Accuracy of point-of-care natriuretic peptide testing in

Confidential: For Review Only

Accuracy of point-of-care natriuretic peptide testing in the

diagnosis of chronic heart failure in ambulatory care: a systematic review and meta-analysis

Journal: BMJ

Manuscript ID BMJ.2017.042797

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 11-Dec-2017

Complete List of Authors: Taylor, Kathryn; University of Oxford, Nuffield Department of Primary Care Health Sciences Verbakel, Jan; University of Oxford, Nuffield Department of Primary Care Health Sciences; KU Leuven, Department of Development and Regeneration Feakins, Benjamin; University of Oxford, Nuffield Department of Primary Care Health Sciences Price, Christopher; University of Oxford, Nuffield Department of Primary Care Health Sciences Perera, Rafael; University of Oxford, Nuffield Department of Primary Care Health Sciences Bankhead, Clare; University of Oxford, Nuffield Department of Primary

Care Health Sciences Pluddemann, Annette ; University of Oxford , Nuffield Dept. of Primary Care Health Sciences,

Keywords: natriuretic peptide, point of care, N terminal pro-brain natriuretic peptide, B type natriuretic peptide, chronic heart failure

https://mc.manuscriptcentral.com/bmj

BMJ


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Accuracy of point-of-care natriuretic peptide testing in the diagnosis of chronic heart failure in

ambulatory care: a systematic review and meta-analysis

Kathryn S Taylor, Jan Y Verbakel, Benjamin G Feakins, Christopher P Price, Rafael Perera, Clare

Bankhead, Annette Plüddemann

Nuffield Department of Primary Care Health Sciences, University of Oxford, OX2 6GG, United

Kingdom

Kathryn S Taylor, Medical Statistician

Jan Y Verbakel, Clinical Lecturer

Benjamin G Feakins, Medical Statistician

Christopher P Price, Honorary Senior Fellow

Rafael Perera, Professor of Medical Statistics

Clare Bankhead, Associate Professor

Annette Plüddemann, Senior Researcher

Correspondence to: A. Plüddemann, [email protected]

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ABSTRACT

Objectives: To assess the diagnostic accuracy of point-of-care natriuretic peptide tests in patients

with suspected chronic heart failure, with a particular focus on the ambulatory care setting.

Design: Systematic review and diagnostic meta-analysis.

Data sources: Ovid MEDLINE, the Cochrane Register of Controlled Trials, the Cochrane Database of

Systematic Reviews, Database of Abstracts of Reviews of Effects, Embase, Health Technology

Assessment, Science Citation Index and Conference Proceedings Citation Index until 31 March 2017.

Study selection: Eligible studies evaluated point-of-care natriuretic peptide testing (B type

natriuretic peptide [BNP] or N terminal pro-brain natriuretic peptide [NT-proBNP]) against any

relevant reference standard, including laboratory-based tests, echocardiography, clinical

examination or combinations of these, in humans. Studies were excluded if insufficient data was

reported to construct 2x2 tables. No language restrictions were applied.

Results: 44 publications of 41 individual studies met our inclusion criteria and 42 publications of 39

studies were included in our analysis. Of these 39 studies, 31 evaluated BNP point-of-care testing,

and 9 evaluated NT-pro BNP testing. Five studies were undertaken in primary care. At thresholds

>100 pg/mL sensitivity of BNP, measured with the Biosite Triage, was generally high (>0.75).

However, at lower thresholds of <100 pg/mL, sensitivity ranged from 0.46 to 0.97, and specificity

ranged from 0.31 to 0.98. Studies reporting the accuracy of NT-proBNP testing, reported sensitivity

and specificity ranging from 0.59-1.00 and 0.42-0.90, respectively, with specificity increasing at

higher thresholds (≥300 pg/mL). There was no statistically significant difference in diagnostic

accuracy between point-of-care BNP and NT-proBNP tests.

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Conclusions: Given the general lack of studies performed in primary care, the paucity of NT-pro BNP

data and potential methodological limitations in these studies, there is a need for large-scale trials in

primary care, assessing the role of point-of-care natriuretic peptide testing to improve care of

patients with suspected or chronic heart failure.

INTRODUCTION

An estimated 800,000 people in the UK currently have heart failure with over 250,000 new cases of

heart failure in the UK every year. Incidence increases with age and is highest in adults over 75 years

of age. The ageing population and improved survival of individuals with ischaemic heart disease are

likely to lead to a continuing rise in the prevalence of heart failure. Overall a general practitioner

(GP) with a patient population of 2000 will care for approximately 40-50 patients with heart failure

and see 2-3 new cases each year (1).

Since heart failure may be reversible with appropriate treatment in the early stages of disease, it is

important that heart failure is diagnosed as quickly as possible. However, considering its low

prevalence, GPs are unlikely to have sufficient experience to identify more subtle presentations of

heart failure. Although heart failure is frequently diagnosed by GPs, it is only confirmed by

echocardiography in approximately one third of cases (2). Whilst echocardiography is a sensitive test

when performed by cardiologists (sensitivity = 89%; 95% CI 77%–95%) (3), its sensitivity is much

lower (53%) when carried out by GPs (4). Therefore, recent National Institute for Health and Clinical

Excellence (NICE) and European Society for Cardiology (ESC) guidelines on the initial diagnosis of

chronic heart failure (CHF) and referral for echocardiography recommend the use of B-type

natriuretic peptide (BNP) in combination with clinical assessment (5, 6).

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BNP is a protein, produced from heart muscle cells as a pro-hormone (proBNP) and released into the

cardiovascular system in response to ventricular dilation and pressure overload (7). The pro-

hormone is split by a protease and secreted as the physiologically active C-terminal fragment (BNP)

and the inactive N-terminal fragment (NT-proBNP), which has a longer half-life than that of BNP.

There is no clear consensus about the appropriate BNP threshold for diagnosing CHF. The 2016 ESC

guidelines recommend an upper limit of normal in the non-acute setting for BNP of 35 pg/mL and for

NT-proBNP of 125 pg/mL to rule out heart failure, while in the acute setting higher values should be

used (BNP <100pg/mL, NT-proBNP <300 pg/mL) (6). In contrast, NICE in England suggests a BNP

threshold of 100 pg/mL and NT-proBNP threshold of 400 pg/mL for referral of patients with

suspected heart failure.

Although several hospital laboratories carry out BNP testing, few return results within a day. Point-

of-care (POC) BNP testing can considerably reduce turnaround time and could lead to quicker

workup of dyspnoea by GPs, more timely referral, earlier initial treatment and less uncertainty and

anxiety for patients. There are several POC natriuretic peptide testing devices currently on the

market, which either measure BNP or NT-proBNP.

Systematic reviews have been compiled on the role and accuracy of BNP and NT-proBNP in the

diagnosis of CHF (3, 8-11), however none have focussed specifically on the accuracy of POC testing,

particularly in the ambulatory care setting. Therefore, this review assessed the diagnostic accuracy

of POC natriuretic peptide tests in patients with suspected or confirmed CHF, with a particular focus

on the ambulatory care setting.

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METHODS

Search strategy

Our search strategy (See Appendix 1 in the supplementary material for the protocol) was based on a

combination of subject headings and terms relating to heart failure, the natriuretic peptides (BNP

and NT-proBNP), terms relating to POC testing (including point-of-care, rapid, same time,

immediate, bed-side) and the known POC index devices (Biosite Triage, Cardiac Reader, Abbott

iSTAT, RAMP, Cobas h 232, Alere Heart Check). We searched the following electronic databases from

inception until 31 March 2017: Ovid MEDLINE (Appendix 2), the Cochrane Register of Controlled

Trials, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects,

Embase, Health Technology Assessment, Science Citation Index and Conference Proceedings Citation

Index. We did not use filters for diagnostic studies in order to maximise the sensitivity of the search

strategy. For unpublished trials, we searched the ClinicalTrials.gov and WHO ICTRP trials registers.

We also used the “related articles” feature in Pubmed and searched reference lists of included

studies to identify further publications.

Selection of included studies

Titles and abstracts of the search results were screened independently by two reviewers and

disagreements were resolved by referral to a third reviewer. Studies of POC BNP and POC NT-

proBNP were included that reported diagnostic accuracy as an outcome, comparing the index test

with any relevant reference standard, including laboratory-based tests, echocardiography, clinical

examination or combinations of these. Case-control and cohort trial study designs were included,

both prospective and retrospective. Although the focus of the review was the ambulatory care

setting, studies with participants with suspected or confirmed CHF in all settings were included, as

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considerations as to what constitutes ’ambulatory care’ can vary between countries and we wanted

to include all studies with relevant populations. We defined ambulatory care as primary, outpatient

or emergency care, reflecting all settings where ambulatory patients with heart failure would

present. No restrictions were made regarding study population numbers and study quality was not

an exclusion criterion. No language restrictions were applied, and studies in languages other than

English were translated. Letters, narrative reviews and other non-primary sources were excluded.

Studies were also excluded if they did not provide sufficient data to allow for the construction of a

2x2 table, they were based on non-humans or non-human samples, or if they presented duplicate

data. If two publications had overlapping populations, they were counted as a single study but only

publications reporting data at new thresholds were included.

Data extraction and management

All data were extracted independently by two reviewers (KT, CB, JV, AP; in pairs) using a pre-defined

data extraction sheet (Appendix 3), cross-checked and disagreements were resolved by discussion or

referral to a third reviewer. If more than one publication with overlapping populations reported

diagnostic accuracy data at the same threshold, data was only extracted from the publication with

the larger population.

Assessment of methodological quality

The quality of included studies was assessed independently by two reviewers (KT, CB, AP; in pairs)

and cross-checked by a third reviewer (JV), using QUADAS-2 (12).

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Data analysis and data synthesis

We extracted binary diagnostic accuracy data and constructed 2x2 tables from all included studies

and all thresholds. To obtain an overview of test accuracy, we plotted sensitivity and specificity

estimates in ROC space for all thresholds for each natriuretic peptide. In these plots we split the data

by the index test and study design. Study design was defined as either case-control or cross-

sectional/cohort. Case-control studies included those described as such and also studies with

selected healthy and unhealthy populations. As results of case-control studies are known to be

susceptible to bias, these studies were excluded from further analysis, which involved splitting by

population (prevalence of CHF) and setting. A study population was defined as having either high (≥

50%) or low (<50%) prevalence of CHF. Study setting was grouped as (a) primary, outpatient or

emergency care; (b) mixed outpatient and inpatient; or (c) inpatient only. We considered primary,

outpatient and emergency care collectively as these correspond best to the ambulatory care setting.

For each natriuretic peptide, we produced paired forest plots with corresponding 95% confidence

intervals, and grouped data into threshold categories as follows: ‘less than 100 pg/mL’, ‘between

100 and 200 pg/mL’, and ‘at or above 200 pg/mL’ for BNP and ‘less than 125 pg/mL’, ‘between 125

and 300 pg/mL’, and ‘at or above 300 pg/mL’ for NT pro-BNP.

Receiver operating characteristic (ROC) graphs and forest plots were plotted and constructed using

R version 3.4.2 (13) and RevMan version 5.3 (14).

