Scottish Heart Failure Nurse Forum

June 9, 2006

B-Type Natriuretic Peptide: Physiology, Pathophysiology

and the Clinical Role

Nancy L. Seymour RN, BSN, CCRN

International Clinical Consultant Manager

Biosite, Inc. International

Program Objectives

Current challenges associated with HF and ACS throughout the healthcare continuum

The physiology and pathophysiology of HF and cardiovascular diseases.

Clinical utility of BNP for diagnosis, assessment of disease severity and risk stratification for ACS in heart failure.

Importance of utilizing BNP to enhance recognition of high-risk patients.

Current research addressing the utility of HF testing at Point-of-Care Testing. 

Challenges in Healthcare

Highest Quality of Care

Patient Satisfaction

Minimizing Overcrowding

Enhancing Operational Efficiency

Optimizing Revenues

Managing Costs

Heart Failure Pathophysiology

Myocardial injuryMyocardial injury Fall in LV performanceFall in LV performance

Activation of RAAS, NPS, SNS, Activation of RAAS, NPS, SNS, AVP, Aldosterone, Cytokines, AVP, Aldosterone, Cytokines, Endothelin & ProstaglandinEndothelin & Prostaglandin

Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionHemodynamic alterationsHemodynamic alterations

Remodeling andRemodeling andprogressiveprogressive

worsening ofworsening ofLV functionLV function Heart failure symptomsHeart failure symptomsMorbidity and Morbidity and

mortalitymortality

Congestive Heart FailureEvolution of Clinical Stages

Normal

AsymptomaticLV Dysfunction

CompensatedCHF

De-compensatedCHF

RefractoryCHF

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptoms exercise Abnormal LV fxn

Symptoms exerciseAbnormal LV fxn

Symptoms not controlled with treatment

Class I

Class II

Class III

Class IV

ACC/AHA HF Classification Guidelines

Stage A Patients at high risk for developing HF but no structural disorder of the

heart

Stage B Patients with structural disorder of the heart but who have never

developed symptoms of HF

Stage C Patients with past or current symptoms of HF associated with

underlying structural disease

Stage D Patients with end-stage disease who require specialized treatment

strategies

ACC/AHA Guidelines, J American College of Cardiology, Vol. 36, No. 7, 2001

U.S. prevalence of 5 million,

worldwide 15 million=2% of

population

5-year survival Males 59%

5-year survival Females 45%

Symptoms Chest x-ray

Echocardiogram

DIAGNOSTIC METHODS UTILZED

Economic Burden & Clinical Challenges

THE HEART FAILURE DILEMMA:

Heart Failure Perspective

Risk for Heart Failure

Lifetime risk one in five for those > 40 yearsCoronary Artery Disease major attributable factorWithout history of AMI, risk is one in nine for males and one in six for females75% with antecedent HTNWhen BP >160/100 risk is one in fourWith BP < 140/90 risk is one in eight

Total estimated costsEstimate that total costs for heart disease in 2004 will be $238.6 billion Heart failure will equal $25.8 billionHospital charges will equal $13.6 billion

American Heart Association Heart Disease and Stroke Statistics, 2004 UpdateLloyd-Jones et al. Circulation, 2002; 10:3068-71

Etiology of Cardiac Dysfunction

Systolic DysfunctionDiminished inotropy

Ejection Fraction <40%

Males 50-70

Impaired contractility

Chamber dilated

Eccentric hypertrophy

Cardiomegaly noted

Ischemic in nature

Audible S3

Levy, R Michigan American College of Emergency Medicine Conference, 2004

Diastolic DysfunctionDiminished compliance Diastolic dysfunction >40%

Elderly females

Impaired compliance chamber narrowed

Concentric hypertrophy

Cardiomegaly absent

Hypertensive in nature

Audible S 4

Evidenced Based Medicine

Focus was on contractility and hemodynamics

Focus now is on neuroendocrine activation, remodeling, ventricular shape, left bundle branch blocks (LBBB), conduction delays and prolonged QRS

Albert, N. Critical Care Nurse Supplement, June 2003.

Clinical Challenges in Heart Failure

Diagnosis of heart failure

Assess the severity of heart failure

Assess the progression of heart failure

Assessment of treatment efficacy

Observation Unit Heart Failure Protocol Entry Criteria

Must have at least 1 from each category 1. B-type natriuretic peptide > 100 pg/mL 2. History a. Orthopnea b. Dyspnea on exertion c. Paroxysmal nocturnal dyspnea d. Shortness of breath e. Swelling of legs or abdomen f. Weight gain 3. Exam a. Jugular venous distension or elevation in pulsation b. Positive abdominal jugular reflux c. S3/S4 d. Inspiratory rales e. Peripheral edema

4. Chest X-Ray a. Cardiomegaly b. Pulmonary vascular congestion c. Kerley B lines d. Pulmonary Edema e. Pleural effusion

Peacock, Frank W.and Albert, N. Reviews in Cardiovascular Medicine. 2002. Volume 3 Supplement 4: Page S44.

