1. BNP: What’s in it for you or is it “another D-dimer”? BNP: What’s in it for you or is it “another D-dimer”? October 7, 2004 Chris Hall - with the help of Debra Isaac, Bryan Young, a bunch of cardiology fellows and Adam Oster

2. CHF: the condition of interest, how common is it? USA prevalence 4.6 x 10 6 cases USA incidence: 550,000 new cases/year That translates into Canadian numbers of: 55,000 new cases/year 55,000 new cases/year 5500 cases/year/province roughly 5500 cases/year/province roughly 2000 cases per year in Calgary…or about 7 per day 2000 cases per year in Calgary…or about 7 per dayCost: $56 billion/year in USA $56 billion/year in USA $39 billion of that re: hospitalization $39 billion of that re: hospitalization

3. Admission rates 75-90% of patients with suspected CHF are admitted Graff et al PROVIDE study, Ann Emerg Med 1999 Graff et al PROVIDE study, Ann Emerg Med 1999 77% of admissions originate in the ED Absent clinical criteria Absent lab criteria BUT…if you are a good clinician, you know who is in CHF and who isn’t…don’t you?

4. The problem with signs and symptoms Poor relationship between symptoms and severity (more about that later) BNP levels correlate with both severity and outcome Harrison et al Ann Emerg Med 2002: BNP predicts future events in ED pts Harrison et al Ann Emerg Med 2002: BNP predicts future events in ED pts Cheng et al JACC 2001: BNP predicts outcome in admitted patients Cheng et al JACC 2001: BNP predicts outcome in admitted patients Bettencourt et al Am J Med 2002: BNP predicts outcome after discharge Bettencourt et al Am J Med 2002: BNP predicts outcome after discharge Maeda et al JACC 1999: Increased BNP is an independent predictor of mortality. Maeda et al JACC 1999: Increased BNP is an independent predictor of mortality.

5. So…. BNP should assist with appropriate treatment and disposition of CHF patients in the ED What the heck is BNP again?????

6. Natriuretic Peptides: Origin and Stimulus of Release Adapted from Burnett JC, J Hypertens 2000;17(Suppl 1):S37-S43 ANP = Atrial Natriuretic Peptide BNP = B-type Natriuretic Peptide CNP = C-type Natriuretic Peptide PeptidePrimary OriginStimulus of Release ANPCardiac atriaAtrial distension BNPVentricular myocardiumVentricular overload CNPEndothelium Endothelial stress

7. Relationship between BNP Concentration and Pulmonary Artery Wedge Pressure R= 0.729 P<.05 PAW 0 2 4 6 01234567 BNP Maisel, A., Kazenegra, R. et al. J Cardiac Failure, Vol. 7, No. 1, 2001 Change per hour PAW (mm Hg) BNP (pg/ml) 0.0 0.2 0.4 0.6 0.8 1.0 0 10 20 30 40

8. BNP vs. NYHA Classification 12.3 95.4 221.5459.1 1006.3 (pg/mL)

9. Cumulative Survival Rates in CHF Patients With Left Ventricular Dysfunction Stratified on Median Plasma BNP Concentration Tsutamoto T. et al. Circulation 1997;96:509-516 0 20 40 60 80 100 01020304050 BNP < 73 pg/ml BNP > 73 pg/ml Months Cumulative Survival (%) p < 0.0001

10. But is it specific?

11. Is it specific? BNP Levels in Patients With Dyspnea Secondary to CHF or COPD N=56N=94 Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

12. So, what’s the ED literature say? The REDHOT trial: Ann Emerg Med October 2004

13. 1. To establish whether BNP levels are associated with outcomes independent of ED physician assessment (Is there a “disconnect” between perceived severity of illness and BNP levels?) 2. To identify BNP levels that might help decide admission or discharge

14. R.E.D.H.O.T. Study Design 10 USA Hospitals BNP Levels Taken Serially Physicians blinded to BNP Concentrations unless <100 Key Outcomes Determined at Both 30 & 90 Days Mortality Mortality Hospital Readmission Hospital Readmission

15. Inclusion Criteria: 18 Years of Age or Older 18 Years of Age or Older CHF Diagnosed by Either Cardiologist or E.D. Physician CHF Diagnosed by Either Cardiologist or E.D. Physician Patient Requires Treatment for CHF Patient Requires Treatment for CHF Exclusion Criteria BNP Levels Equal to or Less Than 100 pg/ml Patients with Current M.I. Or ACS with ST Elevation of 1mm or greater Patients with Renal Failure Requiring Hemodialysis R.E.D.H.O.T. Study Design (Continued)

16. Patient Characteristics Age Male Female Caucasian African American Hx CHF Hx COPD 63.4% 53.9% 46.1% 32.5% 63.4% 76.5% 21.7% N=464 PND JVP Rales S3 Peripheral Edema 59.0% 42.6% 74.8% 19.6% 75.0%