To generate pooled estimates of sensitivity and specificity, we applied bivariate meta-analysis

methods (15). Hierarchical summary ROC meta-analysis methods were used to produce summary

ROC curves with corresponding 95% confidence regions and prediction regions for cross-sectional

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and cohort studies collectively for BNP and NT-proBNP, respectively. Where studies reported data at

multiple thresholds, as this was overlapping data, we selected only one threshold per study,

choosing the lowest threshold, as this was consistent with our focus, on ambulatory rather than

inpatient care. We conducted these analyses using the xtmelogit command in STATA SE version 14.2

(16) and parameters were fed directly into RevMan to produce Cochrane-standardised output.

We analysed data from studies with laboratory-based reference tests separately to data from

studies with clinical assessment-based reference tests and data based on populations with

suspected CHF separately from data based on populations with confirmed CHF.

To assess between-study heterogeneity we used ROC and forest plots. We also assessed between-

study heterogeneity based on the prevalence of CHF by adding prevalence as a covariate to the

bivariate model and applying a Likelihood Ratio Test (16).

As sensitivity analysis we evaluated the effect of removing outliers and the use of a different pooling

method. This method was an extension of the bivariate method of Dukic and Gatsonis (17), which

permits the inclusion of multiple threshold values per study. This method was implemented in R (13)

and point-wise confidence intervals for the sensitivity and specificity, at given thresholds, were

calculated using simulation. The selected thresholds included 100 pg/mL for Biosite Triage (BNP) and

300 pg/mL for the Cardiac Reader (NT Pro-BNP). We produced summary statistics of the thresholds

used, to establish the adherence to those recommended in the ESC and NICE guidelines.

Funnel plots, used to detect publication bias in reviews of RCTs, have been shown to be misleading

for diagnostic test accuracy reviews and alternative methods have poor power (18-20) so we did not

assess reporting bias in this review.

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RESULTS

The search results and the inclusion and exclusion of studies are summarised in Figure 1. The search

identified 2604 references through database and registry searches and an additional 17 publications

were identified by checking reference lists of retrieved reviews and using the “Related articles”

function in Pubmed. After removing duplicates 878 records were screened by title and abstract. Of

these and the references identified through reference list searches, the full text of 116 records was

reviewed, resulting in 44 publications of 41 individual studies (full references are given in Appendix

4) that met our inclusion criteria.

Five of these studies were undertaken in a primary care setting (2 studies assessing BNP and 3

assessing NT-proBNP) (21-25). Three studies provided data for confirmed CHF cases (26-28). Eight

studies had a case-control design and of the 33 cross-sectional/cohort studies, 15 had populations

who were presenting principally with dyspnoea, 6 had populations with several signs and symptoms

of CHF, 5 had populations of echocardiography referrals, two had populations with cardiovascular

risk factors, two had populations of stable CHF referred to cardiac rehabilitation, one had acute

coronary syndrome or worsening HF, one had a population with acute coronary embolism and one

study had a non-cardiac population on mechanical ventilation. (Table S1) The study setting for most

of the included studies was secondary care, with the majority performed in the emergency

department (Table 1). The prevalence of CHF in the studies performed in primary care ranged from

19-44%. Of the studies performed in the emergency care setting, 21 reported a prevalence of CHF

below 50%. The reference test in the majority of studies was clinical assessment with retrospective

review by one or more clinicians (mostly cardiologists), with some studies using echocardiography as

the reference test (Table 2).

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Table 1. Included studies: study design and populations

Reference Design No Prevalence

(%) ǁ

Setting Age** (yrs) Male (%)

Studies included in the analysis

Ajuluchukwu 2010 2 72 (42+30) 58 - high Inpatients. Controls were

staff and escorts. Nigeria.

> 14 not stated

Alehagen 2008 1 440 35 - low CCU admissions,

cardiology ward

admissions and

cardiology outpatients.

Sweden.

65 (82) 57

Alibay 2005 1 160 38 - low Emergency department.

France.

80.1 (13.5) 48

Blondé-Cynober

2011

1 64) 41 - low Inpatients. France. 84.3 (7.4) 31

Chenevier-

Gobeaux 2010

1 378 30 - low Emergency department.

France.

78 (12) 50

Dao 2001 1 250 39 - low Emergency and urgent

care departments. US.

63 (0.86) 94

De Vecchis 2016 1 111‡‡ 44 - low Outpatients. Italy. 58 (47-65) 65

Dokanish 2004 1 122 57 - high Inpatients. US. 56 (13) 51

Fischer 2001 3 145 (95+50) 29 - low Unclear. Germany. Cardiac

61.9 (20-60) ††

Healthy

range 19-86

Cardiac

67.4

Healthy

60

Fuat 2006 1 297 38 - low One-stop diagnostic

clinics in 2 hospitals and

general practices.

England.

73.8 (34-94) †† 37

Gorissen 2007 1 80 50 - low Emergency department.

The Netherlands.

74 (10) 55

Gruson 2009 1 97 20 - low Emergency department.

Belgium.

71 (30-95) §§ 57

Jungbauer 2012§ 2 222 (151+71) 16, 24,22

or 38¶

- low

Outpatients. Controls

were healthy hospital

employees. Germany.

Confirmed

62.9 (12.1)

Healthy

39.7 (15.1)

Confirmed

71.5

Healthy

40.8

Knudsen 2004 1 155 (48) 48 - low Emergency department.

Norway.

Male

74 (66-79)

Female

78 (71-84)

44.5

San Diego Vets†

Krishnaswamy

2001

Lubien 2002

1

1

400

294

63 - high

40 - low

Outpatients and

inpatients. US. Secondary

care, outpatients.US.

65.7 (12.2)

64.5 (5.5)

96

Lainchbury 2003 1 205 34 - low Emergency department.

New Zealand.

70 (14) 49

Lee Lewandrawski

2007

3 606

(271+208+127)

91 - high

(of 271

confirmed)

Hospitals and medical

centre. US.

Confirmed

63.9 (19-95) ††

Confirmed

63

Logeart 2002 1 163 71 - high Emergency department.

France.

67.4 (14.8) 67

Maisel 2001 1 200 48 - low Inpatients and

outpatients. US.

65.3 (0.9) 95

BNP study*

Maisel 2002

Maisel 2003

Pahle 2009§

1

1

1

1586

1586

1583

(740+843)

47 - low

47 - low

47 - low

Emergency department



64 (17)

64 (17)

Elevated BP

67 (54-78)

56

56

Elevated BP

51.8

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Normal BP

64 (49-76)

Normal BP

60

Mak 2004 1 100 16 - low Inpatients and

outpatients. US.

64 (13) 97

Monfort 2015 1 163‡‡ 69 - high

(class II-IV)

Cardiac rehabilitation.

France.

Median 58 81

Prontera 2005 3 284 (214+91)

57 - high

(of 213)

Unclear. Italy. Confirmed

62 (13)

Healthy

43.2 (13.4)

Confirmed

77

Healthy

44

Prosen 2011 1 218 59 - high Pre-hospital emergency.

Slovenia.

63.3 (16.1) 71

Ro 2011 1 250 43 - low Emergency dept. US. 70.7 (13.8) 57.8

Shao 2005 1 103 61 - high Unclear. China. Not stated Not stated

Storti 2004 3 296 (202+94) 59 - high

(of 227)

Cardiac inpatients. Italy. Cardiac

59.3 (20.5)

Confirmed

Not stated

Healthy

43.5 (14)

Cardiac

70.3

Confirmed

Not stated

Healthy

39.4

Su 2015 1 268

56 - high

(of 203)

Emergency department.

China

All

74.1 (7.9)

All

56.3

Tang 2005 2 348

(241 +107)

69 - high Secondary care. US. Confirmed

M 69.4, F 69.1

Normal

M 44.0, F 44.9

Not stated

Taylor 2017 1 304 34 - low Primary care. England. 73.9 (8.8) 40.8

Tomonaga 2011 4 369

(218 in POCT

group)

44 - low

(of 70 from

POCT

group)

Primary care.

Switzerland.

POCT group

65 (16)

POCT group

57.9

Verdu 2012 1 220 24 - low Primary care. Spain. 73.2 (19.2) 34.5

Villacorta 2002 1 70

51 - high Emergency department.

Brazil.

72.4 (15.9) 47

Watson 2016 1 1368

(966 diabetes,

402 non-

diabetes)

19 - low Primary care. Ireland. Diabetes

65.7 (58.6-

71.6)

Non-diabetes

67.9 (59.5-

74.4)

Diabetes

64.9

Non-diab.

47.0

Weekes 2016 1 116 22 - low Emergency dept., US. 59 (26) 51

Wei 2005 1 135 45 - low Outpatients. China. 67.8 (11.9) 63

Wieczorek 2002 2 1050

(409+641)

39 - low Inpatients and

outpatients. US.

Not stated Not stated

Zapata 2014 1 86 58 - high Inpatients. Spain. 63.8 (12.7) 66.3

Zhao 2008 1 195 69 - high Inpatients. China. 72.1 (8.3) 51.8

Eligible studies that are not included in the analysis

Morrison 2002 1 321 42 - low Emergency dept. US. Not stated Not stated

Vanderheyden

2006

1 72 56 - high Inpatients. Belgium. 65 (12) 71

* Breathing Not Properly (BNP) study; † San Diego Veteran study; ‡ Evaluated diagnos[c accuracy using 4 different

definitions of heart failure; §Reported baseline characteristics in groups based on BP status and hypertension history –

numbers given refer to patients with BP status recorded; ǁ As defined by the reference standard, which if based on clinical

assessment, could be using a single test or multiple tests; ¶ Defined by NYHA III/IV, (LVEF<40%, fluid retention and AHA C/D

respectively; **mean (SD) or median (IQR) unless otherwise stated; †† mean (range); ‡‡- All with confirmed heart failure.

Design codes: 1 - cohort or cross-sectional; 2 – case-control; 3- cohort or cross-sectional but akin to a case control study; 4

– cluster randomised controlled trial. Numbers of patients and numbers with heart failure only refer to the patients

included in the analyses of diagnostic accuracy.

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Table 2. Included studies: Point-of-care tests and reference tests

Reference Point-of-care tests Thresholds (pg/mL) Reference tests

Studies included in the analysis

Ajuluhukaru 2010 Cardiac Reader (NT-Pro BNP) ‡ 95,100,105,110,113,115,200,122,124,

125,126,127, 130, 135,140,145

Clinical evaluation and echocardiography. Evaluation of cases

and controls by the study assistant, a senior registrar or one of

the investigators

Alehagen 2008 Cardiac Reader (NT-Pro BNP) ‡ <60, 60-3000,>3000 Roche Elecsys (NT-Pro BNP)

Alibay 2005 Biosite Triage (BNP)1 50,100,150,200 Retrospective review by two senior cardiologists

Blondé-Cynober 2011 Biosite Triage (BNP) 18,100, 129,400,635 Retrospective review by a cardiologist and a geriatrician

Chenevier-Gobeaux

2010

Biosite Triage (BNP)1 100 Retrospective review by two senior emergency physicians.

