BNP as a Diagnostic and Risk Stratifying Test in Cardiology
Submitting InstitutionUniversity of Dundee
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
Our research on brain/B-type naturietic peptide (BNP) has helped to
diagnose both types of heart failure (systolic and diastolic heart
failure) and to identify high-risk aortic stenosis patients for surgery.
We were first to demonstrate the value of BNP as a biomarker for left
ventricular systolic dysfunction, isolated diastolic dysfunction and for
aortic stenosis. BNP testing is now recommended in Guidelines as a
screening test for patients with suspected heart failure (Class I
recommendation) and in the current European Society of Cardiology
consensus statement for diagnosis of diastolic heart failure. The European
Society of Cardiology Guidelines have also introduced BNP testing in the
management of patients with aortic stenosis (Class IIb recommendation).
Around 900,000 people in the UK have heart failure. Both the incidence
and prevalence of heart failure increase steeply with age. Heart failure
accounts for a total of 1 million inpatient bed days and 5% of all
emergency medical admissions to hospital with readmission rates among the
highest for any common condition in the UK. Financially, this adds up to
some 2% of healthcare costs, about two thirds of which are hospital costs.
The costs of GP consultations have been estimated at £45 million per year
with an additional £35 million for GP referrals to outpatient clinics.
Community based drug therapy for heart failure costs the NHS around £129
million per year.
The diagnosis of heart failure is difficult because its symptoms are
non-specific and the physical signs are often not obvious; however, early
and accurate diagnosis is important so that patients can start appropriate
life-saving treatment. The British Heart Foundation-funded research and
development work underpinning this case study was led by Professor Allan Struthers
(Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and
Medical School, Dundee) with assistance from Motwani (British Heart
Foundation research fellow) and Chim Lang (at the time a Lecturer
in the Department) in collaboration with Norman Kennedy (medical
physicist, Ninewells Hospital). We were the first to show that plasma
levels of BNP could be used in clinical practice to detect left
ventricular systolic dysfunction [i]. We followed this with a study of the
diagnostic role of BNP in a community population in another Lancet
publication [ii]. The latter publication provided the evidence leading to
National and International Guidelines recommending BNP testing in patients
with suspected heart failure in the community.
Our work on BNP as a biomarker of left ventricular wall stress led us to
show for the first time that BNP was elevated in patients with the other
form of heart failure (isolated diastolic dysfunction) [iii]. The
diagnosis of heart failure with preserved ejection fraction (HFpEF) due to
diastolic dysfunction is difficult, especially in patients with multiple
co-morbidities. To aid diagnosis, the use of plasma BNP as a biomarker
which is elevated in elevated left ventricular wall stress has been
recommended in Guidelines including the European Society of Cardiology
consensus statement on HFpEF. This test and is used as an inclusion
criterion in most ongoing studies of HFpEF including the on-going
Treatment Of Preserved Cardiac function heart failure with an Aldosterone
anTagonist (TOPCAT) study (see section 4).
Aortic stenosis is the most common valvular disease in Western countries.
Identification of subgroups of symptomatic patients with aortic stenosis
who may benefit from early surgery is a clinical challenge. Our 1997
American Heart Journal publication was the first study to show elevated
plasma BNP in aortic stenosis [iv]. This observation led to international
investigations which provided the evidence underpinning the latest
European Society of Cardiology recommendation on BNP testing in
asymptomatic severe aortic stenosis to select patients for aortic valve
In further recent related work, we have expanded the diagnostic role for
BNP into other populations of patients. We have recently described for the
first time how BNP could be used in primary prevention to detect patients
with silent asymptomatic heart disease such as left ventricular
hypertrophy and silent coronary artery disease [v].
References to the research
i. Motwani JG, McAlpine H, Kennedy N and Struthers AD (1993)
Plasma brain natriuretic peptide as an indicator for
angiotensin-converting-enzyme inhibition after myocardial infarction. Lancet
341, 1109-13 (DOI:10.1016/0140-6736(93)93126-L).
ii. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG,
Poole-Wilson PA and Sutton GC (1997) Value of natriuretic peptides in
assessment of patients with possible new heart failure in primary care. Lancet
350, 1349-53 (DOI:10.1016/S0140-6736(97)06031-5).
iii. Lang CC, Prasad N, McAlpine HM, MacLeod C, Lipworth BJ,
MacDonald TM and Struthers AD (1994) Increased levels of brain
natriuretic peptide in patients with isolated diastolic dysfunction. Am.