Treating the Problem

COPD/ pneumonia

Beta agonist inhalers

Fluids

Antibiotics

Steroids

Acute heart failure

Beta blockers

Diuretics

Recombinant hBNP

Vasodilators

Restrict sodium

Near Patient Testing

Characteristics of an Ideal Marker for HF

• Facilitates diagnosis (highly sensitive, specific)

• Reliable irrespective of age, race/ethnicity, or etiology of HF

• Provides independent prognostic information

• Changes in patient’s clinical condition correlates with changes in the biomarker

• Is readily reproducible across laboratories

• Is available at bedside or in the office to guide therapeutic decision making

Bozkurt B Circulation 2003; 107: 1231-1233

ANPNH 2N-

COOH-

NH2

HOOC-

Urodilatin

BNP

CNP

H2N-

H2N-

HOOC-

HOOC-

ANPNH 2N- SerLeu

ArgArg

SerSer Cys

Phe

Gly

Gly Arg

Cys

Gly

ArgTyr

Asn

PheSer

Gly

LeuSer Gin

Ala

Gly

IIe

Arg

AspMet

COOH-

SS

NH2

HOOC-

Thr

AlaPro

Arg SerLeu

ArgArg

TyrArg

PheSer

AsnCys

GlyLeu

Gly Ser Gin

Ala

Gly

IIe

Arg

AspMet

ArgGlyGly

Phe

Cys

SerSer

SS

Urodilatin

BNP

CNP

SS

SS

H2N-

H2N-

HOOC-

HOOC-

SerPro

LysMet

ValGin

Gly

CysGlySer Phe

GlyLeu

SerLys

GlyCys

Phe

HisArg

ArgLeu

ValLys

Cys

Gly

LeuGly Ser

GlyArg Lys

MetAsp

IIe

Ser

Ser

Ser

Cys

GlyLeu

Gly SerMet

Ser

Gly

IIe

Arg

AspLeuLysLeu

Gly

Arg

Natriuretic Peptides

BNP Relationship to NYHA Objective Vs. Subjective Evaluation

Linear Range 5 pg/ml-5000 pg/ml

Triage BNP package insert. Data on File at Biosite Diagnostics Inc.

0

200

400

600

800

1000

1200

Med

ian

[BN

P] (

pg/m

l)

NYHA I NYHAII NYHA III NYHA IV

Secretion

BNP: secreted from cardiomyocytes an active hormone providing compensatory response to the overload in

the ventricles released in order decrease fluid volume and reduce overload

NT-proBNP : secreted from cardiomyocytes at the same time as BNP Not a hormone, does not assist in decreasing fluid volume Inactive protein, requires adequate kidney function for clearance from

the bloodstream making it questionable for patients with coexisting renal insufficiency

Clearance

BNP is cleared by:

1. Binding to natriuretic peptide receptors

2. Enzymatic degradation

NT-proBNP is cleared:

1. Through the kidneys and is treated as a waste product

CHF and Kidney Disease

Dramatic Preponderance of Disease Overlap:

• CRD Overlap has been estimated 30-50% of CHF

CRD CHF

BNP Utilization….Evidence Based

Diagnosis of Heart Failure

Assessment of HF Disease Severity

Risk Stratification of Patients with Acute Coronary

Syndromes

Risk Stratification of Patients with Heart Failure

Aid in assessment of diastolic dysfunction

HF Clinic

Accident and Emergency Assessment of Heart Failure

BNP Consensus Guidelines

Silver MA et al. Congest Heart Fail. 2004;10(5 suppl 3):1–30.

Treatment Options for HF With BP >90:Diuretics plus nestiride, especially with CKD and pulmonary congestion; consider adding vasodilators if hypertensive; consider adding inotropes for poor perfusion

Treatment Options (cardiac): Consider acute coronarysyndromes

Treatment Options (noncardiac):Consider COPD; pulmonary embolism; asthma; pneumonia; sepsis

Treatment Options:Diuretics as required; consider nesiritide if pulmonary congestion, or for borderline hemodynamic instability, Creat >1.5 mg/dL, CrCl <60 mL/min, BUN >40 mg/dL

Treatment Options for HF With BP <90 or Shock:Diuretics, inotropes, vasodilators and/or nesiritide to follow

Patient presenting with dyspnea

Physical examination, chest

X-ray, ECG, BNP level

BNP <100 pg/mL BNP 100–500 pg/mL BNP >500 pg/mL

HF very unprobable (2%)

HF very probable (95%)

Clinical suspicion of HF or past

history of HF?