17. AdmitDischargeInitialIntent68.3%31.7% AdmitDischargeFinalDisposition90.3%9.7% Decision for admission

18. And of the patients who got discharged… If 90% were admitted, everyone sick must have been admitted… Not so fast

19. Perceived NYHA Class in patients Ultimately discharged home from the ED Discharge Home IIIIIIIVTotalBNP<400pg/ml262-10 BNP  400 pg/ml11221135 78% of discharged patients have BNP  400 pg/ml

20. 30 day follow-up 90 day follow-up Discharged patients: NYHA class and Subsequent mortality

21. So, does that mean everyone needs admission?

22. Perceived NYHA Class in patients Ultimately admitted from the EDIIIIIIIVTotalBNP<200pg/ml114181144 BNP  200 pg/ml1010316893374 11% of all patients admitted with BNP<200 pg/ml 66% of patients admitted with BNP<200pg/ml perceived NYHA III,IV

23. 30 day follow-up 90 day follow-up Admitted patients: NYHA class and Subsequent mortality

24. REDHOT BNP Values & Patient Disposition Previous Data Link High BNP to Morbidity & Mortality Actual BNP Values Blinded to E.D. Physician BNP Median Values ~22% Higher in Patients Discharged Home from E.D.

25. CONCLUSIONS: In patients presenting with shortness of breath to the ED, there is a large “disconnect” between perceived severity of CHF and the BNP level. Even in the setting where CHF severity is perceived as severe, a low BNP level portends a favorable short and long term prognosis

26. The Calgary Implementation Organized plan of implementation to reduce the D dimer, troponin, “all things ordered at presentation” effect Protocol driven approach Also contribute to the literature in organized study format Protocol implementation arranged by billing group to simplify education of MD’s

27. Protocol #1: RGH; multicenter trial sponsored by Roche Patients suspected to have CHF Consented for trial (blood draw and chart review) BNP drawn in ED Randomized to know results or not Compare admission rates, test utilization and outcome in the two groups Determine the effect of BNP measurement on local resource utilization and patient outcome Are USA studies generalizable?

28. Protocol #2: FMC and PLC Patients with SOB suspected to be CHF Consented for involvement in study by ED Involvement consists of BNP drawn and some patients with phone follow-up BNP drawn in ED BNP values not known to MDs Usual treatment and disposition of all patients Phone follow-up only for 300 patients with BNP<100 Determine M&M in 30 and 90 days to determine “safety” of the 100 cutoff locally

29. Research-speak EP considers diagnosis of CHF who demonstrate a BNP level of <100 pg/ml. followed for the rates of pre-specified CHF events and CHF investigative procedures over the 30-day period following their ED visit. Endpoints: Cardiac endpoints (or Safety endpoints) Cardiac endpoints (or Safety endpoints) investigational or diagnostic procedures endpoints (Resource) investigational or diagnostic procedures endpoints (Resource) A 30-day follow-up period re: related to index ED visit. The incidence of Resource endpoints will form the basis for further study into optimal resource utilization for patients who are at low risk of adverse CHF events.

30. Questions?

31. “BNP Guided” E.D. Discharge @ 200pg/ml: Annual Economic Impact Potential: DRG 127 680,106 Admissions in ‘01 680,106 Admissions in ‘01 5.27 Day L.O.S. 5.27 Day L.O.S. $5,414.68 Cost per Patient $5,414.68 Cost per Patient Medicare = 80% Total Costs Medicare = 80% Total Costs $4,600,000,000.00 Total U.S. Inpatient Cost 11% Reduction$506mm Reduction

32. BNP Levels in Patients With Dyspnea Secondary to CHF or COPD N=56N=94 Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

33. BNP Levels in Patients With Edema Diagnosed With CHF or Without CHF N=44 Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

34. Conclusions Conclusions BNP levels accurately reflect the cause of dyspnea and/or edema BNP levels add additional information to that gathered by the physician, allowing the correct diagnosis of congestive heart failure

35. clinical and economic value of BNP measurement clinical and economic value of BNP measurement ER ER  time and volume issues at play!  higher percentage of diagnostic dilemmas  limited access to immediate specialist input  probably highest potential for economic / resource use benefit - reduce cost of “fishing expeditions” - reduce waiting time for unnecessary consults - speed up diagnosis; reduced time in ER until disposition determined - speed up initiation of appropriate rx

36. CHF Patient Population by NYHA Class Source: American Heart Association Class I No limitations of physical activity Class II Slight limitations of physical activity Class III Marked limitations of physical activity Class IV Inability to carry out physical activities without discomfort Class I 1,680,000 (35%) Class IV 240,000 (5%) Class III 1,200,000 (25%) Class II 1,680,000 (35%)