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Early Detection and Assessment

of Heart Failure (HF): The Role ofB-Type Natriuretic Peptide (BNP)

23321UMK040105D (04/05

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Review Objectives

Introduce BNP and its role in HF

Review peer-reviewed data on BNP as a diagnostic tool

Present relevant case studies

Discuss the utility of rapid BNP testing in the physician

office setting

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Patient Case Study - 1

Patient:

79 y/o male

WW2 veteran Previously active, now unable

to mow the lawn

Complaining of mild dyspneaand fatigue

History: Hypertensive:

BP147/85, HR 96

No known heart diseaseThe patient cases are unique clinical presentations. Every patient should beevaluated based on the best clinical judgment of the treating physician.Photo not actual patient.

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Physical Examination:

Oxygen saturation 94%, respiratory rate of 18

Basilar crackles on lung exam

Trace ankle edema bilaterally

The patient cases are unique clinical presentations. Every patientshould be evaluated based on the best clinical judgment of the treatingphysician. Photo not actual patient.

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Disposition:

BNP: 800 pg/mL

Patient referred to ED for admission and further workup

Final diagnosis: Heart Failure

The patient cases are unique clinical presentations. Every patientshould be evaluated based on the best clinical judgment of the treatingphysician. Photo not actual patient.

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The Prevalence of Heart Failure

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Heart Failure Prevalence on the Rise

5 million Americans diagnosed with HF

550,000 new cases per year1

Fourth leading cause of adult hospitalization in U.S.

4.3 million outpatient visits in 20012

60 million individuals at high risk for developing heart

failure

1. American Heart Association, 2002 Heart and Stroke Statistical Update.2. Coronary Heart Disease Statistics: Heart Failure Supplement. 2002 EditiPublication Year: 2004.

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Source: Hunt SA et al. J Am Coll Cardiol. 2001;38:210121

ACC/AHA Practice Guidelines:

Approaches to HF Stages

A

B

C

High Risk for Developing HFHypertension

CAD

Diabetes mellitusFamily history of cardiomyopathy

Asymptomatic HFLV systolic dysfunction

Previous MIAsymptomatic valvular disease

Symptomatic HFKnown structural heart diseaseShortness of breath and fatigue

Reduced exercise tolerance

RefractoryEnd-Stage HF

Marked symptoms at restdespite maximalmedical therapyD

60 Million

10 Million

6 Million

600,000

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Common Risk Factors Associated

with Development of CHF

Hypertension

Coronary Artery Disease Diabetes

Hyperlipidemia

Family history of cardiomyopathy

Only early detection and treatment is likely to stem thecurrent epidemic of heart failure (HF).

Source: Silver M. Congestive Heart Failure, 2003; 1

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Pre-Pro-BNP1-134

26-aa sig

sequen

N-terminal

Pro-BNP1-76

BNP77-108

Pro-BNP1-108

t1/2= 18 min

WALLSTRESS

Natriuresis Vasodilatation RAAS

Release of BNP

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Renin-

Angiotensin-

Aldosterone

BNP

ANP

Vasoconstriction

Sodium retentionPotassium wasting

Natriuresis

Inhibition of RAAVasodepression

Its All About Balance

Renin-

Angiotensin-Aldosterone

BNPANP

VasoconstrictionSodium retentionPotassium wasting

NatriuresisInhibition of RAAVasodepression

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Heart Failure Pathophysiology

Myocardial injury Fall in LV performance

Activation of RAS, NPS, SNS, ET,

AVP and others

Myocardial toxicityPeripheral vasoconstrictio

Hemodynamic alteration

Remodeling and

progressive

worsening of

LV function Heart failure symptomsMorbidity and mortality

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The Cardiovascular Disease Continuum:

Clinical Implications

Source: Adapted from Dzau V et al. Am Heart J. 1991; 121:1244-126

Risk Factors:

Obesity,Insulin Resistance

EndothelialDysfunction

Vascular Disease(Atherosclerosis)

Pathological

Remodeling(LVH)

Heart Attack

(MyocardialDysfunction)