HF probable (90%)

“Rapid Measurement of B-type Natriuretic Peptide in the Emergency Diagnosis of

Heart Failure”

Publication: New England Journal of Medicine

Purpose: To validate and characterize the use of BNP levels in the diagnosis of CHF

Alan S. Maisel, M.D., F.A.C.C., Principal InvestigatorPeter A. McCullough, M.D., M.P.H., F.A.C.C., Co-Principal Investigator

7 Field Centers from three countries

Prospective study of 1586 patients who presented to ED

with dyspnea

BNP measurement obtained during the initial ED evaluation

BNP results were blinded to physicians

ED Physicians were asked to assign a value of 0 to 100%

of clinical certainty of HF

Study Design / Methods

BNP vs NHANES and FraminghamCriteria: Comparative Accuracy

50

70

90

Acc

ura

cy (

%)

NHANES Framingham BNP

N = 1586 * P < 0.0001

67

73

83

Conclusions

BNP measurements will improve the ability of clinicians to

differentiate patients with dyspnea due to CHF from those with

dyspnea due to other causes in acute care settings

Mean BNP values reflect functional class in those with heart

failure

BNP has a high degree of sensitivity, specificity and accuracy

for the diagnosis of heart failure

“B-Type Natriuretic Peptide and Clinical Judgment in Emergency Diagnosis of

Heart Failure”

Analysis From Breathing Not Properly (BNP) Multinational Study

Purpose: Determine the degree to which B-type natriuretic peptide (BNP) adds to clinical

judgment in the diagnosis of CHF

McCullough, et alCirculation, Vol.106, No 4, 2002

FREQUENCY HISTOGRAM

Pre Test Probability of CHF (Blinded to BNP)

0

50

100

150

200

250

300

350

Nu

mb

er o

f C

ases

0 10 20 30 40 50 60 70 80 90 100

Pretest Probability of CHF

Significant Indecision Exists 43 %

Conclusions

BNP can add to clinical judgment and enhance diagnostic

accuracy in patients with acute dyspnea

BNP can clarify the diagnosis when clinical indecision

exists

Risk Stratification with ACS

Acute Coronary Syndromes

Unstable Angina (UA)

Non ST-Segment Myocardial Infarction (NSTEMI)

ST-Segment Elevation Myocardial Infarction (STEMI)

Professional Guidelines* Have Been Established for AMI Management

Diagnosis of AMI based on at least 2 of 3 criteria A clinical history of ischemic-type chest discomfort Changes in serially obtained ECG tracings Temporal changes in cardiac markers

Initial patient evaluation within 20 minutes of ED arrival

“Door to needle time” < 30 minutes

Turn around Time (TAT) for cardiac markers should be 30 minutes

Percutaneous Coronary Intervention/PTCA 60-90 minutes

* WHO, AHA, ACC, **NACB

“The Prognostic Value of B-Type Natriuretic Peptide in Patients with

Acute Coronary Syndromes”

Purpose: To evaluate the prognostic utility of BNP in ACS

de Lemos, J.S. et al

New England Journal of Medicine

October, 2001

Study Design/Methods

2525 patients from the TIMI (Thrombolysis in Myocardial

Infarction) 16 trial included

Specimens obtained at 40 +/-20 hours after onset of

ischemic symptoms

End points of death or nonfatal MI were evaluated at 30

days and 10 months

De Lemos, et al. N England J Med, Vol 345, No. 14, 2001

Survival by BNP Quartile Analysis

Time (days)0 50 100 150 200 250 300

02

46

810

Mor

tali

ty, P

erce

nt

Quartile 4

Quartile 2

Quartile 3

Quartile 1

(137.9 to 1456.6 pg/ml)

(81.3 to 137.8 pg/ml)

( 43.7 to 81.2 pg/ml)

(5.0 to 43.6 pg/ml)

Conclusions

BNP provides powerful risk stratification information across a spectrum of Acute Coronary Syndromes (ACS)

BNP of 80 pg/ml is an appropriate risk threshold among patients with ACS

Prognosis via neurohormonal activation (BNP) are distinct from those of myocyte necrosis (TnI)

BNP measurement should be considered after an ACS in order to identify patients at high and low risk for adverse outcomes. Treatments including increased surveillance, pharmacologic and interventional therapy should be adjusted accordingly

BNP: A Novel blood early blood marker of Acute MI in patients with chest pain

and no ST elevation

Publication: European Heart Journal

Purpose: To evaluate BNP for risk assessment with non-diagnostic EKG

Bassan R. et al.

