1. B-type Natriuretic Peptide (BNP) in the Diagnosis of Acute Congestive Heart Failure (CHF) Scott M Silvers, MD 1 st Annual Pan American Conference Emergency Medicine Clinical Policies November 6 – 7, 2003

6. Lecture Outline Introduction to BNP Case Critical Question Literature Search Critical Literature Evaluation Evidence-based Recommendations

7. 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

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

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

10. Case Current 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 Examination T= 37°C HR= 110 BP= 170/90 RR= 40 SO2 (air)= 87% She is unable to speak long sentences. Neck veins: difficult to assess Heart: difficult to hear over her lung sounds Lungs: diffuse wheezing with decreased breath sounds and rales at the bases Abdomen: normal Extremities: warm with moderate pitting edema

11. Chest X-ray

12. 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?

13. Curiosity Poll How many people have a BNP assay available to them where they practice?

14. 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

15. 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)

16. 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

17. 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

18. Typical Study Methodology CHF Gold Standard Clinical findings Chest x-ray Echocardiography Nuclear cardiology Cardiac Catheterization Framingham and NHANES scores Clinical response to therapies

19. Critical Literature Evaluation: BNP in Diagnosing CHF 5 published studies to date –2 report data from the same sample

20. Critical Literature Evaluation: BNP in Diagnosing CHF StudyYearNDesign CHF Prevalence Study Grade Davis, et al 199452 Prospective Unblinded 62%3 Dao, et al (Maisel) 2001250 Prospective Unblinded 39%3 Morrison, et al (Maisel) 2002321 Prospective Blinded 42%2 Maisel, et al Breathing Not Properly (BNP) 20021586 Prospective Blinded Multinational 47%1 McCullough, et al (Maisel) 20021,538 Prospective Blinded Multinational 47%2

21. 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 CHF Sensitivity = 97%Specificity = 62% NPV = 96% PPV = 71% Study Grade = 1

22. 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)

23. Critical Literature Evaluation Study BNP Cutoff pmol/L Sens % Spec % PPV % NPV % Comments Davis, et al 22 (100 pg/ml) 93909390 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) 98929098 Small sample size Not blinded: ED Dx or BNP VA patients (Male) Not consecutive patients Morrison, et al (Maisel) 21 (94 pg/ml) 98869883 Moderate sample size VA patients (95% Male) Not blinded to ED Dx

24. Critical Literature Evaluation Study BNP Cutoff pmol/L Sens % Spec % PPV % NPV % Comments Davis, et al 22 (100 pg/ml) 93909390 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) 98929098 Small sample size Not blinded: ED Diagnosis or BNP VA patients (Male) Not consecutive patients Morrison, et al (Maisel) 21 (94 pg/ml) 98869883 Moderate sample size VA patients (95% Male) Not blinded to ED Dx

25. Critical Literature Evaluation Study BNP Cutoff pmol/L Clinical CHF Prob % Sen % Spec % PPV % NPV % Comments Maisel et al 22 (100 pg/ml) All 90767989 Large sample size Not consecutive patients 11 (50 pg/ml) 97627196 McCullough et al (Maisel) 22 (100 pg/ml) 80--10049969168 Excluded 3% without clinical CHF assessment Not consecutive patients 0--7994707493

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

27. 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.

28. 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

29. 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%).

30. 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%)

31. 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.

32. 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.

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