Dao 2001 Biosite Triage (BNP) 80,100,115,120,150 Retrospective review by two cardiologists

De Vecchis 2016 Alere (BNP)1 412 NYHA Classification

Dokanish 2004 Biosite Triage (BNP) 250 Retrospective review by one cardiologist

Fischer 2001 Biosite Triage (BNP)1 130 Echocardiography

Fuat 2006 Biosite Triage (BNP) 40,100 Echocardiography

Gorissen 2007 Biosite Triage (BNP)1 78,225,260,309 Retrospective review by a cardiologist and a pulmonologist

Gruson 2009 Biosite SOB panel (BNP) 100 Retrospective review

Jungbauer 2012 Cardiac Reader (NT-Pro BNP) ‡

Biosite Triage (BNP)

410

117

Based on clinical signs, physical exam and echocardiography.

Knudsen 2004 Biosite Triage (BNP) 50, 100,150,200 Retrospective review by two cardiologists

San Diego Veterans†

Krishnaswamy 2001

Lubien 2002

Biosite Triage (BNP

Biosite Triage (BNP))

49,62,75,110,160,345

additional 17.5,62,92,130

Retrospective review of echo, admission treatment for heart

failure and visits to the ED for health failure

Echocardiography

Lainchbury 2003 Biosite Triage (BNP)1 69,104,208,277,346 Retrospective review by two cardiologists with third cardiologist

as adjudicator

Lee Lewandrawski 2007 RAMP (NT-Pro BNP) 125 (<75 years), 450 (≥75 years) Roche Elecsys (NT-Pro BNP)

Logeart 2002 Biosite Triage (BNP)2 80,100,150,200,250,300,400 Retrospective review by two cardiologists and one pneumologist.

Maisel 2001 Biosite Triage (BNP) 38.5,46,55,65,75 Echocardiography

BNP study*

Maisel 2002


50,80,100,125,150

Retrospective review by two cardiologists

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Maisel 2003

Pahle 2009



additional 200,300,400

additional 120,140,160,180

Retrospective review

Retrospective review

Mak 2004 Biosite Triage (BNP) 90,173,279,402 Echocardiography

Monfort 2015 Alere (BNP)1 159 NYHA Classification

Prontera 2005 Biosite Triage (BNP) 5.1, 29 Retrospective review

Prosen 2011 Cardiac Reader (NT-Pro BNP) ‡ 1000 Retrospective review by cardiologists and/or intensive care

physicians

Ro 2011 Biosite Triage (BNP)

Abbott iStat (BNP)

100

100

Siemens Adviar Centaur (BNP)

Based on discharge diagnosis, echo (when available), and the

assessment of a consulting cardiologist

Shao 2005 Biosite Triage (BNP) 100 Echocardiography and cardiac catheterization

Storti 2004 Biosite Triage (BNP)1 40.7 Based on clinical (presence of suggestive symptoms) and

echocardiographic evidence

Su 2015 RAMP (NT-Pro BNP) 600 Retrospective review

Tang 2005 Biosite Triage (BNP)1 52,74,100 Retrospective review

Taylor 2017 Cardiac Reader (NT-Pro BNP) ‡ 125,400 Retrospective review by expert panel

Tomonaga 2011 Cardiac Reader (NT-Pro BNP) ‡ 125 Retrospective review

Verdu 2012 Cardiac Reader (NT-Pro BNP) ‡ 125,280,400 Retrospective review by one cardiologist

Villacorta 2002 Biosite Triage (BNP) 200 Retrospective review by one cardiologist

Watson 2016 Biosite Triage (BNP) 10,15,25,30,50 Echocardiography

Weekes 2016 Abbott iStat (BNP) 90 Echocardiography

Wei 2005 Biosite Triage (BNP) 40 Retrospective review by two cardiologists

Wieczorek 2002 Biosite Triage (BNP) 100 Retrospective review by one physician

Zapata 2014 Biosite Triage (BNP)1 125,100 Echocardiography

Zhao 2008 Biosite Triage (BNP) 50,80,100,130,150 Cardiac catheterisation

Eligible studies that are not included in the analysis

Morrison 2002 Biosite Triage (BNP) 94,105,135,195,240 Retrospective review by two cardiologists

Vanderheyden 2006 Biosite Triage (BNP)1 29.3,50,100,139 Cardiac catheterisation

* Breathing Not Properly (BNP) study; † San Diego Veteran study; ‡ Roche Cardiac Reader/Cobas h232 1 Both a point-of-care test and a laboratory test were compared with the same reference test in order to indirectly compare the point-of-care test with the laboratory test. Only the point-of-

care test is listed in the table; Two point-of-care tests (Biosite Triage, to measure BNP, and Hewlett Packard Sonos 1500, to provide Doppler Echocardiography) were compared with the same

reference test in order to indirectly compare BNP with Doppler echo.

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For the index tests a variety of thresholds were employed, ranging from 5.1-412 pg/mL for BNP and

<60 to >3000 pg/mL for NT-proBNP (Table 2). Thirty-one studies reported data for BNP and 9

reported data for NT-proBNP. Among the studies quoting diagnostic accuracy statistics at unique

values of thresholds, the most common threshold for BNP was 100pg/mL (58%, 18 studies) and the

most common threshold for NT-proBNP was 125 pg/mL (44%, 4 studies). No studies reported BNP

data at 35 pg/mL and no studies reported NT-proBNP data at 300 pg/mL. Two studies (22%)

reported NT-proBNP data at 400 pg/mL.

Methodological quality of included studies

All included studies were assessed using the QUADAS-2 framework. The overall risk of bias and

applicability concerns are summarised in Figures 2 and 3. With regards to patient selection, the risk

of bias overall was generally low as studies mostly included consecutive series of patients

appropriate to the study question. However, the applicability concerns were ranked as High with

respect to the question of this systematic review, as the spectrum of patients was frequently not

those who would be representative of those in an ambulatory care population. The risk of bias

regarding the index test was mostly ranked as Unclear, generally because in most studies it was

unclear whether the threshold(s) used had been pre-specified with some using study-derived

thresholds, and whether the index test was performed blinded to the results of the reference test.

The latter also resulted in an overall ranking of Unclear with regards to applicability concerns, as it

was unclear how the POC natriuretic tests would perform if interpreted without knowledge of the

results of the reference tests, as would be the case if they were performed in ambulatory and

primary care as part of a diagnostic work-up. The risk of bias and applicability regarding the

reference standard were both assessed to be Low, as an appropriate reference standard of clinical

examination and echocardiography was employed in most studies. The domain of flow and timing

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was rated as generally low risk of bias; however, several studies were rated as unclear risk of bias in

this domain as the time interval between tests was frequently not explicitly reported.

Our analysis of the diagnostic accuracy of the peptides was based on data from 42 publications of 39

individual studies which both met our inclusion criteria and provided usable data (Figure 1).

B type natriuretic peptide

Comparisons with clinical assessment

Figure 4 provides an overview of the results from 33 publications reporting data from 30 individual

studies on the accuracy of POC BNP tests compared to clinical assessment, grouped by study design

and index test manufacturer for all thresholds. The majority of studies assessed the accuracy of the

Biosite Triage test compared to clinical assessment using a cross-sectional or cohort design (grey

symbols). Two studies were identified that reported the accuracy of the Abbott iSTAT test (red

symbols). Overall, there was considerable variation in the reported sensitivity and specificity

between studies. The values representing the lowest sensitivity arose from three studies on

inpatient and outpatient populations with a low prevalence of CHF, using BNP thresholds of above

345 pg/mL.

When reviewing the accuracy of the POC BNP test in populations with a high (grey symbols)

compared to a low prevalence (red symbols) of CHF in primary care, outpatient and emergency

settings, the results also showed considerable variation between studies and at different thresholds

(Figure S1). The studies representing the lowest sensitivity (0.36 and 0.50) employed higher

thresholds of 345 pg/mL and 402 pg/mL, respectively (29, 30).

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For cross sectional/cohort studies with low prevalence of CHF in the same settings, overall the

sensitivity of this test was generally higher and slightly less variable than the specificity across the

different studies, particularly as the threshold increased (Figure 5). Of note however, at thresholds

below 100 pg/mL several studies reported low sensitivities and specificities (below 0.8) of the test

and also variations in sensitivity and specificity did not appear to correlate with increasing threshold.

Overall at a threshold of <100 pg/mL sensitivity ranged from 0.46 (95%CI: 0.32-0.61) to 0.98 (95%CI:

0.93-1.00), and specificity ranged from 0.31 (95%CI: 0.22-0.41) to 0.98 (95%CI: 0.95-1.00). The two

studies (21, 25) performed in a primary care setting, reported sensitivity ranging from 0.46 (95%CI:

0.32-0.61) to 0.92 (95%CI: 0.81-0.98) and specificity from 0.38 (95%CI: 0.31-0.46) to 0.82 (95%CI:

0.79-0.85), at a range of thresholds below 100 pg/mL (10-50 ng/ml). The study by Watson et al (25),

which reported the lowest sensitivity, included a population with very low prevalence as the study

included patients with cardiovascular disease risk factors, not symptoms of CHF.

Considering cross-sectional/cohort studies with high prevalence of CHF in the same settings (Figure

S2) and cross-sectional/cohort studies with low prevalence of CHF in mixed inpatient and outpatient

settings (Figure S3), there were fewer studies and the variations in sensitivity and specificity

correlated with increasing threshold.

Comparisons with laboratory measurement

One study (31) compared two BNP index tests, Biosite Triage and Abbott iSTAT, with a laboratory

reference test (Siemens Advia Centaur). For the Biosite Triage comparison, they reported sensitivity

0.92 and specificity 0.86, and for the Abbott iSTAT comparison, sensitivity of 0.99 and specificity of

0.79.

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N Terminal pro-brain natriuretic peptide

Comparisons with clinical assessment

The majority of studies reported results for the Cardiac Reader NT-proBNP test compared to clinical

assessment. Figure 6 provides an overview of the results from seven individual studies reporting the

accuracy of POC NT-proBNP compared to clinical assessment, grouped by study design and index

test manufacturer for all reported thresholds. Two different index tests were evaluated; the Roche

Cardiac Reader NT-proBNP (six studies, red symbols) and RAMP NT-proBNP test (Response

Biomedical Corporation; one study, grey symbol). Three of these studies were performed in a

primary care setting (22-24). Overall sensitivity and specificity were somewhat less variable than

those reported for BNP, with the exception of one study (22) where the reported sensitivity and

specificity were lower than those reported in other studies. This study was performed in a primary

care population, however a risk of bias was identified with regards to the reference test and patients

were pre-selected using a clinical decision rule.

Considering the studies with cross-sectional/cohort design, the paired sensitivity and specificity plots

for the Cardiac Reader test show high sensitivity (above 0.8) with low to moderate specificity at a

threshold of 125 pg/mL (ranging from 0.42-0.72) and increased specificity at higher thresholds

(Figure 7). For thresholds above 300 pg/mL, sensitivity ranged between 0.59 (95%CI 0.49-0.68) and

0.92(95%CI 0.86-0.96), while specificity ranged from 0.79 (95%CI: 0.73-0.84) to 0.90 (95%CI: 0.84-

0.94). These studies were all performed in a primary care setting.

