Early Detection and Assessment of Heart Failure (HF): The Role of B-Type Natriuretic Peptide (BNP)

23321UMK040105D (04/05)

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

Patient Case Study - 1

Patient: 79 y/o male WW2 veteran Previously active, now unable to mow the lawn Complaining of mild dyspnea and fatigue History: Hypertensive: BP147/85, HR 96 No known heart disease
The patient cases are unique clinical presentations. Every patient should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

Patient Case Study - 1

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 patient should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

Patient Case Study - 1

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 patient should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

The Prevalence of Heart Failure

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 Edition, Publication Year: 2004.

ACC/AHA Practice Guidelines: Approaches to HF Stages

Refractory End-Stage HF

D C B A

Marked symptoms at rest despite maximal medical therapy

600,000 6 Million 10 Million 60 Million

Symptomatic HF
Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance

Asymptomatic HF
LV systolic dysfunction Previous MI Asymptomatic valvular disease

High Risk for Developing HF

Hypertension CAD Diabetes mellitus Family history of cardiomyopathy

Source: Hunt SA et al. J Am Coll Cardiol. 2001;38:21012113.

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 the current epidemic of heart failure (HF).

Source: Silver M. Congestive Heart Failure, 2003; 1-6.

Release of BNP
Pre-Pro-BNP1-134
26-aa signal sequence

Pro-BNP1-108

N-terminal Pro-BNP1-76 WALL

STRESS

BNP77-108
t1/2 = 18 min

Natriuresis Vasodilatation RAAS

Its All About Balance

BNP ANP BNP Natriuresis ANP

Inhibition of RAA Vasodepression Natriuresis

ReninReninAngiotensinAngiotensinAldosterone Aldosterone
Vasoconstriction Sodium retention Vasoconstriction Potassium wasting Sodium retention

Inhibition of RAA Vasodepression

Potassium wasting

Heart Failure Pathophysiology

Myocardial injury Fall in LV performance

Activation of RAS, NPS, SNS, ET, AVP and others Peripheral vasoconstriction Hemodynamic alterations

Myocardial toxicity

Morbidity and mortality

Remodeling and progressive worsening of LV function

Heart failure symptoms

The Cardiovascular Disease Continuum: Clinical Implications

Endothelial Dysfunction
Heart Attack (Myocardial Dysfunction)

Pathological Remodeling (LVH)

BNP

BNP

Maladaptive Remodeling

Vascular Disease BNP (Atherosclerosis) Endothelial BNP Dysfunction Risk Factors: Obesity, BNP Insulin Resistance

Left Ventricular Enlargement

BNP

Heart Failure

BNP

Death
BNP = 0

Source: Adapted from Dzau V et al. Am Heart J. 1991; 121:1244-1263

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

Careful physical exam was performed on heart failure patients about to undergo a right heart catheterization 52 patients, mostly New York Heart Association (NYHA) III, average ejection fraction (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. 10/93.

Specificity and Sensitivity in Diagnosing CHF

100 patients presenting to the ER with signs or symptoms of congestive heart failure (e.g., dyspnea, edema, weight gain)
Specificity Elevated Neck Veins Third Heart Sound Crackles in the Lungs BNP (cutoff value of 100 pg/mL) 92% 90% 81% 98% Sensitivity 34% 26% 57% 100%

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

Relative Diagnostic Contribution: Traditional Diagnostic Tools & BNP

Variable History of myocardial infarction History of chronic heart failure Rales Lower extremity edema Cardiomegaly Cephalization Interstitial edema Abnormal electrocardiogram B-type natriuretic peptide level 100 pg/ml

Odds Ratio 2.5 4.3 1.6 2.3 2.3 6.4 7.0 1.9 12.3

Source: Adapted from Knudsen C. et al, Am J Med. 2004;116(6):363-368.

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 is complementary to other methods used for diagnosis and assessment of HF Is available as a test that can be performed in the physician office laboratory

BNP Has Revolutionized the Diagnosis and Assessment of HF

3,500 3,000 2,500 2,000 1,500 1,000 500 0

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

May '02

May'01

3-May

Mar'01

Nov'01

Mar'02

Nov-02

4-May

3-Mar

3-Nov

4-Mar

Jul '02

Jan'02

Sep '02

3-Sep

Peer-reviewed literature exists describing the use of BNP in prognosis, ischemia, valvular disease and treatment monitoring

Sep'01

4-Sep

4-Nov

3-Jan

Jul'01

4-Jan

3-Jul

4-Jul

Primary Care Physicians Can Have the Greatest Impact on Appropriate Heart Failure Care
Other

Cardiologists
17%

10%

73%

Primary Care Physicians

BNP Utility Has Evolved to the Outpatient Setting

ER 20%
OP 37%
ER 72%

Ward 9% ICU 11%

OP 8%

ER 27%

OP 47%

ICU 18% Ward 15%

Ward 20%

ICU 16%

N = 537 Year 2001

N = 1466 Year 2002

N = 2072 Year 2003

Source: Harrison A, Maisel AS et al, Clinical Chemistry 2004; Vol. 50, No. 9: 1714-1715.

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.

Source: Maisel, A. et al. J. American College of Cardiology, Vol. 37, No. 2, 2001.

