B-type Natriuretic Peptide(BNP) in the Diagnosis of

Acute Congestive Heart Failure (CHF)

Scott M Silvers, MD

1st Annual Pan American Conference

Emergency Medicine Clinical Policies

November 6 – 7, 2003

Lecture Outline

• Introduction to BNP

• Case

• Critical Question

• Literature Search

• Critical Literature Evaluation

• Evidence-based Recommendations

Introduction to BNP

• 32-aa polypeptide• Found in heart ventricles• Produced with ventricular

stretch and volume• Results in vasodilation,

natriuresis, diuresis, and reduced preload

• Increases with worsening heart failure

Introduction to BNP

Maisel AS, et al. N Engl J Med. 2002;347(3):161-167.

Introduction to BNP

Morrison LK, et al. J American Coll of Card. 2002;39(2):202-209.

CaseCurrent History:

Ms. GM is a 76 yo woman with a history only of obstructive lung disease who presents to the emergency department with 2 days of progressively worsening shortness of breath.

Physical ExaminationT= 37°C HR= 110 BP= 170/90 RR= 40 SO2 (air)= 87%She is unable to speak long sentences.Neck veins: difficult to assessHeart: difficult to hear over her lung soundsLungs: diffuse wheezing with decreased breath sounds and rales at the basesAbdomen: normalExtremities: warm with moderate pitting edema

Chest X-ray

Critical Question

What is the utility of a B-type natriuretic peptide (BNP) measurement in the diagnosis of congestive heart failure among patients

presenting to an emergency department with shortness of breath?

Curiosity Poll

How many people have a BNP assay available to them where they practice?

Literature Search

• Medline January 1995 – Present• Keywords

– “Brain natriuretic peptide”, “B-type natriuretic peptide,” “B natriuretic peptide,” or “BNP”

1, 745 papers

• Limits– Human subjects, clinical trials, meta-analyses 164 papers

Literature Search

• Abstracts of clinical studies reviewed– Patients presenting with shortness of breath to

“acute care” centers 5 papers

– Reviews and clinical policies 2000 - present (references crosschecked)

Typical Study Methodology

Inclusion Criteria• Adult patients presenting to an “acute care” facility• Primary complaint shortness of breath

Exclusion Criteria• Obvious non-CHF cause of shortness of breath• Renal Failure• Acute myocardial infarction

Typical Study Methodology

• Evaluation by an emergency physician• Assessment of clinical probability of CHF• BNP assay sent

– Results not revealed to emergency physician

• Patient treated and dispositioned• Physician team blinded to BNP

measurement assign final diagnosis after evaluation of case

Typical Study Methodology

CHF “Gold Standard”

• Clinical findings• Chest x-ray • Echocardiography• Nuclear cardiology• Cardiac Catheterization• Framingham and NHANES scores• Clinical response to therapies

Critical Literature Evaluation:BNP in Diagnosing CHF

• 5 published studies to date– 2 report data from the same sample

Critical Literature Evaluation:BNP in Diagnosing CHF

Study Year N DesignCHF

PrevalenceStudy Grade

Davis, et al 1994 52Prospective

Unblinded62% 3

Dao, et al

(Maisel)2001 250

Prospective

Unblinded39% 3

Morrison, et al

(Maisel)2002 321

Prospective

Blinded42% 2

Maisel, et al

“Breathing Not Properly” (BNP)

2002 1586Prospective

Blinded

Multinational47% 1

McCullough, et al

(Maisel)2002 1,538

Prospective

Blinded

Multinational47% 2

Critical Literature Evaluation:BNP in Diagnosing CHF

Maisel et al, (NEJM 2002)

• Prospective, multinational; N = 1,586• All “clinical risk” patients evaluated as one sample• BNP < 22 pmol/L (100 pg/ml) for detecting CHF

Sensitivity = 90%Specificity = 76% NPV = 89% PPV = 79%

• BNP < 11 pmol/L (50 pg/ml) for detecting CHFSensitivity = 97%Specificity = 62% NPV = 96% PPV = 71%

• Study Grade = 1

Critical Literature Evaluation:BNP in Diagnosing CHF

McCullough et al, (Circulation 2002)• Prospective, multinational; N = 1,538• Excluded 48 patients without “clinical risk” assessement• BNP < 22 pmol/L (100 pg/ml)• “Low and Intermediate” clinical probability (0 – 79%)

