Title: A Systematic Review of BNP and NT-proBNP in the Management of Heart Failure:
Overview and Methods
Journal: Heart Failure
Authors: Mark Oremus, Robert McKelvie, Andrew Don-Wauchope, Pasqualina L. Santaguida,
Usman Ali, Cynthia Balion, Stephen Hill, Ronald Booth, Judy A. Brown, Amy Bustamam,
Nazmul Sohel, and Parminder Raina
Corresponding Author and Contact Requests:
Parminder Raina, PhD
Department of Clinical Epidemiology and Biostatistics
McMaster University
1280 Main Street West
MIP Suite 309A
Hamilton, Ontario
Canada L8S 4K1
Email: praina@mcmaster.ca
Tel: 905-525-9140 x22197
Table AF2-1: Inclusion and Exclusion Criteria
Population
Intervention/Prognostic Factors
KQ1 Presentation with HF
Measures of BNP/NTsymptoms.
proBNP at admission
Exclusion: Participants
or discharge or
≤18 years of age,
measure of change in
presenting with already BNP/NT-proBNP
diagnosed acute HF or
between admission
known exacerbation of
and discharge.
stable chronic HF,
comorbid conditions
impacting BNP results
(e.g., heart transplant,
obesity, hypertrophic
cardiomyopathy,
valvular lesions).
KQ2 Presentation with HF
Measures of BNP/NTsymptoms.
proBNP at admission
Exclusion: Participants
or discharge or
≤18 years of age,
measure of change in
presenting with already BNP/NT-proBNP
diagnosed acute HF or
between admission
known exacerbation of
and discharge.
stable chronic HF,
comorbid conditions
impacting BNP results
(e.g., heart transplant,
obesity, hypertrophic
cardiomyopathy,
valvular lesions).
Comparators
Outcomes
Timing of Follow-up
Setting
Any method of
diagnosing HF that
does not use BNP or
NT-proBNP.
Test performance
characteristics (i.e.,
sensitivity, specificity,
positive and negative
LRs, diagnostic odds
ratio [DOR], area under
the ROC curve),
cutpoints, effect of
various determinants
(e.g., age, sex, and
comorbidities) on the
test performance,
adverse effects related
to test administration.
Test performance
characteristics (i.e.,
sensitivity, specificity,
positive and negative
LRs, diagnostic odds
ratio [DOR], area under
the ROC curve),
cutpoints, effect of
various determinants
(e.g., age, sex, and
comorbidities) on the
test performance,
adverse effects related
to test administration.
Any length of follow-up
acceptable.
Emergency or urgent
care departments only.
Any length of follow-up
acceptable.
Primary care settings
only.
Any method of
diagnosing HF that
does not use BNP or
NT-proBNP.
Table AF2-1: Inclusion and Exclusion Criteria
Population
Intervention/Prognostic Factors
KQ3 Any HF (with or without BNP or NT-proBNP
any comorbidity).
measured at
Exclusion: Risk of CAD admission, discharge,
or with CAD, risk of HF or change between
without documented
admission and
HF (e.g., diabetes and
discharge.
renal failure).
Exclusions: Univariate
analysis only.
KQ4
Any HF (with or without
any comorbidity).
Exclusion: Risk of CAD
or with CAD, risk of HF
without documented
HF (e.g., diabetes and
renal failure).
BNP or NT-proBNP
measured at
admission, discharge,
or change between
admission and
discharge; any other
prognostic factors
compared with BNP or
NT-proBNP using the
appropriate statistical
metrics.*
Exclusion: Studies that
used simple extensions
of AUC without
accounting for time or
events, studies that
used only the log rank
test.
Comparators
Outcomes
Timing of Follow-up
Setting
NYHA functional
classification of stages
of HF, ejection fraction,
degree of hyponatremia, decreasing
peak exercise oxygen
uptake, decreasing
hematocrit, widened
QRS interval on 12lead electrocardiogram,
chronic hypotension,
resting tachycardia,
renal insufficiency,
intolerance to
conventional therapy,
refractory volume
overload, or risk
prediction scores (e.g.,
Seattle HF Model).
NYHA functional
classification of stages
of HF, ejection fraction,
degree of hyponatremia, decreasing
peak exercise oxygen
uptake, decreasing
hematocrit, widened
QRS interval on 12lead electrocardiogram,
chronic hypotension,
resting tachycardia,
renal insufficiency,
intolerance to
conventional therapy,
refractory volume
overload, or risk
prediction scores (e.g.,
Seattle HF Model).
Mortality including allcause and HF,
morbidity including
hospitalization
(including HF, allcause, planned, and
unplanned), change in
NYHA class, quality of
life.
Any length of follow-up
acceptable.
Acute care hospitals,
outpatient
clinics/ambulatory care
settings, hospital
settings, or family
practice settings.
Mortality including allcause and HF,
morbidity including
hospitalization
(including HF, allcause, planned, and
unplanned), change in
NYHA class, quality of
life.
Any length of follow-up
acceptable.
Acute care hospitals,
outpatient
clinics/ambulatory care
settings, hospital
settings, or family
practice settings.
Table AF2-1: Inclusion and Exclusion Criteria
Population
Intervention/Prognostic Factors
KQ5 No disease (a
BNP or NT-proBNP
nonselected or general measured at
population).
admission, discharge,
Exclusion: Use of any
or change between
specific disease to
admission and
include or exclude
discharge.
participants from study.
KQ6
Receiving treatment for
chronic HF.
Exclusion: Persons
admitted with known
HF or acute HF.
KQ7
Adults with or without
HF.
Any medical therapy
based on BNP or NTproBNP concentration.
Comparators
Outcomes
Timing of Follow-up
Setting
Any predictive scoring
system (e.g.,
Framingham).
Mortality including allcause and HF,
morbidity including
hospitalization
(including HF, allcause, planned, and
unplanned), change in
NYHA class, quality of
life.
Mortality including allcause and HF,
morbidity including
hospitalization
(including HF, allcause, planned, and
unplanned), change in
NYHA class, quality of
life.
Calculation of
biological variation.
Any length of follow-up
acceptable.
Primary care settings
only.
Any length of follow-up
acceptable.
Any setting acceptable.
Medical therapy based
on usual care for HF
patients (no BNP or
NT-proBNP
concentration).
Multiple measurements N/A
Any length of follow-up
Any setting acceptable.
of BNP or NT-proBNP
acceptable.
in study participants.
*Includes likelihood-based measures, such as LR and LR chi-square (global chi-square and incremental chi-square), indices of calibration, such as the HosmerLemeshow statistic (goodness-of-fit test), discrimination statistics, such as c-index or c-statistics, and measures of risk reclassification, such as Net
Reclassification Improvement and Integrated Discrimination Improvement (IDI).
Notes: For all KQs, study participants had to be at least 18 years of age and an FDA-approved assay designed specifically for BNP or NT-proBNP had to be used
to measure the peptide. No exclusions unless otherwise stated in table cells.
Abbreviations: AUC = area under the curve; BNP = brain natriuretic peptide; CAD = coronary artery disease; DOR = diagnostic odds ratio; FDA = Food and Drug
Administration; HF = heart failure; KQ = key question; LR = likelihood ratio; N/A = not applicable; NT-proBNP = N-terminal prohormone of brain natriuretic peptide;
NYHA = New York Heart Association.