensified at clinician discretion
Battlescarred [28] New Zealand 2001–2006 HF clinic 3 years 2 weekly until treatment target met then 3 monthly NT-proBNP < 1300 pg/ml Framingham HF score of < 2 All-cause mortality BNP group: therapy intensified according to stepwise algorithm to achieve target NT-BNP and congestion score < 2
Control group: therapy intensified to achieve target congestion score < 2
Stars-BNP [23] France Not stated HF clinic 15 months Months 1, 2, and 3, and then 3 monthly thereafter BNP level < 100 pg/ml Clinical assessment Composite of HF mortality or HF hospitalisation BNP group: therapy intensified according to clinical guidelines to maintain target NT-BNP
Control group: therapy intensified at clinician discretion
Protect [30] USA 2006–2010 HF clinic At least 6 months As required to meet treatment target and then 3 monthly (for max 12 months) NT-proBNP ≤ 1000 pg/ml Clinical assessment Composite of worsening HF, HF hospitalisation and cardiovascular events BNP group: therapy intensified according to clinical guidelines to maintain target NT-BNP
Control group: therapy intensified at clinician discretion
Guide-IT [11] USA 2013–2016 HF clinic 15 months Initial visits at 2 and 6 weeks and then every 3 months. A follow-up visit 2 weeks after any therapy adjustment NT-proBNP < 1000 pg/ml Clinical assessment Composite of cardiovascular death and HF hospitalisation BNP group: therapy intensified at clinician discretion but in line with clinical guidelines to achieve target NT-BNP
Control group: therapy intensified at clinician discretion but in line with clinical guidelines
Eligible studies that did not provide IPD or aggregate data
Karavidas [45]
Published as abstract only
Greece Not stated Not stated 12 months Not stated Not stated but likely no set target Clinical assessment Not clear. Composite of all-cause mortality cardiovascular hospitalisation? Not stated
Home [46]
Clinical trial registration only
Ireland, UK, Australia and Canada 2011–2014 Not stated 6 months 1, 3, and 6 months Not stated but likely no set target Not stated Average number of ‘hard’ events per subject (HF mortality, hospitalisation for HF, unplanned outpatient episodes for decompensated HF (including change in diuretic therapy) BNP group: therapy intensified at clinician discretion using BNP information
Control group: As above but without the BNP information
Optima [47]
Published as poster only
Czech Republic Not stated Not stated Not stated Not stated Not stated but likely a BNP lowering strategy Clinical assessment Composite of cardiovascular mortality, HF hospitalisation and outpatient episodes of worsening HF requiring an increase in diuretic by at least 50% BNP group: therapy intensified to ‘normalise’ plasma BNP levels.
Control group: therapy intensified at clinician discretion according to guidelines.
Koshkina et al. [48]
Published as abstract only
Russian Federation Not stated HF clinic Mean (SD) 10 ± 2.5 months Not stated NT-proBNP < 1000 pg/ml or at least 50% of the initial Clinical assessment Total cardiovascular events Not stated
Ex Improve CHF [49]
Study ongoing
Canada 2007–ongoing HF clinic Minimum 12 months Not stated No set target Clinical assessment Composite of all-cause mortality and HF hospitalisation BNP group: therapy intensified at clinician discretion using BNP information
Control group: As above but without the BNP information
  1. *Time-CHF reported results separately for patients with heart failure with reduced ejection fraction (HFrEF) [26] and patients with heart failure with preserved ejection fraction (HFpEF) [33]