Sensitivity and specificities were consistently high in the case control studies (Figure S4).

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Comparisons with laboratory measurement

Two studies (27, 32) compared NT-Pro BNP index tests with laboratory reference tests. Alehagen

2006 (32) reported diagnostic accuracy statistics for the Cardiac Reader test compared with the

Roche Elecsys 2010 laboratory test, at thresholds <60, 60-300 and >3000 pg/mL. They reported

sensitivities of 0.82-0.97 and specificities of 0.80-0.99. Lee-Lewandrowski 2007 (27) reported

diagnostic accuracy statistics of the RAMP (Response Biomedical) test compared with the Roche

Elecsys 2010 laboratory test, at thresholds 125 pg/mL for patients <75 years and 450 pg/mL for

patients ≥75 years. For patients with confirmed CHF, they reported sensitivity of 0.99 and specificity

of 1.00. For a reference group including healthy individuals as well as patients without CHF this

study reported a sensitivity of 0.83 and specificity of 0.97.

Comparison of diagnostic accuracy of the two peptides

The summary ROC plots assessing BNP and NT-proBNP tests, each compared to clinical assessment

and considering the lowest threshold for each study, indicates very slightly increased accuracy of NT-

proBNP compared to BNP (Figure 8), but the difference is not statistically significant [Biosite Triage

(BNP) pooled sensitivity 0.95 (0.92-0.97), pooled specificity 0.65 (0.54-0.75); Cardiac Reader (NT Pro-

BNP) pooled sensitivity 0.97 (0.77-1.00), pooled specificity 0.69 (0.49-0.84)].

Removing the outlier (22) did not alter this result (Biosite Triage (BNP) pooled sensitivity 0.95 (0.92-

0.97), pooled specificity 0.65 (0.54-0.75); Cardiac Reader (NT Pro-BNP) pooled sensitivity 0.99 (0.75-

1.00), pooled specificity 0.77 (0.62-0.87) (Figure 9). The confidence region and prediction region

were extremely wide for NT Pro-BNP due to the paucity of data (not shown).

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Assessing at all thresholds produced consistent results with BNP and NT-proBNP having comparable

diagnostic accuracy (Figure 10). The shapes of the ROC plots were similar and the confidence

intervals were generally overlapping. There was a cluster of BNP points around the point estimate of

sensitivity 0.85 and specificity 0.80 whilst the NT Pro BNP points were more scattered due to the

paucity of data.

We did not find evidence of between-study heterogeneity on the basis of prevalence of CHF

(Likelihood Ratio Test, p=1.0).

DISCUSSION

Main findings

At thresholds above 100 pg/mL sensitivity of BNP, measured with the Biosite Triage, was generally

high. However, at lower thresholds of <100 pg/mL, sensitivity ranged from 0.46 to 0.97, and

specificity ranged from 0.31 to 0.98. Fewer studies assessed the accuracy of NT-proBNP, measured

with the Cardiac Reader, reporting sensitivity and specificity ranging from 0.59-1.00 and 0.42-0.90,

respectively, with specificity increasing at higher thresholds (≥200 pg/mL). There was no statistically

significant difference in diagnostic accuracy between POC BNP and NT-proBNP.

Only 5 of the 33 included studies were performed in a primary care setting with varying prevalence

of CHF (19-44%). Two of these studies assessed the accuracy of BNP, reporting a range of sensitivity

(0.46-0.92) and specificity (0.38-0.82) measures at thresholds ≤100pg/mL, as recommended by both

NICE and the ESC guidelines. Three studies assessed the accuracy of NT-proBNP in primary care,

reporting sensitivity ranging from 0.85- 1.00 and specificity ranging from 0.42-0.72 at the ESC

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recommended threshold of 125 pg/mL. At the NICE-recommended threshold for referral of 400

pg/mL, reported sensitivity ranged from 0.59-0.88 and specificity from 0.79-0.90.

Strengths and limitations

This study provides a comprehensive review of the diagnostic accuracy of POC BNP and NT-proBNP

tests in the diagnosis of CHF in ambulatory care at all thresholds. However, a limitation to our

analysis was the paucity of NT-proBNP data. The risk of bias assessment of included studies

highlighted in particular that in several studies it was unclear whether assessors interpreting the

results of the index test (POC BNP or NT-proBNP) were blinded to the outcome of the reference test

(e.g. clinical assessment, echocardiography). The lack of blinding may lead to an overestimation of

the test accuracy (33). Therefore, if applied in general practice independent of a reference test, its

performance remains to be seen. Furthermore, the heterogeneity in assessment of the reference

standard across studies, may affect generalisability of these findings to settings with different

diagnostic protocols for patients with CHF, resulting in different specificity of the test at hand.

Comparison with previous findings

Diagnostic accuracy of POC BNP and NT-proBNP was found to be similar, as was reported in a

previous review for all BNP and NT-proBNP tests including laboratory tests (11). Similarly, a meta-

analysis focussing on studies with paired measurement of NT-proBNP and BNP in the emergency

department, found no difference (34), and similar results were reported in another meta-analysis

focusing on the value of NT-proBNP and BNP in patients presenting with dyspnoea (35). In our study

we employed a meta-analysis method allowing the use of all available data at different thresholds,

therefore providing a comprehensive analysis (17). The study by Roberts et al. assessing the

diagnostic accuracy of natriuretic peptides for acute heart failure, concluded that the use of BNP and

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NT-proBNP at 2012 ESC guidelines thresholds had excellent ability to rule out a diagnosis of acute

heart failure as reported sensitivities were sufficiently high (approaching 1), although all studies

were performed in the hospital setting and focussed on laboratory tests (11).

Implications for clinical practice

The sensitivities of POC tests in the ambulatory care setting assessed in this review were far more

variable, particularly in the primary care setting, making it unclear whether these tests could act as a

rule-out test for CHF in primary care. Also, the generally low specificity of these tests in primary care

may limit their use as a test to aid ruling in CHF in primary care, although overall the NT-proBNP test

may perform slightly better than the BNP test with higher sensitivity and generally less variability

reported in the sensitivity and specificity across most studies.

As with any test, the results need to be put into context of general clinical assessment and

interpreted as such. If the clinical presentation is clearly indicating CHF or, alternatively, a different

diagnosis, clinical judgment should prevail over a single POC test result.

The limited data from studies performed in a primary care setting suggests that diagnostic accuracy

of POC BNP and NT-proBNP at lower thresholds is perhaps insufficient. It should also be noted that

in many studies the thresholds employed are likely to be too high to be applicable to primary care.

However, some studies reported a high sensitivity, particularly for NT-proBNP, ruling out CHF. In

patients with a positive (NT proBNP test after clinical assessment, imaging could help identify CHF in

ambulatory care as well and ensure there is appropriate safety netting through follow-up

appointments.

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Implications for future research

Given the general lack of studies performed in a primary care setting and potential methodological

limitations in these studies, there is a need for large-scale trials in primary care assessing the role of

POC natriuretic peptide testing to improve care of patients with heart failure.

CONCLUSIONS

The sensitivity of POC testing of BNP and NT-proBNP at thresholds above 100 pg/mL is generally

high. At lower thresholds, as recommended by recent guidelines, results seem to vary, especially in

settings relevant to ambulatory care. NT-proBNP might be marginally better at ruling out CHF;

however, prospective trials would need to confirm this. Additional testing such as imaging might

improve care of patients with CHF, managed in ambulatory care.

What is already known

Due to improved survival rates, prevalence of heart failure will continue to rise. If detected early,

heart failure may be reversible with appropriate treatment.

Point-of-care testing of natriuretic peptides in primary care and other ambulatory settings could

enable the identification and rapid referral of patients with heart failure.

The 2012 ESC and NICE have recommended the use of natriuretic peptides in aiding the diagnosis of

heart failure, but the diagnostic accuracy at these thresholds in ambulatory care is unknown.

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What this study adds

B type natriuretic peptide and N terminal pro-brain natriuretic peptide have variable ability to rule

out chronic heart failure in patients in ambulatory care at the rule-out thresholds recommended in

the 2012 ESC and NICE guidelines for heart failure.

As the specificity of natriuretic peptides is modest and variable, confirmatory diagnostic testing by

cardiac imaging and appropriate follow-up is essential in the case of positive results.

The addition of testing for serum natriuretic peptides to assess patients with heart failure in

ambulatory care could potentially improve care, if appropriate safety netting is in place.

Acknowledgements

The authors thank Nia Roberts for assistance with conducting the search strategy, the Stakeholder

Group and Steering Committee of our NIHR Programme Grant for discussions that inspired this

paper, and Elizabeth Holloway and Marion Judd (members of the Patient & Public Involvement

Group) for suggestions that have improved the text.

Competing Interests

Kathryn Taylor receives funding from the NIHR Programme for Applied Research.

Jan Y Verbakel receives funding from the NIHR Diagnostic Evidence Co-operative (DEC).

Benjamin G Feakins receives funding from the NIHR Monitoring Grant and Research Capability Fund.

Christopher P Price receives funding from the NIHR Diagnostic Evidence Co-operative (DEC).

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Rafael Perera receives funding from the NIHR Oxford Biomedical Research Centre Programme, the

NIHR Programme for Applied Research, the NIHR HPRU Gastrointestinal Infections Group, and the

NIHR Diagnostic Evidence Co-operative (DEC).

Clare Bankhead receives funding from the NIHR Oxford Biomedical Research Centre Programme, the

NIHR Programme for Applied Research and Cancer Research UK.

Annette Plüddemann receives funding from the NIHR, the NIHR School of Primary Care Research

(SPCR) and the NIHR Diagnostic Evidence Co-operative (DEC).

Funding

This article presents independent research funded by the National Institute for Health Research

(NIHR) under the Programme Grants for Applied Research programme (RP-PG-1210-12003). The

views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the

Department of Health.

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of

all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis

to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ and any

other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our

licence (http://group.bmj.com/products/journals/instructions-for-authors/licence-forms).

Transparency declaration: The lead author (the manuscript’s guarantor) affirms that the manuscript

is an honest, accurate, and transparent account of the study being reported; that no important

aspects of the study have been omitted; and that any discrepancies from the study as planned (and,

if relevant, registered) have been explained.

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35. Worster A, Balion CM, Hill SA, Santaguida P, Ismaila A, McKelvie R, Reichert SM, McQueen

MJ, Booker L, Raina PS. 2008. Diagnostic accuracy of BNP and NT-proBNP in patients

presenting to acute care settings with dyspnea: a systematic review. Clin Biochem 41: 250-9

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Figure Legends

Figure 1. PRISMA flow diagram. *Two studies were reported by more than one publication.

Figure 2. QUADAS-2 Risk of bias and applicability concerns summary showing review authors'

judgements about each domain for each included study. Based on 44 references (41 studies).

Figure 3. QUADAS-2. Risk of bias and applicability concerns graph showing review authors'

judgements about each domain presented as percentages across included studies. Based on 44

references (41 studies).