BNP Levels in Patients with Dyspnea Secondary to CHF or COPD

1200 1000 BNP pg/ml 800 600 400 200 0 86 +/- 39 1076 +/- 138

COPD
N=56

CHF
N=94

Cause of Dyspnea

Source: Maisel, A. et al. J. American College of Cardiology, Vol. 37, No. 2, 2001.

BNP Levels Associated with Baseline Left Ventricular Dysfunction and with CHF
1200 1000 BNP pg/ml 800 600 400 200 0 38+/-4 No CHF
N=139

1076+/-138

141+/-31

LV Dysfunction No acute CHF

N=14

CHF
N=97

Source: Maisel, A. et al. J. American College of Cardiology, Vol. 37, No. 2, 2001.

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

Number of Patients with the Indicated BNP Levels Diagnoses Overdiagnosed Underdiagnosed Number of Patients 15 15 Mean BNP Concentration 46 13 747 337 >80 pg/ml 1 15 <80 pg/ml 14 0

Source: Maisel, A. et al. J. American College of Cardiology, Vol. 37, No. 2, 2001.

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. American College of Cardiology, Vol. 37, No. 2, 2001.

Landmark NEJM Breathing Not Properly (B.N.P.) Study:

Rapid Measurement of B-Type Natriuretic Peptide in the Emergency Diagnosis of Heart Failure

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

Maisel, A., et al. The New England Journal of Medicine, Vol. 347: 161-167, 2002

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 ED evaluation 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 Medicine, Vol. 347, 161-167, 2002.

Frequency Bar Graph

Clinical Probability of Heart Failure (blinded to BNP results) Significant Indecision Exists
350 300 250 200 150 100 50 0
0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0

Pretest Probability of Heart Failure

Source: (B.N.P. Sub-study) McCullough,P et al. Circulation, July 2002

BNP Adds to Clinical Judgement

N = 1538 with ED probability of CHF recorded
Clinical Judgment
P < 0.0001 for BNP vs. Clinical Judgment or Combined vs. Clinical Judgment

74.0

BNP Level

81.1

Combined

81.6

70

71

72

73

74

75

76

77

78

79

80

81

82

83

Accuracy (%)

Source: (B.N.P. Sub-study) McCullough,P et al. Circulation, July 2002

Conclusions
Study Conclusions:

BNP measurements improve the ability of clinicians to differentiate patients with dyspnea due to CHF from those with dyspnea from other causes Mean BNP values are related to functional class in those with 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, 2002.

Utility of BNP in Outpatient HF Management

Targets in Assessing Disease Severity

Many conditions include a target to assess disease severity:

Hypertension Diabetes Hypercholesterolemia

Blood Pressure Blood Sugar Level, HbA1c Cholesterol

Patient Case Study - 2

Patient: 64 y/o male
Presents to the HF clinic for routine monthly visit He is complaining of mild fatigue

History:
Current medicine: Lisinopril and metoprolol-XL History of heart failure

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

Patient Case Study - 2

Physical Examination VS: Neck: Ext: CV: Baseline BNP: Temp 98.6, O2 Sat 98%, BP 138/95 No jugular vein distension Warm & dry Regular heart rate and rhythm 357 pg/mL

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

Patient Case Study - 2

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 patient should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

BNP Response to Treatment

P < .0001

30 20

BNP (pg/mL)

10 0 -10 -20 -30

Placebo
(N = 1979)

Valsartan (N = 1940)
Source: Latini, R., Masson S., et al. Circulation, Vol. 106, No. 19, 2002 .

Utility of BNP in the Physician Office

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. Echocardiography and strongly consider referral to a cardiologist for further workup to screen for early LV dysfunction Consider referral to the ED or hospital admission Consider other etiologies for patient presentation Suspicion of immediate life-threatening disease If BNP < 40 Symptoms are not likely due to CHF If BNP 40 and <400 consider: Heart Failure MI Pulmonary embolism Pneunomia and other causes of dyspnea If BNP 400 CHF is very likely Interpret BNP Obtain Patient History Perform Physical Examination Perform EKG Order BNP test Order Chest X-Ray Order other laboratory tests

No

Yes

Source: Maisel A, Koon J, Krishnaswamy P, Kazanegra R, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction, American Heart Journal 2001; 141: 367-374.

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. JACC 5/2004 and Wang et al, Circulation 2/2004 2. McCullough Am J Kidney Dis 2003. 3. Leuchte BNP in PPH JACC 2004, Kucher Circ 2003. 4. Maisel JACC 2003.

Patient Case Study - 3

Patient: 52 y/o female Dyspnea on exertion over the last few days Orthopnea and nonproductive cough History: Hypertension Tobacco Use
The patient cases are unique clinical presentations. Every patient should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

Patient Case Study - 3

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 .04 Chest X-Ray see next slide

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

Patient Case Study 3 (Chest X-Ray)

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

Patient Case Study - 3

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 should be evaluated based on the best clinical judgment of the treating physician. Photo not actual patient.

Advances in Rapid Diagnostic Testing

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.

Assay Procedure
Step 1 Step 2

Step 3

Add whole blood to device

Insert device into Triage Meter Read Results

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 manual for full descriptors and instructions regarding the use of these codes.