Left VentricularEnlargement

Heart Failure

Death

EndothelialDysfunction

MaladaptivRemodelin

BNP

BNP

BNP

BNP BNP

BNP

BNP

BNP = 0

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Careful physical exam was performed on heart failure patients about toundergo a right heart catheterization

52 patients, mostly New York Heart Association (NYHA) III, average ejectionfraction (EF) 18%

If rales were present, all had a wedge pressure >18, very specific (100%)

However only 9 of 37 with a wedge pressure >18 had rales, very insensitive(sensitivity < 25%)

Soclear lung fields tell you very little about the fluid status in heart failure

Source: Butman et al. J Amer Coll Cardiol. 10/9

HF Diagnostic Dilemma:Cardiovascular Examination in Patients with Severe Congestive Heart Failure (CH

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Specificity and Sensitivity in Diagnosing CHF

100%98%BNP (cutoff value of 100 pg/mL)

57%81%Crackles in the Lungs

26%90%Third Heart Sound

34%92%Elevated Neck Veins

SensitivitySpecificity

100 patients presenting to the ER with signs or symptomsof congestive heart failure (e.g., dyspnea, edema, weight

gain)

Dao and colleagues, 49th Annual Scientific Session the American College of Cardiology

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Source: Adapted from Knudsen C. et al,

Am J Med. 2004;116(6):363-368.

Variable Odds Ratio

History of myocardial infarction 2.5

History of chronic heart failure 4.3

Rales 1.6

Lower extremity edema 2.3

Cardiomegaly 2.3

Cephalization 6.4

Interstitial edema 7.0

Abnormal electrocardiogram 1.9

B-type natriuretic peptide level 100 pg/ml 12.3

Relative Diagnostic Contribution:

Traditional Diagnostic Tools & BNP

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B-Type Natriuretic Peptide (BNP)

Current diagnostic tests are highly sensitive and

specific

Can be used reliably regardless of age, race, gender

or HF etiology

Provides unique clinical information that iscomplementary to other methods used for diagnosis

and assessment of HF

Is available as a test that can be performed in thephysician office laboratory

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BNP Has Revolutionized the

Diagnosis and Assessment of HF

0

500

1,000

1,500

2,000

2,500

3,000

3,500

Mar'01

May'01

Jul'01

Sep'01

Nov'01

Jan'02

Mar'02

May'02

Jul'02

Sep'02

Nov-02

3-Jan

3-Mar

3-May

3-Jul

3-Sep

3-Nov

4-Jan

4-Mar

4-May

4-Jul

4-Sep

4-Nov

Since 2001, over 2,800 U.S. hospitalshave adopted the Triage BNP Test

Peer-reviewed literature exists describing the use of BNP in

prognosis, ischemia, valvular disease and treatment monitoring

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Primary Care Physicians Can Have the Greatest

Impact on Appropriate Heart Failure Care

10%

73%

17%

Primary Care

Physicians

Cardiologists

Other

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BNP Utility Has Evolved

to the Outpatient Setting

Source: Harrison A, Maisel AS et al,Clinical Chemistry 2004; Vol. 50, No. 9: 1714-17

ICU

11%

ER

72%

OP

8%Ward

9%

N = 537

Year 2001N = 1466

Year 2002N = 2072

Year 2003

ICU

18%

ER

20%

OP

47%

Ward

15%Ward

20%

OP

37%

ER

27%

ICU

16%

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Source: Maisel, A. et al. J. American College of Cardiolo

Vol. 37, No. 2, 2001.

HF Diagnosis Study: Methods

250 patients presenting to the ED with shortness of breath

Data recorded: history, physical exam, lab tests

ED assessment

BNP values recorded

Later assessment: confirmation of the diagnosis

2 cardiologists with access to any later tests (echos), hospital

course, response to Rx, etc.

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BNP Levels in Patients with Dyspnea

Secondary to CHF or COPD

86 +/- 39

1076 +/- 138

0

200

400

600

800

1000

1200

BNPp

g/ml

COPD CHF

Cause of Dyspnea

Source: Maisel, A. et al. J. American College of Cardiolo

Vol. 37, No. 2, 2001.

