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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]