Figure 4. Receiver-Operating-Characteristics plot of B type natriuretic peptide compared to clinical

assessment, grouped by study design and index test, for all thresholds. Based on data for 30 studies

(33 references). Size of symbol indicates study size. Design: Circle – case-control study; Triangle –

cross-sectional/cohort study. Index test: Red ─ Abbod iSTAT; Grey ─ Biosite Triage.

Figure 5. Paired forest plots, at three threshold levels, for B type natriuretic peptide compared with

clinical assessment, for cross-sectional/cohort studies with populations of low prevalence of chronic

heart failure in primary, outpatient and emergency settings . Based on data for 14 studies (16

references). All index tests were Biosite Triage. Watson 2016a* refers to a population with diabetes

and Watson 2016b* refers to a non-diabetes population.

Figure 6. Receiver-Operating-Characteristics plot of N-Terminal pro-B type natriuretic peptide

compared with clinical assessment, grouped by study design and index test and for all thresholds.

Based on data for 7 studies. Size of symbol indicates study size. Design: Circle – case-control study;

Triangle – cross-sectional/cohort study. Index test: Red ─ Cardiac Reader; Grey – RAMP.

Figure 7. Paired forest plots, at two threshold levels, for N-Terminal pro-B type natriuretic peptide

compared with clinical assessment and for cross-sectional/cohort studies. Based on data for 4

studies. All index tests were Cardiac Reader.

Figure 8. Summary Receiver-Operating-Characteristics plots for B type natriuretic peptide and N-

Terminal pro-B type natriuretic peptide, compared with clinical assessment, for cross-

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sectional/cohort studies and selecting the lowest threshold for each study. Based on data for 26

studies; 4 NT-Pro BNP and 22 BNP studies. Size of symbol indicates study size. There were

insufficient studies to draw meaningful prediction and confidence regions for NT-Pro BNP. BNP

(Biosite Triage, Black) pooled sensitivity 0.95 (0.92-0.97), pooled specificity 0.65 (0.54-0.75). NT Pro-

BNP (Cardiac Reader, Red) pooled sensitivity 0.97 (0.77-1.00), pooled specificity 0.69 (0.49-0.84).

Figure 9. Summary Receiver-Operating-Characteristics plots for sensitivity analysis: Removing

outliers. Based on data for 25 studies; 3 NT-Pro BNP and 22 BNP studies. Size of symbol indicates

study size. BNP (Biosite Triage, Black) pooled sensitivity 0.95 (0.92-0.97), pooled specificity 0.65

(0.54-0.75). NT ProBNP (Cardiac Reader, Red) pooled sensitivity 0.99 (0.75-1.00), pooled specificity

0.77 (0.62-0.87)

Figure 10. Summary Receiver-Operating-Characteristics plots for B type natriuretic peptide and N-

Terminal pro-B type natriuretic peptide, compared with clinical assessment, for cross-

sectional/cohort studies and all thresholds. Based on data for 29 references (26 studies); 4 NT-Pro

BNP and 22 BNP studies. Size of symbol indicates study size. Index test: Red – Cardiac Reader (NT-

Pro BNP); Grey- Biosite Triage (BNP).

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Figure 1. PRISMA flow diagram. *Two studies were reported by more than one publication.

190x107mm (300 x 300 DPI)

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Figure 2. QUADAS-2 Risk of bias and applicability concerns summary showing review authors' judgements about each domain for each included study. Based on 44 references (41 studies).

402x1333mm (300 x 300 DPI)

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Figure 3. QUADAS-2. Risk of bias and applicability concerns graph showing review authors' judgements about each domain presented as percentages across included studies. Based on 44 references (41 studies).

53x15mm (300 x 300 DPI)

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Figure 4. Receiver-Operating-Characteristics plot of B type natriuretic peptide compared to clinical assessment, grouped by study design and index test, for all thresholds. Based on data for 30 studies (33

references). Size of symbol indicates study size. Design: Circle – case-control study; Triangle – cross-

sectional/cohort study. Index test: Red ─ Abbott iSTAT; Grey ─ Biosite Triage.

177x177mm (300 x 300 DPI)

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Figure 5. Paired forest plots, at three threshold levels, for B type natriuretic peptide compared with clinical assessment, for cross-sectional/cohort studies with populations of low prevalence of chronic heart failure in primary, outpatient and emergency settings . Based on data for 14 studies (16 references). All index tests

were Biosite Triage. Watson 2016a* refers to a population with diabetes and Watson 2016b* refers to a non-diabetes population.

271x327mm (300 x 300 DPI)

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Figure 6. Receiver-Operating-Characteristics plot of N-Terminal pro-B type natriuretic peptide compared with clinical assessment, grouped by study design and index test and for all thresholds. Based on data for 7

studies. Size of symbol indicates study size. Design: Circle – case-control study; Triangle – cross-

sectional/cohort study. Index test: Red ─ Cardiac Reader; Grey – RAMP.

177x177mm (300 x 300 DPI)

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Figure 7. Paired forest plots, at two threshold levels, for N-Terminal pro-B type natriuretic peptide compared with clinical assessment and for cross-sectional/cohort studies. Based on data for 4 studies. All index tests

were Cardiac Reader.

77x28mm (300 x 300 DPI)

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Figure 8. Summary Receiver-Operating-Characteristics plots for B type natriuretic peptide and N-Terminal pro-B type natriuretic peptide, compared with clinical assessment, for cross-sectional/cohort studies and selecting the lowest threshold for each study. Based on data for 26 studies; 4 NT-Pro BNP and 22 BNP

studies. Size of symbol indicates study size. There were insufficient studies to draw meaningful prediction and confidence regions for NT-Pro BNP. BNP (Biosite Triage, Black) pooled sensitivity 0.95 (0.92-0.97),

pooled specificity 0.65 (0.54-0.75). NT Pro-BNP (Cardiac Reader, Red) pooled sensitivity 0.97 (0.77-1.00), pooled specificity 0.69 (0.49-0.84).

171x185mm (300 x 300 DPI)

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Figure 9. Summary Receiver-Operating-Characteristics plots for sensitivity analysis: Removing outliers. Based on data for 25 studies; 3 NT-Pro BNP and 22 BNP studies. Size of symbol indicates study size. BNP (Biosite Triage, Black) pooled sensitivity 0.95 (0.92-0.97), pooled specificity 0.65 (0.54-0.75). NT ProBNP

(Cardiac Reader, Red) pooled sensitivity 0.99 (0.75-1.00), pooled specificity 0.77 (0.62-0.87)

171x185mm (300 x 300 DPI)

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Figure 10. Summary Receiver-Operating-Characteristics plots for B type natriuretic peptide and N-Terminal pro-B type natriuretic peptide, compared with clinical assessment, for cross-sectional/cohort studies and all thresholds. Based on data for 29 references (26 studies); 4 NT-Pro BNP and 22 BNP studies. Size of symbol

indicates study size. Index test: Red – Cardiac Reader (NT-Pro BNP); Grey- Biosite Triage (BNP).

177x177mm (300 x 300 DPI)

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Confidential: For Review Only1

SUPPLEMENTARY MATERIAL

Table S1. Inclusion and exclusion criteria

Reference Inclusion criteria Exclusion criteria

Ajuluhukaru 2010 Ages over 14 years. Inpatients with new or

decompensated HF. Clinical evaluation and

echocardiography within 24 hours of admission,.

These are absence of other significant pulmonary

and liver disease, evidence of cardiac disease

demonstrated as cardiac enlargement

CHF patients, if there was current or recent history

of smoking, significant history of chronic

pulmonary, liver, or current renal impairment,

defined as serum creatinine level >160 µmol/L.

Aleghagen 2008 Inpatients with acute coronary syndromes or

worsening HF, and HF outpatients

Incorrect allocation of samples.

Alibay 2005 Admissions for acute dyspnea None stated.

Dao 2001 Presenting to the urgent-care area of the San

Diego Veteran’s Health Care System with

symptoms of dyspnea with shortness of breath as a

prominent complaint. Associated symptoms could

be edema, weight gain, cough or wheezing.

Patients whose dyspnea was clearly not secondary

to CHF (trauma or cardiac tamponade) were

excluded. Patients with acute coronary syndromes

were excluded unless their predominant

presentation was CHF.

Fischer 2001 With underlying cardiac disease and suspected

CHF.

Insufficient samples or clinical data

Fuat 2006 Referrals from general practice of patients with

symptoms and signs suggestive of heart failure

None stated

Gruson 2009 Admitted to ED with dyspnea and/or chest pain None stated

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Jungbauer 2012 Patients with structural heart disease from HF and

implantable cardioverter defibrillator OP clinic

Knudsen 2004 Admitted to the Emergency Department with a

principal complaint of shortness of breath

Patients with chest pain and patients in whom the

shortness of breath was clearly not secondary to

CHF (e.g. trauma).

Krishnaswamy 2001 Referred for echocardiography to assess LV

function

Patients whose referral was to assess valve

disease, to determine whether a vegetation was

present, or to rule out a cardiac cause of a stroke.

Lainchbury 2003 Presenting to the emergency department with

acute dyspnea

If unable to give a blood sample within 8hr of

arrival

Lee Lewandrawski 2007 Three groups. Reference group of apparently

healthy individuals and the reference group of

non-healthy subjects with dyspnea, coronary

artery disease, acute coronary syndrome,

hypertension, diabetes, pulmonary disease

(including pulmonary embolus), or other diagnoses

but without acute or chronic heart failure.

Logeart 2002 patients presenting to the emergency room for

acute severe dyspnea

Patients with acute MI, chest injury, recent

surgery, those with Tx started more than 2h before

arrival and those for which echo was not feasible.

Lubien 2002 Referred for echocardiography to evaluate LV

function

Patients whose referral was to assess valve

disease, to determine whether a vegetation was

present, or to rule out a cardiac cause of stroke.

Patients with an ejection fraction <50% or an LV

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end-diastolic dimension >5.5 mm.

Maisel 2001 Referred for echocardiography to evaluate the

presence or absence of LV dysfunction

Patients with known LV dysfunction and those

referred for echocardiography to assess valve

disease, the presence of a vegetation, or to rule

out a cardiac cause of stroke.

Maisel 2002 Aged 18 and over. Arrival at ED with shortness of

breath as the most prominent symptom.

Patients with unstable angina or whose dyspnea

was clearly not secondary to congestive heart

failure (for example, those with trauma or cardiac

tamponade) and those with acute myocardial

infarction or renal failure.

Maisel 2003 Aged 18 and over. Arrival at ED with shortness of







Mak 2004 Referrals for echocardiographic evaluation of

cardiac structure and function

Patients whose referral was to assess valvular

disease, to determine whether vegetation was

present, or to rule out a cardiac cause of stroke.

Patients with known significant valvular disease

referred for other reasons or found to have

significant valvular disease

Morrison 2002 Patients presenting to urgent care with dyspnea,

with shortness of breath either at rest, with

exertion or upon lying down, as a prominent

Patients whose dyspnea was clearly not secondary

to CHF (knife wounds, trauma and cardiac

tamponade). Patients with unstable angina or

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complaint. Other associated symptoms could be

edema, weight gain, cough or wheezing.

acute myocardial infarction were excluded unless

their predominant presentation was dyspnea."