2004

Bassan: BNP and AMI

631 patients studied with no ST segment elevation

BNP cutoff used was 100 pg/ml

BNP identified 22 more of the 72 patients with AMI at admission than CKMB/trop alone

For patients with a normal troponin at first draw, an elevated BNP conferred a 6 times higher risk of AMI

Bassan R. et al. European Heart Journal Dec 1 2004

EITHERONE

87

*N= 631 patients without ST- segment elevation

0

50

75

100

BNP> 100 pg/ml

CKMB> 5.0 ng/ml

cTnI>1.0 ng/ml

%(95% CI)

SENSITIVITY FOR A.M.I.

p= 0.0000 (in relation to CKMB/cTnI)

71

4651

**

BNP Levels on Admission in Chest Pain Patients

Bassan et al, EHJ 2005; 26: 234-240

Study Conclusions

In patients with chest pain and no ST–segment elevation Admission BNP has significantly better sensitivity than admission CKMB or

TnI for AMI Similar NPV for all three markers

The combined use of admission BNP, CKMB and roponin-I are additive Sensitivity (87%, p= 0.0000) NPV (97%, p < 0.002) for A.M.I.

An elevated admission BNP is an independent predictor of AMI in this population

In chest pain patients without STEMI admission BNP seems to have an adjunctive role for the immediate identification and exclusion of A.M.I.

Bassan et al, EHJ 2005; 26: 234-240

“Predischarge B-Type Natriuretic Peptide (BNP) Assay for Identifying Patients at High Risk of Readmission After Decompensated

Heart Failure ”

Purpose: To determine if predischarge BNP measurements assist in predicting post discharge outcomes of patients admitted for decompensated heart failure.

Logeart D., et alJournal of American College of Cardiology

2004

Treatment intensification &/or home-based intervention might be considered for patients at higher risk

(BNP > 350 pg/mL)

93% risk (31% 1 month)

60% risk

16% risk

Dea

th o

r re

adm

issi

on a

t 6

mon

ths

ANALYSIS

Conclusion

Predischarge BNP testing in patients admitted congestive heart failure (CHF) provides a strong, independent indicator of death or readmission and is more relevant than common clinical or echocardiographic parameters

Study results suggest that the use of predischarge BNP testing as part of routine discharge orders for this population may be beneficial

Heart Failure in the CommunityWho is watching the

playground?

Utility of BNP in the Physician Office Targets in Treatment

• In many conditions treatment can be titrated againsta target:

Hypertension Blood Pressure

Diabetes Blood Sugar HbAlc

Hypercholesterolemia Cholesterol

Targets must be objective, reliable, practical and cost effective

Heart Failure Treatment Targets

• Objective

• Reliable

• Practical

• Cost effective

There is no target for treatment of heart failure used routinely in a physician’s office that is:

P=0.03

Troughton RW et al, Lancet. 2000 Apr 1;355(9210):1112-3.

0

10

20

30

40

50

60

BNP Group Clinical Group

De

ath

, H

os

pit

ali

zati

on

,D

ec

om

pe

ns

ati

on

BNP Guided Management of HF in the Clinic

• 69 patients with impaired systolic function (LVEF <40%) and symptomatic heart failure (NYHA II-IV)

• Randomized to receive treatment guided by either plasma N-BNP concentration or standardized clinical assessment

•Follow-up: minimum 6 months, median 9.5 months

•Endpoints: death, hospitalization, or heart failure decompensation

Effects of Valsartan on Circulating Brain Natriuretic Peptide and Norepinephrine in

Symptomatic Chronic heart Failure The Valsartan Heart Failure Trail (Val-HeFT)

Purpose: To determine if plasma BNP levels is related to severity of HF and is an independent predictor of outcomes in HF

Latini R, et alCirculation

Vol. 106, No. 19, 2002.

Latini, R., Masson S., et al. Circulation, Vol. 106, No. 19, 2002

Study Design/Methods

• Plasma BNP is strongly related to severity of HF and isan independent predictor of outcomes in HF

• Long term effects of ARBs on BNP in patients with HFare not known

• BNP levels were measured in 4,284 patients randomized to valsartan or placebo

Change in Plasma BNP Over Time

Time (months)

* in P

lasm

a B

NP

(p

g/m

L)

(N = 844)

*Mean ± SEM.

