1. TRIAGE OF THE ED PATIENT COMPLAINING OF CHEST PAIN David Plaut Snow, 2004

2. TRIAGE OF THE ED PATIENT COMPLAINING OF CHEST PAIN AMI-DIAGNOSTIC ECG AMI-NON DIAGNOSTIC ECG Questionable Admissions 30% Questionable Admissions 30% ~4% AMI ND-ECG ~4% AMI ND-ECG NO AMI NO AMI 100% 90% 5,000,000 PATIENTS ADMITTED 500,000 PATIENTS SENT HOME 0% CAP TODAY 1:51, 1994 Unstable angina, stable angina and other acute coronary syndromes 30% Unnecessary Admissions 30%

3. (GISSI-3 STUDY POPULATION) Time to Presentation PERCENT OF PATIENTS ONSET TO PRESENTATION (HOURS) Note: 50 % present within 4 Hours

4. Temporal Pattern of Cardiac Markers

5. Reference Range lie on a continuuuuum TCK 0 ------------------------> 180 CK-MB 0 ------------------------> 5 Myo 0 ------------------------> 80 Age? Sex? Muscle mass? Genes ?

6. cTn Reference Value. Normal Value for cTnI 0.0

7. Case A 0.0342.02.51230 h <0.06<80<2.5<5.0<200 cTnI MYO RIMB TCKTime A 40 yr old male with CP for 2 hours. His ECG was non-diagnostic.

8. Case A 0.0312.02.51256 0.0332.02.71312 0.0272.02.31161 0.0342.02.51230 h <0.06<80<2.5<5.0<200 cTnI MYO RIMB TCKTime A 40 yr old male with CP for 2 hours. His ECG was non-diagnostic. DCosta et al. found a negative predictive value of 100% of Myo. at 2 hours. This was confirmed by Kircher and Montague.

9. Case B A 76 yr old male with a history of IHD and mild CHF. Presents with severe chest pain which did not diminish with nitroglycerin. Time MYO cTnI <80 <0.06 0 h 66 <0.06

10. Case B A 76 yr old male with a history of IHD and mild CHF. Presents with severe chest pain which did not diminish with nitroglycerin. TimeMYOcTnI 0 h66<0.06 3 147 0.47 As many as 34% AMI present with a normal cardiac profile.

11. Case B A 76 yr old male with a history of IHD and mild CHF. Presents with severe chest pain which did not diminish with nitroglycerin. TimeMYOcTnI 0 h66<0.06 3 147 0.47 6--- 1.30 As many as 34% AMI present with a normal cardiac profile.

12. Case C 21 43 1.6 4.0 24112 44 82 3.2 24 756 1 54 82 3.5 29 817 0 h <0.06 <80<2.5<5.0<200 cTnIMYO RI MB TCKTime A 48 yr old male complained of CP after working in his field all morning. After trying Maalox he presented to the ED the following morning. Ladenson has found that cTnI remains detectable for as long as 15 days following an AMI.

13. Case D 0.02071.02.13126 0.02021.24.73192 0.02171.35.44110 h <0.06<80<2.5<5.0<200 cTnI MYO RIMB TCK Time A 64 yr old female with known chronic renal failure presents to the ED with some pain in my chest. Her EKG was non-diagnostic. Final diagnosis: Renal failure

14. Case E 1.1 67-- 46 4 0.0 27-- 32 0 h <0.06 <80<2.5<5.0<200 cTnIMyo RICK-MB TCKTime A 83 yr old female with intermittent chest discomfort is admitted to the ED at Huntington Hospital in Pasadena, CA.

15. Case E 2.2 32-- 56 9 1.1 67-- 46 4 5.3 145 3.210.2 13416 0.0 27-- 32 0 h <0.06 <80<2.5<5.0<200 cTnIMyo RICK-MB TCKTime A 83 yr old female with intermittent chest discomfort is admitted to the ED at Huntington Hospital in Pasadena, CA. Final diagnosis: AMI with extension

17. Questions Which marker(s)? When?

18. A 6 hour protocol for chest pain evaluation n = 292 (239 non-MI, 53 MI) Sensitivity: 97.2%, specificity: 93% The negative predictive value: 99.6% The six hour rule-out protocol is… accurate and efficacious. Herren, BMJ 2001 Aug 18; 323:372.