Pahle 2009 Aged 18 and over. Arrival at ED with shortness of







Prontera 2005 Aged 18 and over. With idiopathic or secondary

cardiomyopathy (heart failure group), or healthy

(reference group)

Prosen 2011 Aged 18 and over. Shortness of breath as the

primary complaint (defined as either the sudden

onset of dyspnea without history of chronic

dyspnea or an increase in the severity of chronic

dyspnea)

History of renal insufficiency, trauma, severe

coronary ischemia (unless patient’s predominant

presentation was dyspnea) and other causes of

dyspnea, comprising pneumonia, pulmonary

embolism, carcinoma, pneumothorax, pleural

effusion, intoxication (drugs), anaphylactic

reactions, upper airway obstruction, bronchial

stenosis , gastroesophageal reflux disorder

according to the history, clinical status and

additional lab tests available in the pre-hospital

setting (D-dimer, troponin, C-reactive protein)

Ro 2011 Aged 18 and over. Patients who presented to the

ED with symptoms suggestive of heart failure that

resulted in a BNP test being ordered as part of

Patients who were unwilling or unable to provide

written consent, were already a hospital inpatient,

were participating in any study that was deemed

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their standard of care, and provided signed written

consent.

by the investigator to confound the intended

results of the study, or were considered a

vulnerable population for the study by the

investigator

Shao 2005 Patients with dyspnea External injury, acute coronary syndrome, trauma,

pericardial tamponade.

Storti 2004 Admitted to cardiovascular medical and surgical

departments of hospital from Jan to April 2004

Sykes 2005 Samples were from patients from emergency

centre for whom physician has ordered a BNP test

and patients with elevated creatinine levels

Tang 2005 Patients with a known diagnosis of heart failure

and varying symptom severity (New York Heart

Association [NYHA] class I-IV) .

Any individual receiving intravenous nesiritide

infusions or with significant renal insufficiency.

Tomonaga 2011 Presenting with potentially cardiovascular chest

pain or symptoms

Refusal of consent, presentation >5 days after

symptom onset, recent anticoagulant treatment,

severe renal dysfunction and cancer therapy.

Vanderheyden 2006 Patients with suspected heart disease, referred for

elective diagnostic heart catheterization

Patients with atrial fibrillation, unstable angina,

recent myocardial infarction, severe liver disease,

renal insufficiency defined by a serum

creatinine >176.8 µmol/L and/or estimated

Glomerular Filtration Rate (eGFR) < 60 mL/min

Verdu 2012 Patients for whom echocardiography was

requested by a primary care physician to

Patients with a previous diagnosis of HF or severe

valve disease in the digitized clinical history, those

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investigate suspected HF included in a home care program, and those who

did not give their consent to participate in the

study.

Wei 2005 Hypertensive men.

Wieczorek 2002 Population consisted of outpatients, inpatients and

healthy controls

Patients with ESKD, acute MI

Zapata 2014 Patients under mechanical ventilation, non cardiac

critically ill.

Declined to participate, admitted to ICU for acute

HF, acute MI or cardiac surgery, LVEF<50%, LV end

dia dimension >5.5cm

Zhao 2008 In-hospital patients, all of whom presented

shortness of breath and/or dyspnoea as the most

prominent symptom.

Valvular heart disease, acute coronary syndromes,

pneumothorax, lung cancer, cardiac tamponade,

and liver or renal failure.

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Figure S1. Receiver-Operating-Characteristics (ROC) plot of B type natriuretic peptide compared with

clinical assessment and grouped by setting and prevalence of heart failure, for cross-

sectional/cohort studies and all thresholds

Based on data for 21 studies (24 references). All index tests were Biosite Triage. Size of symbol indicates study size.

Setting: Circle – Primary, outpatient and emergency; Triangle – Mixed outpatient and inpatient; Star – Inpatient.

Prevalence of heart disease with 50% threshold: Red – Low; Grey – High.

Excludes one study (Shao 2005) as the setting was not clear.

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Figure S2. Paired forest plots, at three threshold levels for B type natriuretic peptide compared with

clinical assessment for cross-sectional/cohort studies with populations of high prevalence of heart

failure in primary, outpatient and emergency settings

Based on data for 2 studies. All index tests were Biosite Triage.

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Figure S3. Paired forest plots, at three threshold levels, for B type natriuretic peptide compared with

clinical assessment, for cross-sectional/cohort studies with populations of low prevalence of heart

failure in mixed outpatient and inpatient settings

Based on data for 2 studies. All index tests were Biosite Triage.

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Figure S4. Paired forest plots for N-Terminal pro-B type natriuretic peptide compared with clinical

assessment, at three threshold levels for case-control studies

Based on data for 2 studies. All index tests were Cardiac Reader. Reference tests were clinical assessment based on single

or multiple tests.

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APPENDICES

Appendix 1. Research protocol

Systematic review: Accuracy of point-of-care B-type natriuretic peptide testing in the diagnosis

and monitoring of chronic heart failure

Introduction

Target condition:

An estimated 800,000 people in the UK currently have heart failure with an estimate of over 250 000

new cases of heart failure in the UK every year. Incidence increases with age and is highest in adults

over 75 [1]. The ageing population and improved survival of individuals with ischaemic heart disease

are likely to lead to a continuing rise in the prevalence of heart failure. Overall a general practitioner

(GP) with a patient population of 2000 will care for approximately 40-50 patients with heart failure

and see 2-3 new cases each year.

Since heart failure may be reversible in the early stages it is important that heart failure is diagnosed

as quickly as possible. However, because it has a low incidence, GPs are unlikely to have sufficient

experience to identify more subtle presentations of heart failure. For example, whilst heart failure is

frequently diagnosed by GPs, it is only confirmed by echocardiography in approximately a third of

cases [2]. A recent health technology assessment of the use of B-type natriuretic peptide (BNP) in

the diagnosis of heart failure, compared with ECG and echocardiography found that a normal ECG

can be used to exclude a diagnosis of heart failure but it is relatively non-specific. Whilst ECG is a

sensitive test when performed by cardiologists (sensitivity = 89%; 95% CI 77%–95%) [3], its sensitivity

was much lower (53%) when carried out by GPs [4]. It is for this reason that the most recent NICE

guidelines on chronic heart failure (CHF) have refined the diagnostic algorithm for heart failure,

replacing ECG with serum BNP measurement [5]. POC BNP testing would enable GPs to rapidly refer

the appropriate patients or, if CHF can be excluded, investigate alternative causes of dyspnoea.

Recent National Institute for Health and Clinical Excellence (NICE) and European Society for

Cardiology (ESC) guidelines on the initial diagnosis of CHF and referral for echocardiography

recommend the use of BNP in combination with clinical assessment [5, 6]. NICE guidelines

recommend measurement of serum natriuretic peptides in patients with suspected heart failure

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without previous myocardial infarction (MI), and those with previous MI should be referred for an

urgent echocardiogram [5]. Timely diagnosis and treatment of CHF may result in improved patient

outcomes as has been demonstrated for acute decompensated heart failure (ADHF) [7]. Although

several hospital laboratories carry out BNP testing, few return results within a day. Point-of-care

(POC) BNP testing can considerably reduce turnaround time and could lead to earlier initial

treatment, more timely referral and less uncertainty for patients. Moreover, using POC BNP levels to

quickly rule out heart failure, could allow more rapid initiation of investigation of other causes of

dyspnoea.

Index test:

B-type natriuretic peptide is produced from heart muscle cells as a pro-hormone (proBNP) and

released into the cardiovascular system in response to ventricular dilation and pressure overload [8].

The pro-hormone is split by a protease and secreted as the physiologically active C-terminal

fragment (BNP) and the inactive N-terminal fragment (NT-proBNP). Several POC BNP testing devices

are on the market, which either measure BNP or NT-proBNP (the latter has a longer half-life), for

example:

BNP:

1. Biosite Triage System BNP Test (Biosite Diagnostics Inc., San Diego, CA; Supplied in the UK by

Alere, Stockport [previously Inverness Medical]). This immunoassay that measures BNP

concentration from capillary whole blood samples obtained by finger prick is CE marked and

CLIA waived for use with whole blood. Results are available in 12-15 minutes. Information

provided by the manufacturer reports the device has lower and upper detection limits of 5

pg/ml and 5000 pg/ml, respectively (http://www.alere.com/us/en/product-details/triage-

bnp-test.html). This is a desk-top device which weighs approximately 0.7kg and is portable.

Initial studies claim the test has a 98% diagnostic accuracy at a cut-off value of 80 pg/ml in

an urgent care setting [9].

2. Alere Heart Check System (Alere, Stockport, UK; CE marked). This test measures BNP

concentration from a 15μl sample (obtained by finger prick) and results are available in 15

minutes. The product is handheld. (http://www.alereheartcheck.com/content/alere-heart-

check/home.html)

3. Abbott iSTAT Analyser (Abbott Point of Care, IL, USA; Supplied in the UK by Axis-Shield; CE

marked). This test measures BNP concentration from a 17μl sample (obtained by finger

prick) and results are available in 10 minutes. The device has reported lower and upper

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detection limits of 15 pg/ml and 5000 pg/ml, respectively

(http://www.abbottpointofcare.com/). The product is handheld.

NT-proBNP:

1. RAMP 200 Clinical System (Response Biomedical, BC, Canada; no UK distributor identified;

CE marked). This test measures NT-proBNP from an EDTA whole blood sample, results are

available in 15 minutes. The device has a reported lower limit of detection of18 pg/ml and

an upper limit of linearity of 23,450 pg/ml [10]. The product weighs approximately 2 kg and

is portable.

2. Cobas h 232/Cardiac Reader (Roche Diagnostics, Burgess Hill, UK; CE marked). This test

measures NT-proBNP from a 150μl sample of heparinised venous blood; results available in

12 minutes. The device has reported lower and upper limits of detection of 60 pg/ml and

3000 pg/ml, respectively (https://www.cobas-roche.co.uk). The product is handheld.

Importantly, BNP levels have been found to vary with age, gender and certain diseases (e.g. renal

failure) [8]. It has been suggested that higher cut-off values are used when individuals are >75 years,

female or in renal failure.

Reference standards:

In the literature point-of-care BNP tests are compared to laboratory-based systems (e.g. Roche

Elecsys analyser, Abbott ARCHITECT) and echocardiography and/or clinical examination by

cardiologists is frequently used as the reference standard [2-4, 10-15].

Rationale

Systematic reviews have been compiled on the role and accuracy of BNP and NT-proBNP in the

diagnosis of chronic heart failure [3, 12, 13, 15], however none have focussed specifically on the

accuracy of point-of-care testing, particularly in the primary care setting. As mentioned above,

several devices are currently on the market, however a systematic review on the evidence for the

accuracy of the devices is currently lacking.

Clinical question

In patients presenting to primary care with suspected or confirmed chronic heart failure, what is the

accuracy of point-of-care (POC) BNP devices compared to a reference standard (including

laboratory-based tests, echocardiography or clinical examination or combinations of these) for the

diagnosis and monitoring of chronic heart failure.

