The Use of NT-proBNP and BNP as Biomarkers of Acute Heart Failure

The Use of NT-proBNP and BNP as 

Biomarkers of Acute Heart Failure 

John Backus, Ph.D. 

Director, Scientific Affairs 

© Ortho-Clinical Diagnostics, Inc.

Presentation Outline 

•B-Type Natriuretic Peptides BNP & NT-proBNP 

•B-type Natriuretic Peptide Biology 

•Use of BNP in the Acute Setting 

•Potential benefits of NT-proBNP 

•Non-HF Sources of Elevated NT-proBNP (and BNP) 

•Use of NT-proBNP in the Acute Setting 

•Other Clinical Utilities of NT-proBNP 

© Ortho-Clinical Diagnostics, Inc.

B-type Natriuretic Peptides 

Pre-Pro-BNP 1-134 

26-aa signal 

sequence 

Pro-BNP 1-108 

WALL 

STRESS 

N-terminal 

Pro-BNP 1-76 

t 1/2 = 60-120 min 

BNP 77-108 

t 1/2 = 18 min 

Source: Medscape.com (10/12/2009) 

3

Use of BNP Assay 

• “…useful in establishing or excluding the diagnosis of 

CHF in patients with acute dyspnea.” 

• 100 pg/ml cutoff (for ruling out) 

• 90 % sensitivity 

• 76% specificity 

• 89% NPV 

• BNP > 500 pg/ml PPV=90% 

• Grey zone 100pg/ml-500pg/ml where there are a 

number of conditions that could cause increased levels 

Source: Maisel et al, New Eng J Med (2002) 347:161-167. 

4

“Breathing Not Properly” Multinational Study 

Source: Maisel et al, New Eng J Med (2002) 347:161-167. 

5

B-Type Natriuretic Peptide 

“…BNP concentrations are higher in females and 

increase with increasing age…Given that HF is, 

to a large extent, a disease of the aging and that 

the prevalence of HF in younger groups is low 

compared with age groups >55, it is likely that 

the use of age- and gender-related cutoffs will 

improve the clinical sensivity of all BNP assays 

while maintaining a high specificity.” 

Source: Wu et. Al, Clin Chem (2004) 50:867-873. 

6

ValHeft Study: 2006 

LVEF: left ventricular ejection fraction 

LVIDd: left ventricular diameter in diastole 

Source: Masson et al, Clin Chem (2006) 52:1528-1538. 

7

An NT-proBNP cut-point of 900 pg/mL Performs 

Similarly to a BNP cut-point of 100 pg/mL 

PRIDE (NT-proBNP) 

Breathing Not Properly (BNP) 

Sources: Januzzi et al, Eur Heart J (2006) 27: 839-845. 

Maisel et al, New Eng J Med (2002) 347:161-167. 

8

NT-proBNP Levels by Diagnosis 

in Patients with Acute Dyspnea 

Source: Januzzi et al, - Eur Heart J (2006) 27: 330-337. 

9

Why NT-proBNP 

I. NT-proBNP is more stable than BNP* 

Mean recovery of BNP was less than 70% after one day of storage at –20°C and 

decreased to less than 50% after two to four months of storage 

II. 

III. 

IV. 

NT-proBNP values are generally more precise** 

NT-proBNP assays have shown excellent within run and total precision with total CV 

ranging from 2.9% to 6.1%. In contrast, total CV for BNP ranged from 9.9% to 12.5%, 

which is approximately 2-3 fold higher than the NT-proBNP method. 

NT-proBNP is a better predictor of patient outcomes*** 

NT-proBNP was superior to BNP for predicting mortality and morbidity (P=0.032) or 

hospitalization for HF (P=0.0143) 

NT-proBNP assays are harmonized**** 

Common source of antibodies (Roche) 

Age-related cut off values established 

Sources: * Mueller et al, Clin Chem Lab Med (2004) 42:942-944. 

** Yeo et al, Clin Chim Acta (2003) 338:107-15. 

*** Masson et al, Clin Chem (2006) 52:1528-38 . 

**** Januzzi et al, Am J Cardiol (2008) 101: 9A-15A. 

10

VITROS ® NT-proBNP – Method Comparison 

NT-proBNP 

– Adopted in Clinical Practice Guidelines 

– Optimal accuracy and precision 

– Method Comparison: Demonstrates 

excellent agreement across measuring 

range 

Source : Pub. No. GEM1315_EN_US Version 4.0 

Trademarks not owned by Ortho Clinical Diagnostics 

are the property of their respective owners 

11

Potential Causes of NT-proBNP Elevation 

Source: 

Januzzi et al, - Am J Cardiol (2008) 101: 29A-38A. 

12

NT-proBNP in the Acute Setting 

13

ICON Study Group: 

James Januzzi, Aaron Baggish (Boston) 

Antoni Bayes-Genis (Barcelona) 

Roland RJ van Kimmenade, Yigal Pinto (Maastricht) 

A. Mark Richards, John Lainchbury (Christchurch) 

Source: Januzzi et al, Eur Heart J (2006) 27: 839-845. 