PlaceboBaseline = 177.6

ValsartanBaseline = 183.5

(N = 1890)

(N = 1710)

(N = 1850) (N = 1633) (N = 823)

P < 0.001P <

0.001P < 0.001

0 4 12 24-40

-30

-20

-10

0

10

20

Latini, R., Masson S., et al. Circulation, Vol. 106, No. 19, 2002

Conclusions

• In the largest neurohormonal study in patients withmild to moderate HF, BNP rose progressively, consistentwith progressive deterioration of HF

Optimal Medical Management for patients with advanced LV

Systolic Dysfunction

“Core” oral pharmacologic therapies

Angiotensin-converting enzyme inhibitor at target dose*

Beta-blocker at target dose

Digoxin at low dose

Spironolactone at low dose

Loop diuretic at dose to maintain euvolemia

Nonpharmacolgic therapies

2000-mg sodium dietDaily weight monitoringDaily activity and exerciseFluid restriction (if persistent hypervolemia and hyponatremia)

Surgical therapiesCoronary artery revascularizationRepair of Mitral RegurgitationReplacement of aortic valve

A Look at the Future

(Mars 2004)

New Advances for Treating Heart Failure

Biventricular Devices

Cardiac resynchronization therapy

Implantable hemodynamic monitor

Angiogenesis

Proteomics

Percutaneous ventricular assist device (pVAD)

Steefel, L Nursing Spectrum, Feb 23, 2003Abraham W.T., et al. Cardiac Therapies in Chronic Heart Failure., NEJM 2002; 346:1845-1853.

Future Markers for Risk StratificationCAD - ACS - CHF

Coronary Artery DiseaseLipids, CRP, ImagingRisk of event (CAD)

Clinical Condition Biochemical MarkerClinical Value

Hosp

ital S

tay

for

AC

S

Plaque Rupture

Cardiac Ischemia IMA Presence or absence of event

Myocyte Necrosis cTnI, CKMB, MyoPresence or absence of eventcTnI – size of infarct

Muscle Overload BNP Effect of infarct on cardiacfunction – long term risk

Chronic Heart Failure BNP Ability of heart to cope withmissing muscle

MPO, MMP’s Detection of unstable plaque

9 Cardiologists and 3 Emergency Physicians

4 month Internet writing

• Followed by a consensus panel meeting

• Further refinements and publication ready

• Topical

• 153 references

Silver MA et al. Congest Heart Fail. 2004;10(5 suppl 3):1–30.

Adhere National Registry

The Adhere Registry Core Module (CM) is the observational registry of the management of patients treated in-hospital for acute HF

The Adhere Registry Longitudinal Module (LM) is a prospective registry of severe heart failure patients in the outpatient setting

The Adhere Registry Emergency Module (EM) is a comprehensive registry of heart failure patients initially treated in the emergency department to improve disease management.

Biosite ® IncorporatedDiscovery of novel protein-based

markers for chronic, debilitating and life-

threatening diseases

Development of rapid, bedside tests to

support clinical practice:

Drug Toxicology

Acute Myocardial Infarction/

Acute Coronary

Syndrome

(MPO pending)

Heart Failure

Shortness of Breath Panel

D-dimer

Stroke (pending)

Sepsis (pending)

Triage® BNP Highlights

Triage BNP is indicated as an aid in the diagnosis of heart failure, severity of disease,

and for risk stratification for ACS. (Linear range 5-5000 pg/ml)

Diagnosis of patients presenting with non-specific symptoms associated with HF,

including SOB, edema, fatigue, nausea or suspected diastolic heart failure

No interference with typically prescribed heart related drugs

No statistically significant changes in BNP concentrations with hypertension, diabetes,

renal insufficiency & COPD

100 pg/ml has general specificity of 98% and negative predictive values greater than

98%1

Available for Outpatient setting, A & E, Chest Pain Unit, and In-patient arena.

Triage BNP package insert. Data on File at Biosite Diagnostics Inc.1 Dao Q, Krishnaswamy P, Kazanegra R, Harrison A et al. Journal of the American College of Cardiology 2001; 37: 379-385.2 Triage® BNP Package Insert. 3 Lubien E, DeMaria A, Krishnaswamy P, Clopton P, et al. Circulation; 105: 595-601.4 De Lemos J, Morrow D, et al. The New England Journal of Medicine 2001; 345: 1014-1021.

Thank youfor your kind attention!

International Liaison for the American Association of Heart Failure Nurses

www.aahfn.org