Therefore:

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Population: patients with suspected chronic heart failure, or patients with chronic heart failure

currently being monitored. The setting of particular interest is Primary Care, but patients from other

settings (hospital, specialist clinic) will also be included

Index test: POC/near patient/bedside BNP tests

Reference standard: laboratory-based BNP tests or echocardiography or clinical examination or

combinations of these.

Target condition: chronic heart failure

Objective

Compiling a systematic review and meta-analysis (if appropriate) of studies that investigate the

diagnostic accuracy of POC BNP tests in patients with dyspnoea/suspected heart failure or with a

diagnosis of heart failure. While the review will include studies from any setting, we will also seek to

summarise the evidence in primary care, if possible.

Methods and Data Collection:

Inclusion criteria:

1. Study designs: To include cross-sectional, longitudinal and case-control designs; both

prospective and retrospective. Randomised controlled trials, cohort and case-control studies will

be included.

2. Index test and Reference standard: Studies comparing POC-BNP and/or POC NT-proBNP tests

with any reference standard (including but not limited to laboratory-based tests,

echocardiography or clinical examination or combinations of these). Studies comparing different

POC tests with each other may also be considered, but will need to include a comparison with a

laboratory or clinical reference standard. The index test will be any portable test that can be

performed at the point of care that does not require laboratory services. Large bench-top

devices will be excluded.

3. Outcomes: Studies reporting accuracy measures, such as sensitivity, specificity, likelihood ratios

and predictive values, Bland-Altman plots etc. will be included.

4. Participants and setting: Studies with participants with suspected or confirmed Chronic Heart

Failure of any age in all settings will be included. No restrictions will be made regarding

population numbers.

5. Study quality will not be a basis for exclusion.

6. Language: Any language.

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Exclusion criteria:

1. Not in humans/ using non-human samples

2. Not a primary study

3. Does not include point-of-care BNP or point-of-care NT-proBNP testing

4. No reference standard or comparator

5. Diagnostic accuracy not reported as an outcome

6. Data not provided to allow for construction of 2x2 table

Search Strategy:

The search strategy will be developed in consultation with a healthcare librarian experienced with

supporting systematic reviews. Multiple electronic databases will be searched including, but not

confined to, MEDLINE, EMBASE, the Cochrane library, TRIP database and the Science Citation Index.

Free text and MeSH headings will be used. The search may use relevant filters, but in order to

maximise sensitivity, will not be limited to these. The reference lists of relevant studies will be

examined and additional tools such as the “related articles” feature in PubMed will also be used to

identify relevant publications. Clinical trials registries will be searched and manufacturers of POC

BNP/NT-proBNP devices will be contacted for information on any unpublished studies.

Study Selection:

Search results will be screened by two reviewers independently. Full text of relevant studies will be

obtained and assessed for inclusion by each reviewer. Disagreements will be resolved by discussion

or referral to a third reviewer. Study identification will be summarised in a PRISMA flow diagram.

Data extraction:

A data extraction form will be developed and data extraction will be performed independently by 2

reviewers, cross-checked and disagreements will be resolved by discussion or referral to a third

reviewer.

Extracted data will include:

1. Study identification- author, year, and location.

2. Study details- cohort, case-control, randomised trial. To include cross-sectional, longitudinal and

case-control designs; both prospective and retrospective.

3. Participants or samples: to include number, and age, gender, condition(s), illness severity, etc.

4. Setting: primary care, out-of-hours, emergency care, hospital or clinic setting

5. Index test – details of POC test used (e.g. manufacturer, type, etc.) and user (e.g. clinician, nurse,

laboratory worker, patient etc.)

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6. Comparator or reference test – details of nature of reference test (e.g. laboratory, clinical

examination, ECG, etc.)

7. Outcome measures – diagnostic accuracy measures (e.g. sensitivity, specificity, likelihood ratios,

predictive values, etc.) and primary data for 2x2 tables.

Quality assessment:

QUADAS2 (the Revised Tool for Quality Assessment of Diagnostic Accuracy Studies; [16]) will be used

to assess the study quality of each included study and will be reported in table or graphics form.

Data analysis:

Summary Tables

Summary tables will detail the patient sample, study design, the test under evaluation, the

thresholds at which accuracy has been reported, and the comparator.

Meta-analysis

For each test, RevMan will be used to produce paired forest plots to explore the between-study

variability of sensitivity and specificity across the included studies. For each study estimate of

sensitivity and specificity, corresponding 95% confidence intervals will be shown to illustrate the

uncertainty related to each study estimate. If accuracy has been reported at multiple common

thresholds, forest plots will be sub-grouped on threshold.

Bivariate meta-analysis methods will be used to generate pooled estimates of sensitivity and

specificity where sufficient data is available for each test. Hierarchical summary ROC meta-analysis

methods will be used to produce summary ROC curves with corresponding 95% confidence region

and prediction region. We will use the xtmelogit command in Stata for these analyses and feed

parameters directly into Revman to produce Cochrane-standardised output.

Investigations of heterogeneity

Two approaches will be used to explore the sources of between-study heterogeneity: 1) adjusting

for possible sources by adding them as covariates to the bivariate model 2) carrying out sub-group

analyses (e.g. subgroup analysis excluding studies using a case-control design, which is known to

introduce bias). The latter will only be carried out if there is sufficient data available and sub-group

specific pooled estimates are thought to be of clinical relevance.

Sensitivity analyses

If there appear to be any outliers in the data, these studies will be removed from the analysis to

evaluate the impact on the overall pooled estimates.

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Assessment of reporting bias

Funnel plots used to detect publication bias in reviews of RCTs have also been shown to be

misleading for DTA reviews [17-19]. Assessment of reporting bias will therefore not be included in

this review.

References

1. Townsend, N., et al., Coronary heart disease statistics 2012 edition, 2012, British Heart

Foundation: London.

2. Zaphiriou, A., et al., The diagnostic accuracy of plasma BNP and NTproBNP in patients

referred from primary care with suspected heart failure: results of the UK natriuretic peptide

study. Eur J Heart Fail, 2005. 7(4): p. 537-41.

3. Mant, J., et al., Systematic review and individual patient data meta-analysis of diagnosis of

heart failure, with modelling of implications of different diagnostic strategies in primary care.

Health Technol Assess, 2009. 13(32): p. 1-207, iii.

4. Zuber, M., et al., Value of brain natriuretic peptides in primary care patients with the clinical

diagnosis of chronic heart failure. Scand Cardiovasc J, 2009. 43(5): p. 324-9.

5. National Institute for Health and Clinical Excellence Guideline 108: Chronic heart failure

national clinical guideline for diagnosis and management in primary and secondary care,

2010.

6. Dickstein, K., et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart

failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart

failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart

Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care

Medicine (ESICM). Eur J Heart Fail, 2008. 10(10): p. 933-89.

7. Peacock, W.F.t., et al., Impact of early initiation of intravenous therapy for acute

decompensated heart failure on outcomes in ADHERE. Cardiology, 2007. 107(1): p. 44-51.

8. Balion, C., et al., Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart

failure. Evid Rep Technol Assess (Full Rep), 2006(142): p. 1-147.

9. Dao, Q., et al., Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure

in an urgent-care setting. J Am Coll Cardiol, 2001. 37(2): p. 379-85.

10. Lee-Lewandrowski, E., et al., Multi-center validation of the Response Biomedical Corporation

RAMP NT-proBNP assay with comparison to the Roche Diagnostics GmbH Elecsys proBNP

assay. Clin Chim Acta, 2007. 386(1-2): p. 20-4.

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11. Alehagen, U. and M. Janzon, A clinician's experience of using the Cardiac Reader NT-proBNP

point-of-care assay in a clinical setting. Eur J Heart Fail, 2008. 10(3): p. 260-6.

12. Korenstein, D., et al., The utility of B-type natriuretic peptide in the diagnosis of heart failure

in the emergency department: a systematic review. BMC Emerg Med, 2007. 7: p. 6.

13. Latour-Perez, J., et al., Accuracy of B-type natriuretic peptide levels in the diagnosis of left

ventricular dysfunction and heart failure: a systematic review. Eur J Heart Fail, 2006. 8(4): p.

390-9.

14. Shah, K., et al., Comparability of Results between Point-of-Care and Automated Instruments

to Measure B-type Natriuretic Peptide. West J Emerg Med, 2010. 11(1): p. 44-8.

15. Wang, C.S., et al., Does this dyspneic patient in the emergency department have congestive

heart failure? JAMA, 2005. 294(15): p. 1944-56.

16. Whiting, P.F., et al., QUADAS-2: a revised tool for the quality assessment of diagnostic

accuracy studies. Ann Intern Med, 2011. 155(8): p. 529-36.

17. Deeks, J.J., P. Macaskill, and L. Irwig, The performance of tests of publication bias and other

sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin

Epidemiol, 2005. 58(9): p. 882-93.

18. Leeflang, M.M., et al., Systematic reviews of diagnostic test accuracy. Ann Intern Med, 2008.

149(12): p. 889-97.

19. Song, F., et al., Asymmetric funnel plots and publication bias in meta-analyses of diagnostic

accuracy. Int J Epidemiol, 2002. 31(1): p. 88-95.

Appendix 2. MEDLINE search terms

# Searches

1 exp Heart Failure/

2 (heart adj5 fail*).ti,ab.

3 (cardiac adj5 (fail* or insufficien*)).ti,ab.

4 (chf or hf).ti,ab.

5 1 or 2 or 3 or 4

6 exp natriuretic peptides/ or natriuretic peptide, brain/

7 ((brain or btype or b type) adj3 natriuretic peptide*).ti,ab.

8 bnp.ti,ab.

9 (ntprobnp or ntpro bnp or nt pro bnp).ti,ab.

10 (probnp or pro bnp).ti,ab.

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11 ((n terminal or ntpro or nt pro) adj5 natriuretic peptide*).ti,ab.

12 6 or 7 or 8 or 9 or 10 or 11

13 ((immediate$ or rapid$ or same time or same visit or near patient or instant$ or portable or

handheld or hand-held or bedside or bed-side) adj3 (test$ or turnaround or analys$ or analyz$ or

measure$ or assay$ or monitor* or device*)).tw.

14 (fingerprick or finger prick).tw.

15 (poc or poct or "point of care").tw.

16 Point-of-Care Systems/

17 13 or 14 or 15 or 16

18 5 and 12 and 17


handheld or hand-held or bedside or bed-side) adj5 ((brain or btype or b type) adj3 natriuretic

peptide*)).ti,ab.


handheld or hand-held or bedside or bed-side) adj5 bnp).ti,ab.


handheld or hand-held or bedside or bed-side) adj5 (probnp or pro bnp)).ti,ab.


handheld or hand-held or bedside or bed-side) adj5 (ntprobnp or ntpro bnp or nt pro bnp)).ti,ab.


handheld or hand-held or bedside or bed-side) adj5 ((n terminal or ntpro or nt pro) adj5

natriuretic peptide*)).ti,ab.

24 (biosite triage or alere heart check or heart check system or abbott istat or ramp 200 or cobas h

232 or cardiac reader).ti,ab.

25 19 or 20 or 21 or 22 or 23 or 24

26 5 and 25

27 18 or 26

28 exp animals/ not humans.sh.