Heart J. 127, 1635-636 (DOI:
iv. Prasad N, Bridges N, Lang CC, Clarkson P, Struthers
AD, MacDonald TM (1997) Brain natriuretic peptide plasma concentrations in
patients with aortic stenosis. Am. Heart J. 133, 477-479 (DOI:
v. Nadir MA, Rekhraj S, Wei L, Lim TK, Davidson J, MacDonald TM, Lang
CC, Dow E, Struthers AD (2012) Improving the Primary Prevention of
Cardiovascular events by using Biomarkers to identify Individuals with
Silent Heart Disease. J. Am. Coll. Cardiology 60, 960-8
• Struthers AD, Pringle TH, McNeil G: The potential use of
natriuretic peptide in clinical cardiology; British Heart Foundation
• Cowie M, Coats A, Struthers AD: Sensitivity, specificity and
predictive value of natriuretic peptide levels in detecting ventricular
dysfunction in those with a new primary care diagnosis of heart failure;
British Heart Foundation (1995-1997) £10,205.
• Struthers AD, Pringle S, Goudie B, Sullivan F: Improving the
diagnosis of heart failure in general practice; British Heart Foundation
• Struthers AD, Pringle S, Goudie B, Sullivan, Donnan P: Near
patient BNP and portable echocardiography in general practice; British
Heart Foundation (2004-2006) £124,670.
• Struthers AD, Lang CC, MacDonald T, Houston G: The
potential to improve primary prevention by using BNP as an indicator of
silent pan-cardiac target organ damage: the 5P study; British Heart
Foundation (2007-2013) £323,958.
Details of the impact
Our BNP research has helped to hasten the diagnosis of heart failure
There are considerable clinical difficulties involved in diagnosing heart
failure by symptoms alone. Our early work on BNP published in the Lancet
1993 and in 1997 lead to intense research into the utility of BNP in the
diagnosis of heart failure which has confirmed its accuracy. As a result,
all current Guidelines including the European Society of Cardiology 2012
Guidelines advocate the measurement of plasma concentrations of BNP in the
diagnosis of chronic heart failure, either in combination with, or as an
alternative to, an electrocardiogram [1,2]. The availability of BNP as a
diagnostic test has important implications. Firstly, when applied early in
the diagnostic process in patients with suspected cardiac failure, a
negative BNP test can help rule out congestive heart failure and thus
avoid unnecessary tests and referral to clinics. Secondly, BNP assessment
can hasten the correct diagnosis of heart failure allowing prompt delivery
of evidence based treatment and thereby reduce the morbidity and mortality
associated with heart failure . The inclusion of BNP testing in the
recent 2010 NICE Guidelines  will have a major clinical impact .
These Guidelines was supported by a 2009 Health Technology Assessment
which showed that BNP testing is cost-effective and that measuring BNP is
the single most useful test to add to the diagnostic process in primary
care . A costing report for implementing the 2010 NICE guidance on BNP
testing to rule out heart failure estimated that there will be a £3.8
million net saving and a 23% reduced risk per patient of being admitted to
hospital within the first six months with the implementation of BNP
Our BNP research has helped to introduce BNP as a biomarker to
identify at-risk patients for clinical trials
We were the first to utilize BNP as a biomarker to identify patients with
left ventricular systolic dysfunction for therapy (angiotensin converting
enzyme inhibitors). This concept is currently adopted in clinical trials
to identify at risk heart failure patients for study inclusion. Examples
of trials that used BNP to select patients are the Eplerenone or Placebo
in Addition to Standard Heart Failure Medicines (EMPHASIS-HF) trial and
the ongoing PARADIGM study (Efficacy and Safety of LCZ696 Compared to
Enalapril on Morbidity and Mortality of Patients With Chronic Heart
Our BNP research has helped to diagnose HFpEF / diastolic dysfunction
We were also the first to show that BNP was elevated and related to
diastolic filling in patients with isolated diastolic dysfunction. Half of
patients with heart failure have preserved ejection fraction with similar
morbidity and mortality to heart failure with reduced ejection fraction.