N=56 N=94

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BNP Levels Associated with Baseline Left Ventricular

Dysfunction and with CHF

Source: Maisel, A. et al. J. American College of Cardiolog

Vol. 37, No. 2, 2001.

38+/-4141+/-31

1076+/-138

0

200

400

600

800

1000

1200

BNP

pg/ml

No CHF LV Dysfunction

No acute CHF

CHF

N=139 N=14 N=97

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Correction of Misdiagnosed Cases

Using BNP with a Cut-off of 80 pg/ml

Diagnoses

Number of

Patients

Mean BNP

Concentration >80 pg/ml

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Study Conclusions

BNP levels accurately reflect the cause of dyspnea in patients

presenting to the emergency department

BNP levels add additional information to that gathered by the

physician, allowing the correct diagnosis of congestive heart

failure

Source: Maisel, A. et al. J. AmericanCollege of CardiolVol. 37, No. 2, 2001.

L d k NEJM B thi N t P l (B N P ) St d

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Study Objective:To validate the use of a cardiovascular biomarker,BNP, as an aid in the diagnosis of CHF

Landmark NEJM Breathing Not Properly (B.N.P.) StudRapid Measurement of B-Type Natriuretic Peptide in the Emergency Diagnosis of Heart Fail

Maisel, A., et al.The New England Journal of Medicine,

Vol. 347: 161-167, 2002

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Study Design: B.N.P. Multinational Study

Study Methods:

7 clinical sites from three countries

Prospective study of 1586 patients who presented with

dyspnea

BNP measurement obtained during the initial EDevaluation

BNP results were blinded to physicians

Physicians were asked to assign a value of 0 to 100%for clinical certainty of HF

Source: Maisel, A et al. The New England Journal of Medicin

Vol. 347, 161-167, 2002.

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Frequency Bar Graph

0

50

100

150

200

250

300

350

0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0

Clinical Probability of Heart Failure (blinded to BNP results)

Pretest Probability of Heart Failure

Significant Indecision Exists

Source: (B.N.P. Sub-study) McCullough,P et al. Circulation, July 20

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BNP Adds to Clinical Judgement

81.6

74.0

81.1

70 71 72 73 74 75 76 77 78 79 80 81 82 83

Combined

BNP Level

ClinicalJudgment

Accuracy (%)

P< 0.0001 for BNP vs. Clinical Judgment

or Combined vs. Clinical Judgment

N = 1538 with ED probability of CHF recorded

Source: (B.N.P. Sub-study)

McCullough,P et al. Circulation, July 2002

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Conclusions

Study Conclusions:

BNP measurements improve the ability of clinicians todifferentiate patients with dyspnea due to CHF from those

with dyspnea from other causes

Mean BNP values are related to functional class in thosewith heart failure

BNP has a high degree of sensitivity, specificity and

accuracy for the diagnosis of heart failure

Source: Maisel, A et al.

The New England Journal of Medicine, Vol. 347, 161-167, 200

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Utility of BNP in

Outpatient HF Management

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Targets in Assessing Disease Severity

Many conditions include a target to assess disease severity:

Hypertension Blood Pressure

Diabetes Blood Sugar Level, HbA1

Hypercholesterolemia Cholesterol

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Patient:

64 y/o male

Presents to the HF clinic for routinemonthly visit

He is complaining of mild fatigue

History:

Current medicine: Lisinopril andmetoprolol-XL

History of heart failure

The patient cases are unique clinical presentations. Every patient should be evaluabased on the best clinical judgment of the treating physician. Photo not actual patien

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Physical Examination

VS: Temp 98.6, O2 Sat 98%, BP 138/95

Neck: No jugular vein distension

Ext: Warm & dry

CV: Regular heart rate and rhythmBaseline BNP: 357 pg/mL

The patient cases are unique clinical presentations. Every patientshould be evaluated based on the best clinical judgment of thetreating physician. Photo not actual patient.

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Disposition:

BNP test ordered to assess patient in conjunction with physical exam.