29 27 not 28

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Appendix 3. Variables in data extraction sheet

To evaluate eligibility: First author; study reference; title; journal details; and, eligibility criteria

To record study design: First author; study reference; study aim; design; whether data was collected

prospectively, retrospectively or unclear; consecutive recruitment or not; population or samples;

inclusion criteria; age and gender data for study population and control population (if relevant);

setting; country; cause of heart failure; interval between index and reference test; details about

each index test (name/company/type, what is measured, sample type, threshold used, whether

threshold was pre-specified, whether or not all patients were tested); details about each reference

test (name/company/type, what is measured, sample type, threshold used, whether threshold was

pre-specified, whether or not all patients were tested, whether or not they received the same

reference test); target condition; primary and secondary outcomes; funding source.

To evaluate methodological quality: All QUADAS-2 variables

To record the diagnostic accuracy results: First author; study reference; total number of patients;

number of patients with heart failure; name of index test; name of reference test; what is measured

(BNP or NT Pro-BNP); statistical measure; patient subgroup (if relevant); target condition; threshold;

units; value; lower confidence interval; upper confidence interval.

Authors’ analysis: Basic conclusions of study; our general comments

Appendix 4. References of included studies, listed alphabetically

Ajuluchukwu J, Ekure E, Mbakwem A. et al. Reliability and accuracy of point-of-care amino-terminal probrain natriuretic peptide in congestive heart failure patients. Internet J Cardiol. 2010;9(2) Alehagen U, Janzon M. 2008. A clinician's experience of using the Cardiac Reader NT-proBNP point-of-care assay in a clinical setting. Eur J of Heart Fail 10: 260-6 Alibay Y, Beauchet A, El Mahmoud R, et al. Plasma N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in assessment of acute dyspnea. Biomed Pharmacother. 2005 Jan-Feb;59(1-2):20-4. Epub 2005 Jan 20. Blondé-Cynober F, Morineau G, Estrugo B, et al. Diagnostic and prognostic value of brain natriuretic peptide (BNP) concentrations in very elderly heart disease patients: specific geriatric cut-off and impacts of age, gender, renal dysfunction, and nutritional status. Arch Gerontol Geriatr. 2011 Jan-Feb;52(1):106-10. doi: 10.1016/j.archger.2010.02.010. Epub 2010 Mar 11. Breathing Not Properly (BNP) study

Maisel AS, Krishnaswamy P, Nowak RM, et al. Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002 Jul 18;347(3):161-7.

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Maisel AS, McCord J, Nowak RM, et al Breathing Not Properly Multinational Study Investigators. Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. J Am

Coll Cardiol. 2003 Jun 4;41(11):2010-7. Pahle AS, Sørli D, Omland T, et al. Impact of systemic hypertension on the diagnostic performance of B-type natriuretic peptide in patients with acute dyspnea. Am J Cardiol. 2009 Oct 1;104(7):966-71. doi: 10.1016/j.amjcard.2009.05.039.

Chenevier-Gobeaux C, Guerin S, André S, et al. doi: 10.1373/clinchem.2010.145417. Epub 2010 Sep 2. Midregional pro-atrial natriuretic peptide for the diagnosis of cardiac-related dyspnea according to renal function in the emergency department: a comparison with B-type natriuretic peptide (BNP) and N-terminal proBNP. Clin Chem. 2010 Nov;56(11):1708-17. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001 Feb;37(2):379-85. De Vecchis R, Ariano C. 2016. Measuring B-Type Natriuretic Peptide From Capillary Blood or Venous Sample: Is It the Same? Cardiol Res 7: 51-8. Dokainish H, Zoghbi WA, Lakkis NM, et al. Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. Am J Cardiol. 2004 May 1;93(9):1130-5. Fischer Y, Filzmaier K, Stiegler H, et al. Evaluation of a new, rapid bedside test for quantitative determination of B-type natriuretic peptide. Clin Chem. 2001 Mar;47(3):591-4. Fuat A, Murphy JJ, Hungin AP, et al. 2006. The diagnostic accuracy and utility of a B-type natriuretic peptide test in a community population of patients with suspected heart failure. Br J Gen Pract 56: 327-33 Gorissen C, Baumgarten R, de Groot M, et al. Analytical and clinical performance of three natriuretic peptide tests in the emergency room. Clin Chem Lab Med. 2007;45(5):678-84. Gruson D, Thys F, Ketelslegers JM, et al. Multimarker panel in patients admitted to emergency department: a comparison with reference methods. Clin Biochem. 2009 Feb;42(3):185-8. doi: 10.1016/j.clinbiochem.2008.08.078. Epub 2008 Sep 3. Jungbauer CG, Kaess B, Buchner S, et al. Equal performance of novel N-terminal proBNP (Cardiac proBNP®) and established BNP (Triage BNP®) point-of-care tests. Biomark Med. 2012 Dec;6(6):789-96. doi: 10.2217/bmm.12.67. Knudsen CW, Riis JS, Finsen AV, et al. Diagnostic value of a rapid test for B-type natriuretic peptide in patients presenting with acute dyspnoe: effect of age and gender. Eur J Heart Fail. 2004 Jan;6(1):55-62. Lainchbury JG, Campbell E, Frampton CM, et al. Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am

Coll Cardiol. 2003 Aug 20;42(4):728-35.

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Lee-Lewandrowski E, Januzzi JL, Green SM, et al. 2007. Multi-center validation of the Response Biomedical Corporation RAMP NT-proBNP assay with comparison to the Roche Diagnostics GmbH Elecsys proBNP assay. Clinica Chimica Acta 386: 20-4 Logeart D, Saudubray C, Beyne P, et al. Comparative value of Doppler echocardiography and B-type natriuretic peptide assay in the etiologic diagnosis of acute dyspnea. J Am Coll Cardiol. 2002 Nov 20;40(10):1794-800. Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am

Heart J. 2001 Mar;141(3):367-74. Mak GS, DeMaria A, Clopton P, Maisel AS. 2004. Utility of B-natriuretic peptide in the evaluation of left ventricular diastolic function: Comparison with tissue Doppler imaging recordings. Am Heart Jl 148: 895-902 Monfort A, Da Silva K, Vodovar N, et al. 2015. Clinical evaluation of the Heart Check system, a new quantitative measurement of fresh capillary BNP. Biomark Med 9: 1323-30 Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am

Coll Cardiol. 2002 Jan 16;39(2):202-9. Prontera C, Storti S, Emdin M, et al. Comparison of a fully automated immunoassay with a point-of-care testing method for B-type natriuretic peptide. Clin Chem. 2005 Jul;51(7):1274-6. Prosen G, Klemen P, Štrnad M, Grmec S. Combination of lung ultrasound (a comet-tail sign) and N-terminal pro-brain natriuretic peptide in differentiating acute heart failure from chronic obstructive pulmonary disease and asthma as cause of acute dyspnea in prehospital emergency setting. Crit

Care. 2011;15(2):R114. doi: 10.1186/cc10140. Epub 2011 Apr 14. Ro R, Thode HC, Jr., Taylor M, Gulla J, Tetrault E, Singer AJ. 2011. Comparison of the diagnostic characteristics of two B-type natriuretic peptide point-of-care devices. J Emerg Med 41: 661-7 San Diego Veterans study

Krishnaswamy P, Lubien E, Clopton P, et al. 2001. Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Amer J of Med 111: 274-9 Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation. 2002 Feb 5;105(5):595-601.

Shao LW, Han Y, Wang ZK, Sun J. The diagnostic application of bedside measurement of plasma brain natriuretic in patients with heart failure. Zhonghua Nei Ke Za Zhi. 2005 Feb;44(2):99-101. [Article in Chinese] Storti S, Prontera C, Emdin M, et al. Analytical performance and clinical results of a fully automated MEIA system for brain natriuretic peptide assay: comparison with a point of care testing method. Clin Chem Lab Med. 2004;42(10):1178-85.

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Su Q, Liu H1, Zhang X1, et al. Diagnostic values of NT-proBNP in acute dyspnea among elderly patients. Int J Clin Exp Pathol. 2015 Oct 1;8(10):13471-6. eCollection 2015. Tang WH, Philip K, Hazen SL, et al. Comparative sensitivities between different plasma B-type natriuretic peptide assays in patients with minimally symptomatic heart failure. Clin Cornerstone. 2005;7 Suppl 1:S18-24. Taylor CJ, Roalfe AK, Iles R, et al. 2017. Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study. Br J Gen Pract 67: e94-e102 Tomonaga Y, Gutzwiller F, Luscher TF, et al. 2011. Diagnostic accuracy of point-of-care testing for acute coronary syndromes, heart failure and thromboembolic events in primary care: a cluster-randomised controlled trial. BMC Family Practice 12: 12 Vanderheyden M, Bartunek, Claeys G, et al. Head to head comparison of N-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in patients with/without left ventricular systolic dysfunction. Clin Biochem. 2006 Jun;39(6):640-5. Epub 2006 Mar 3. Verdu JM, Comin-Colet J, Domingo M, Lupon J, Gomez M, Molina L, Casacuberta JM, Munoz MA, Mena A, Bruguera-Cortada J. 2012. Rapid point-of-care NT-proBNP optimal cut-off point for heart failure diagnosis in primary care. Revista Espanola de Cardiologia 65: 613-9 Villacorta H, Duarte A, Duarte NM, et al. The role of B-type natriuretic peptide in the diagnosis of congestive heart failure in patients presenting to an emergency department with dyspnea. Arq Bras

Cardiol. 2002 Dec;79(6):569-72, 564-8. Watson C, James S, O'Connell E, Gallagher J, O'Reilly J, Tallon E, Baugh J, O'Connell J, O'Shea D, Ledwidge M, McDonald K. 2016. Influence of diabetes on natriuretic peptide thresholds in screening for Stage B heart failure. Biomarkers 21: 538-43 Weekes AJ, Thacker G, Troha D, et al. Diagnostic Accuracy of Right Ventricular Dysfunction Markers in Normotensive Emergency Department Patients With Acute Pulmonary Embolism. Ann Emerg Med. 2016 Sep;68(3):277-91. doi: 10.1016/j.annemergmed.2016.01.027. Epub 2016 Mar 11. Wei T, Zeng C, Chen L, et al. Bedside tests of B-type natriuretic peptide in the diagnosis of left ventricular diastolic dysfunction in hypertensive patients. Eur J Heart Fail. 2005 Jan;7(1):75-9. Wieczorek SJ, Wu AH, Christenson R, et al. A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: a multicenter evaluation. Am Heart J. 2002 Nov;144(5):834-9. Zapata L, Betbesé AJ, Roglan A, et al. Use of B-type natriuretic peptides to detect the existence and severity of diastolic dysfunction in non-cardiac critically ill patients: a pilot study. Minerva Anestesiol. 2014 Feb;80(2):194-203. Epub 2013 Oct 31. Zhao SQ, Hu YM, Li Q, et al. The clinical value of rapid assay for plasma B-type natriuretic peptide in differentiating congestive heart failure from pulmonary causes of dyspnoea. Int J Clin Pract. 2008 Feb;62(2):214-20. Epub 2007 Dec 11.

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