19. A 90 minute accelerated critical pathway for chest pain evaluation All AMIs were diagnosed within 90 min. Negative predictive value: 100% Ninety percent of patients with negative cardiac markers and a negative ECG at 90 minutes were discharged home Ng, S., Am J Cardiol 2001 Sept 15;88(6) 611-7 n = 1285

20. Evaluation of a 90 minute protocol Sensitivity: 96.9% Negative predictive value: 99.6% Addition of CK-MB did not improve the sensitivity or the NPV Addition of a 3 hour draw did not improve sensitivity or the NPV McCord, Circulation.2001 Sept 25;104(13):1454-6 n= 817

21. Suggested Protocol T 0 Draw sample for cTn (and Myo?) If cTn is diagnostic discontinue order If cTn is not diagnostic Draw 2nd sample 2 - 3 hrs. later If cTn is diagnostic discontinue order If cTn is not diagnostic Draw 3d sample 2 - 3 hrs. later

22. TRIAGE OF ED PATIENTS COMPLAINING OF CHEST PAIN CAP TODAY 1:51, 1994 Unstable angina, stable angina and other acute coronary syndromes ~ 30%

23. Unstable angina is a time bomb … A 68 yr old male with SOB, known chronic renal failure and acute renal insufficiency presents to the ED. His EKG was non-diagnostic. TimecTnI 0 h0.36 90.35 330.32 Final diagnosis: Renal failure with CAD. Patient was discharged.

24. waiting to EXPLODE ! TimecTnI 0 0.46 20.69 62.90 Three weeks later patient returned with severe chest pain and radiating left arm pain.

25. Serum cardiac troponin I values in unstable angina. 74 patients with chest pain at rest, electrocardiographic evidence of myocardial ischemia, and normal values of CK-MB Death or nonfatal myocardial infarction was more frequent in patients with elevated cTnI (27.7% vs 5.3%) than those with normal values. Ottani F Am Heart J 1999 Feb;137(2):284-91

26. cTnI to Predict Risk of Mortality in ACS Antman et al. NEJM 1996; 335:1342-9

27. TRIAGE OF ED PATIENTS COMPLAINING OF CHEST PAIN CAP TODAY 1:51, 1994 Unstable angina, stable angina and other acute coronary syndromes ~ 30%

28. 28 35% of CHDoOccurs in people with TC <200 mg/dL Adapted from Castelli. Atherosclerosis. 1996;124(suppl):S1-S9. 150 200 No CHD Total Cholesterol (mg/dL) 250 300 Framingham Heart Study26-Year Follow-up CHD Total Cholesterol Distribution: CHD vs. Non-CHD Population

29. Questions: Why add another test? Why should it be hs-CRP?

30. 30 Is there clinical evidence that hs-CRP, a marker of low grade vascular inflammation, predicts future coronary events?

31. 31 hs-CRP and Risk of Future MI in Apparently Healthy Men P<0.001 P=0.03 Quartile of hs-CRP (range, mg/dL) P Trend <0.001 < 0.055 0.056–0.114 0.056–0.114 0.115–0.210 0.115–0.210 0.211 0.211 Relative Risk of MI Ridker. N Engl J Med. 1997;336:973–979. 0 1 2 3 1 234

32. 32 hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women Quartile of hs-CRP (range, mg/dL ) Relative Risk Ridker. Circulation. 1998;98:731–733. P Trend <0.002 < 0.15 0.15–0.37 0.15–0.37 0.37–0.73 0.37–0.73 > 0.73 > 0.73 0 1 2 3 4 5 6 1234 Any event MI or stroke

33. 33 hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI TC:HDL Ratio Ridker. Circulation. 1998;97:2007–2011. hs-CRP Relative Risk

34. 34 Is there clinical evidence that the effect of hs-CRP on cardiovascular risk can be modified by preventive therapies?

35. hs-CRP, Aspirin, and Risks of Future Myocardial Infarction 1 2 3 4 0 1 2 3 4 Placebo Aspirin Relative Risk Myocardial Infarction Quartile of C-Reactive Protein Ridker PM, N Engl J Med 1997;336:973-9

36. What are the recommended guidelines for the use of hs-CRP assays?

37. Guidelines for Use of hs-CRP the writing group recommends against screening the entire adult population for hs-CRP…. it is reasonable to measure hs-CRP as an adjunct…to further assess absolute risk for CAD primary prevention. Circulation 107 (Jan) 499, 2003

38. Relative Risk and Average hs-CRP hs-CRP < 1.0 mg/L Low 1.0 -- 3.0 Average >3.01 High

39. The Importance of the D-dimer Assay and Its Use in the Clinical Setting David Plaut

40. Thromboembolism Incidence & Mortality DVT affects 2 million Americans per year Without treatment, PE mortality ~ 30% With treatment of heparin or TPA, mortality is <2% Only 15-25% of patients suspected of DVT/PE actually have DVT/PE.