BNP level was 1015 pg/mL

Dose of ACE-I increased and Lasix added

One week later BNP 417

Potential hospital admission averted

The patient cases are unique clinical presentations. Every patientshould be evaluated based on the best clinical judgment of thetreating physician. Photo not actual patient.

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BNP Response to Treatment

(N = 1979) (N = 1940)Placebo Valsartan

20

30

10

0

-10

-20

-30

P< .0001

BNP(pg/mL)

Source: Latini, R., Masson S., et a

Circulation, Vol. 106, No. 19, 2002

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Utility of BNP in

the Physician Office

Algorithm for Use of BNP Testing in a Primary Care

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Source: Maisel A, Koon J, Krishnaswamy P, Kazanegra R, et al. Utility of B-natriuretic peptide as a rapid, point-of-care testfor screening patients undergoing echocardiography to determine left ventricular dysfunction, American Heart Journal 2001; 141

Algorithm for Use of BNP Testing in a Primary Care

Setting in Patients with No Known History of CHF

Patients present with signs

and/or symptoms of CHF.

These include: shortness of

breath, edema, fatigue, JVD,

dyspnea on exertion,

paroxysmal nocturnal dyspnea,

unexplained weight gain,

auscultatory rales or

crackles.

Patients with hypertension,

CAD, previous MI, obesity,

and/or diabetes are at

increased risk for development

of HF. These risk factors

should heighten suspicion for

possible CHF.

Obtain Patient History

Perform Physical Examination Perform EKG Order BNP test Order Chest X-Ray

Order other laboratory tests

Interpret BNP

If BNP 40 and

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Caveats to BNP Interpretation

Obesity

Levels noted to be slightly decreased1

Renal function

Levels slightly elevated but still useful as a diagnostic test2

Pulmonary embolism/Pulmonary HTN

Grey zone BNPs3

Diastolic Dysfunction

Usually less elevation than seen in systolic4

1. Mehra et al. JACC5/2004 and Wang et al, Circulation 2/2. McCullough Am J Kidney Dis2003.3. Leuchte BNP in PPH JACC2004, Kucher Circ 2003.4. Maisel JACC2003.

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Patient:

52 y/o female

Dyspnea on exertion over thelast few days

Orthopnea and nonproductive

cough

History:

Hypertension

Tobacco Use

The patient cases are unique clinical presentations. Every patient should beevaluated based on the best clinical judgment of the treating physician. Photonot actual patient.

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Physical Examination:

RR 18, O2 sat 95% on room air

2+ pedal edema

BMI 36

Distant but symmetric breath sounds

EKG nonspecific t wave inversions

Creatinine 1.0, blood glucose 231, troponin .04Chest X-Ray see next slide

The patient cases are unique clinical presentations. Every patieshould be evaluated based on the best clinical judgment of thetreating physician. Photo not actual patient.

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Patient Case Study 3 (Chest X-Ray)

The patient cases are unique clinical presentations. Every patiebe evaluated based on the best clinical judgment of the treatingphysician. Photo not actual patient.

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Disposition:

Pulmonary function testing reveals marked outflow

obstruction

BNP: 18 pg/mL

Patient did well with bronchodilation therapy Lower extremity edema was simply lymphedema

The patient cases are unique clinical presentations. Every patient sbe evaluated based on the best clinical judgment of the treatingphysician. Photo not actual patient.

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Advances in Rapid Diagnostic Testing

i

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The Triage BNP Test

Triage Platform also provides:

Cardiac markers

Troponin I

Myoglobin

CK-MB

D-dimer TOX Drug Screening

In development:

High sensitivity C-Reactive Protein

Stroke Panel

Contact Biosite Customer Service

for a distributor in your area.

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Assay Procedure

Step 1

Add whole blood to device

Step 2

Insert device into Triage Meter

Step 3

Read Results

Th T i BNP T

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The Triage BNP Test

A Rapid BNP Test

Results in approximately 15 minutes

Whole Blood Testing

Quantitative Measurements

Built-in Quality Control

Potentially relevant CPT Code 83880*

*CPT is a copyright and trademark of the AMA. Please consult the current CPT manuafull descriptors and instructions regarding the use of these codes.

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