Sensitivity = 94%Specificity = 70% NPV = 93% PPV = 74%

• “High” clinical probability (80 – 100%)Sensitivity = 49%Specificity = 96% NPV = 68% PPV = 91%

• Study Grade = 2 (Post-study Analysis)

Critical Literature Evaluation

StudyBNP Cutoff

pmol/L

Sens

%

Spec

%

PPV

%

NPV

%Comments

Davis,

et al22

(100 pg/ml)93 90 93 90

•Small sample size

•Not blinded: ED Dx or BNP

•Nuclear study to assess EF

•Not consecutive patients

Dao, et al

(Maisel)18

(80 pg/ml)98 92 90 98

•Small sample size

•Not blinded: ED Dx or BNP

•VA patients (Male)

•Not consecutive patients

Morrison,

et al

(Maisel)

21(94 pg/ml)

98 86 98 83•Moderate sample size

•VA patients (95% Male)

•Not blinded to ED Dx

Critical Literature Evaluation

StudyBNP Cutoff

pmol/L

Sens

%

Spec

%

PPV

%

NPV

%Comments

Davis,

et al22

(100 pg/ml)93 90 93 90

•Small sample size

•Not blinded: ED Diagnosis or BNP

•Nuclear study to assess EF

•Not consecutive patients

Dao, et al

(Maisel)18

(80 pg/ml)98 92 90 98

•Small sample size

•Not blinded: ED Diagnosis or BNP

•VA patients (Male)

•Not consecutive patients

Morrison,

et al

(Maisel)

21(94 pg/ml)

98 86 98 83•Moderate sample size

•VA patients (95% Male)

•Not blinded to ED Dx

Critical Literature Evaluation

Study

BNP

Cutoff

pmol/L

Clinical CHF

Prob %

Sen

%

Spec

%

PPV

%

NPV

%Comments

Maisel

et al

22(100 pg/ml)

All 90 76 79 89

•Large sample size

•Not consecutive patients11(50 pg/ml)

97 62 71 96

McCullough

et al

(Maisel)

22(100 pg/ml)

80--100 49 96 91 68 •Excluded 3% without clinical CHF assessment

•Not consecutive patients0--79 94 70 74 93

Critical Literature Evaluation

Maisel AS, et al. N Engl J Med. 2002;347(3):161-167.

Critical Literature Evaluation

• Possible Limitation of BNP– Among rats given acute CHF, BNP may take

over 1 hour to rise.

Nakagawa O, et al. J Clin Invest. 1995;96:1280-1287.

Evidenced-based Recommendations

Includes• Patients presenting to an emergency department• Primary complaint shortness of breath

Excludes• Obvious non-CHF cause of shortness of breath• Renal Failure• Acute myocardial infarction

Evidenced-based Recommendations

Level A Recommendations

• A BNP < 11 pmol/L (50 pg/ml) may be used to help rule-out the diagnosis of congestive heart failure when the diagnosis is uncertain. (Probability < 4%).

Evidenced-based Recommendations

Level B Recommedations• Among low and intermediate “clinical probability”

patients, a BNP < 22 pmol/L (100 pg/ml) may be used to help rule-out the diagnosis of congestive heart failure. (Probability < 5%)

• Among patients without a history of CHF, a BNP > 88 pmol/L (400 pg/ml) may be used to rule-in the diagnosis of CHF when the diagnosis is uncertain. (Probability > 95%)

• A BNP > 220 pmol/L (1,000 pg/ml) may be used to rule-in the diagnosis of acute CHF among patients presenting with a history of CHF. (Probability > 95%)

Evidenced-based Recommendations

Level C Recommendations

• When evaluating a patient who presents with possible CHF within 1 hour from symptom onset, use caution in the interpretation of a low BNP level as BNP may take over 1 hour to rise.

Key References• Davis M, et al. Plasma brain natriuretic peptide in assessment of acute

dyspnea. Lancet. 1994;343:440-444.• Dao Q, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive

heart failure in an urgent-care setting. J Amer Coll Card. 2001;37(2):379-385.• Morrison LK, et al. Utility of a rapid B-natriuretic peptide assay in

differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Amer Coll Card. 2002;39(2):202-209.

• Maisel AS, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. New Eng J Med. 2002;347(3):161-167.

• McCullough PA, et al. B-typenatriuretic peptide and clinical judgement in emergency diagnosis of heart failure – Analysis from breathing not properly (BNP) multinational study. Circulation. 2002;106:416-422.

• Nakagawa O, et al. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. J Clin Invest. 1995;96:1280-1287.

The End