14

NT-proBNP Levels by Diagnosis 

in Patients with Acute Dyspnea 


15

NT-proBNP Levels in Acute Heart Failure 

as a Function of Heart Failure Severity 


16

NT-proBNP Levels Predict Survival 

in Patients with Acute Heart Failure 


17

Elevated NT-proBNP and Impaired Renal 

Function Predict Poor Outcome in Acute HF 

Source: 

Baggish et al, - Am J Cardiol (2008) 101: 49A-55A. 

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Age-independent Rule-out Cut-point 

• International Collaborative of NT-proBNP (ICON) Study data (acute setting): 

• 300 pg/ml, age independent 

• 99% sensitive 

• 60% specific 

• 98% NPV 


19

Age-stratified Rule-in Cut-points 

• International Collaborative of NT-proBNP (ICON) Study data (acute setting): 

To Diagnose Acute Heart Failure 

Age strata 

All 75 years 

1800 pg/ml 

85% 

73% 

92% 

55% 

83% 

*Very superior to single cut-point strategy in multivariable bootstrapping models 


20

NT-proBNP vs BNP for Acute Heart Failure 

General Summary 

• Individuals with heart failure typically have approximately 8-10X higher 

levels of NT-proBNP versus BNP. 

• Close to half of this difference is due to the difference in molecular weight of the two molecules 

(NT-proBNP is about 2.5X larger than BNP). 

• The rest is likely due to the fact that NT-proBNP has higher in vivo stability. 

• As an aid in the diagnosis of acute heart failure, a single NT-proBNP 

cut-point of 900 pg/mL offers performance essentially equivalent to a 

BNP cut-point of 100 pg/mL. 

• The ICON triple “rule-in” NT-proBNP cutpoints for acute heart failure 

(age-specific cutpoints of 450, 900, and 1800 pg/mL) are designed to 

account for the impacts of age and renal function 

• Both BNP and NT-proBNP increase with increasing age and decreasing renal function. 

• The ICON triple NT-proBNP cutpoints are designed to provide similar information, but with better 

performance, relative to the BNP cut-point of 100 pg/mL. 

• Relative to BNP, NT-proBNP also offers the benefits of platform 

harmonization and enhanced analyte stability, both in vitro and in vivo 

Source: 

Januzzi et al. Am. J. Cardiol 2008; 101: 29A-38A. 

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Other Clinical Utilities of NT-proBNP 

22

VITROS ® NT-proBNP – Intended Use 


© Ortho-Clinical Diagnostics, Inc. 

23

NT-proBNP Decision Thresholds 

Defined in Individuals With No Acute Symptoms 


© Ortho-Clinical Diagnostics, Inc. 

24

NT-proBNP-Tailored CHF Therapy 

The PROTECT Trial as an Example 

Source: 

Bhardwaj et al. Am Heart J 2010;159: 532-538.e1. 

25

Inclusion/Exclusion Criteria 

Inclusion Criteria 

• Age > 21 years of age 

• Left ventricular ejection fraction ≤ 40% 

• New York Heart Association class II-IV symptoms 

• Hospitalization, ED visit, or outpatient therapy for ADHF within 6 months 

Exclusion criteria 

• Serum creatinine > 2.5 mg/dl 

• Inoperable aortic valve disease 

• Life expectancy

Study Endpoints 

•1 endpoint 

•Total cardiovascular 

events* 

• Worsening HF † 

• HF hospitalization 

• ACS 

• Ventricular arrhythmia 

• Cerebral ischemia 

• Cardiovascular death 

•2 endpoints 

•Quality of life 

•Changes in echo 

parameters 

• LV ejection fraction 

• LVESVi 

• LVEDVi 

*Assessed using generalized estimating equations 

† 

Requiring at least 2 from the following: symptoms of congestion or falling cardiac output, 

signs of new congestion on exam, use of “bail out” decongestive therapy, or rising NT-proBNP 

in the un-blinded arm 

Source: Januzzi et al. clinicaltrialresults.org/Slides/PROTECT%20Presentation%20FINAL.ppt, accessed March 27, 2012 

27

NT-proBNP Concentrations 

Baseline Follow-up P 

Overall 2118 1321 .02 

By treatment allocation 

Treatment Baseline Follow-up P 

SOC 1946 1844 .61 

NT-proBNP 2344 1125 .01 

P = .03 for SOC follow-up versus NT-proBNP follow-up 

44.3% of NT-proBNP subjects 1000 pg/mL 


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Primary Endpoint 

100 events 

P =.009 

SOC 


58 events 

*Logistic Odds NT-proBNP = 0.44 

(95% CI= .22-.84; P =.019) 

*Adjusted for age, LVEF, NYHA Class, and eGFR 


29

Mean number of events 

Age and outcomes 

SOC 


P =.008 P =.005 

Age < 75 years 

Age ≥ 75 years 

*No interaction between age and NT-proBNP guided care was found (P =.11) 


30

Events as a function of NT-proBNP 

P 3000 pg/mL 

Achieved NT-proBNP value 


31

PROTECT: Summary 

•NT-proBNP guided care was superior to SOC 

management for the reduction of total cardiovascular 

events. 

•Particular effects on worsening HF and HF hospitalization 

•Comparable benefits seen in elderly patients 

•Compared to SOC, NT-proBNP guided care was 

associated with more significant improvements in 

both QOL and echo parameters. 

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QUESTIONS 

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The Use of NT-proBNP and BNP as Biomarkers of Acute Heart Failure

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