41. What is the role of D-Dimer Assays in PE and DVT?

42. Causes of Elevated D-dimer Atherosclerosis Trauma Hepatic diseaseDIC Infection Pregnancy InflammationAge Cancer DVT Thrombolytic Rx PE

43. What is the importance of a negative D-dimer test? If D-Dimer is negative, then there are no clots being dissolved = no DVT or PE The value lies in the ability of d-dimer assays to rule out the Dx of DVT and PE

44. Clinical policy, College Emergency Physicians, 2003 Patient management recommendations Level A (high clinical certainty) None specified Ann. Emer. Med 41: 257, 2003

45. Clinical policy, College Emergency Physicians, 2003 Patient management recommendations Level B (moderate) Low pretest probability of PE use the following tests to exclude PE: 1. A negative quantitative d-dimer 2. A negative qualitative d dimer if Wells score 2 or less.

46. Clinical policy, College Emergency Physicians, 2003 Patient management recommendations Level C (low) Low pretest prob. of PE use the following tests to exclude PE: A negative quantitative d-dimer or a negative qualitative d dimer (when not used with Wells system)

47. Wells et al. criteria Suspected DVT 3.0 Alternate Dx is less likely than PE3.0 Heart rate >100 1.5 Immobilized or surgery in last 4 wk 1.5 Previous DVT/PE 1.5 Hemoptysis 1.0 Malignancy (treated within is 6 mo.)1.0 Wells, PS et al. Thromb Haemost. 83: 416, 2000

48. Wells score and probabilities for PE ScoreProbability 0 - 2 3.6% 3 - 6 20 >6 67

49. Use of D dimer to rule out DVT/PE Prevalence = 29% Sensitivity = 99.5 NPV = 99 Specificity = 41 n= 671 Am. J. Resp. Care 156: 492, 1997

50. Validity of D-dimer for DVT ( Venography) Ten studies with 945 patients Sensitivity = 97% ( 89 – 100) NPV = 97 ( 92 – 100) Specificity = 54 ( 34 – 80) Brill-Edwards, P Thromb. Hemosta. 82: 688, 1999

51. Validity of D-dimer for PE ( Various) Ten studies with 1329 patients Sensitivity = 99% (93 – 100) NPV = 99 (92 – 100) Specificity = 28 ( 10 – 50) Brill-Edwards, P Thromb. Hemosta. 82: 688, 1999

52. Hospitalization and Congestive Heart Failure lMajor public health problem worldwide lMost frequent cause of hospitalization in patients older than 65 years lFourth leading cause of adult hospitalization in US lDRG 127 (Congestive Heart Failure): l Primary diagnosis 1,000,000 hospitalizations/ yr l Secondary diagnosis 2,000,000 hospitalizations/ yr.

53. Total = $38.1 billion (5.4% of total healthcare coats) OConnell JB et al. J Heart Lung Transplant. 1994;13:S107-S112 Hospitalization: The Predominant Contributor to CHF Costs

54. myocyte pre proBNP (134 aa) proBNP (108 aa) signal peptide (26 aa) secretion NT-proBNP (1-76) BNP (77-108) Release of BNP from Cardiac Myocytes

55. Total <45 45 - 54 55 - 64 65 - 74 75 + n 1411 56 472 455308 120 mean 67.8 64.6 82.1 110.8 242.8 SD 83.7 96.2 107.795.2 211.1 median 41.4 39.6 57.783.4 191.1 95th % 167 174 208 318 717 proBNP: Expected Values for Healthy Subjects

56. Male Femal e Expected values are also gender-dependent (n = 2980) proBNP: Expected Values for Healthy Subjects

57. Triage® BNP Test Package Insert BNP vs. NYHA Classification 12.3 95.4 221.5 459.1 1006.3 (pg/mL)

58. 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 < 0.001

59. Log BNP (pmol/l) LVEF (%) 0 20 40 60 80 100 01.02.03.0 Y = -0.7, p<0.001 Davis et al. Lancet 1994;343:440-4. BNP vs. EF by Echocardiography

60. 0 1 2 3 4 05001000150020002500 Distance (ft) Log BNP (pg/mL) r = 0.513 Wieczorek S, Wu AHB, et al. Unpublished data BNP vs. Six-Minute Walk Study by Wu et.al.

61. BNP Concentration and the Degree of CHF Severity BNP Concentration (pg/ml) 186 ± 22 791 ± 165 2013 ± 266 n = 27 n = 34 n = 36 CHF Severity MildModerateSevere 0 500 1000 1500 2000 2500 61

62. Ready for Prime Time? Cardiologists and internists may now have a tool with which to determine whether a patient has congestive heart failure and to measure its severity, much as physicians routinely measure serum creatinine in patients with renal disease and perform liver-function tests in patients with hepatic disorders. Kenneth L. Baughman, MD N Engl J Med 2002;347:158-159

63. THANK YOU!! Davidplaut@yahoo.com

64. Case C 2.3 563 4 0.4 222 2 0.0 63 0 h cTnI <0.06 MYO <80 Time A 67 yr old male with a history of cardiac problems presents to the ED with shortness of breath and pain in his left elbow.