Diagnosis of HFpEF is challenging, especially in patients with multiple
co-morbidities. The diagnosis of heart failure with reduced ejection
fraction now requires coupling exertional dyspnoea and a normal left
ventricular ejection fraction with objective measures of diastolic
dysfunction such as the measurement of plasma BNP. This use of BNP is now
recommended by most experts for the diagnosis of HFpEF  and as an
inclusion criterion in studies of HFpEF such as the TOPCAT study of
aldosterone antagonist therapy for adults with heart failure and preserved
systolic function . The current NICE Guidelines also recommend BNP
testing in heart failure as "Earlier diagnosis and treatment of associated
conditions (such as hypertension) in patients with HFpEF who are found to
have raised BNP levels is likely to result in a decrease in the number of
these patients needing hospital admission" .
Our BNP research has helped in the management of asymptomatic aortic
Identification of subgroups of symptomatic patients with aortic stenosis
who may benefit from early surgery is a clinical challenge. We were the
first to demonstrate elevated plasma BNP in aortic stenosis and this led
to international investigations of the prognostic value of BNP in aortic
stenosis which underpin the latest 2012 European Society of Cardiology
recommendation for BNP testing in asymptomatic severe aortic stenosis to
select patients for aortic valve replacement (Level C, Class IIb
Our BNP research has prompted the development of commercial assays for
The success of BNP testing in routine clinical settings is attested by
the fact that BNP tests is available on both mainframe laboratory systems
as well as point-of-care analysers. Tests for measuring BNP are now
offered by all major in vitro diagnostics players including
companies such as Abbott, Alere, Roche, Siemens, OCD and Beckman-Coulter.
In a report on point-of-care diagnostic testing world markets, it was
stated that in terms of `market drivers ranked in order of impact', BNP
testing was placed third out of twelve drivers  demonstrating that
these commercial BNP assays have a direct economical impact .
Sources to corroborate the impact
- McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein
K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber
L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik
PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors
AA, Zannad F, Zeiher A; ESC Committee for Practice Guidelines (2012) ESC
Guidelines for the diagnosis and treatment of acute and chronic heart
failure 2012: The Task Force for the Diagnosis and Treatment of Acute
and Chronic Heart Failure 2012 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association (HFA) of
the ESC. Eur. Heart J. 33, 1787-1847
- Letter of Corroboration from the Chairperson, European Society of
Cardiology Clinical Practice Guidelines Task Force.
- National Heart Foundation of Australia (2011) Guidelines for the
prevention, detection and management of chronic heart failure in
Australia, updated 2011. ISBN 978-1-921748-71-4; available at:
- Letter of Corroboration from the Chair, National Heart Foundation of
Australia, Cardiac Society of Australia and New Zealand, Chronic Heart
Failure Guidelines Expert Writing Panel.
- Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, Mant D,
McManus RJ, Holder R, Deeks J, Fletcher K, Qume M, Sohanpal S, Sanders
S, Hobbs FD (2009) 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. 13, 1-232. http://www.journalslibrary.nihr.ac.uk/hta/volume-13/issue-32.
- Paradigm HF Trial: http://clinicaltrials.gov/ct2/show/NCT01035255
- National Clinical Guideline Centre (2010) Chronic heart failure: the
management of chronic heart failure in adults in primary and secondary
care London: National Clinical Guideline Centre. Available from: http://guidance.nice.org.uk/CG108/Guidance/pdf/English;
National Institute for Health and Clinical Excellence (2010) Costing
Report — Chronic Heart Failure: Implementing NICE guidance. http://www.nice.org.uk/nicemedia/live/13099/51015/51015.pdf
- Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell
N, Diaz R, Fleg JL, Gordeev I, McKinlay S, O'Meara E, Shaburishvili T,
Pitt B, Pfeffer MA. (2011) Rationale and design of the treatment of
preserved cardiac function heart failure with an aldosterone antagonist
trial: a randomized, controlled study of spironolactone in patients with
symptomatic heart failure and preserved ejection fraction. Am. Heart
J. 162, 966-972 (DOI: 10.1016/j.ahj.2011.09.007).
- Joint Task Force on the Management of Valvular Heart Disease of the
European Society of Cardiology (ESC); European Association for
Cardio-Thoracic Surgery (EACTS) (2012) Guidelines on the management of
valvular heart disease (version 2012) Eur. Heart J. 33,
2451-2496 (DOI: 10.1093/eurheartj/ehs109).
- TriMark Publications, LLC (2013) Point of Care Diagnostic Testing
World Markets July 2013. Sample available at:
- Letter of Corroboration from the Commercial Director, Axis-Shield