1. Cardiac Biomarkers W. Frank Peacock, M.D., FACEP Professor, Emergency Medicine Cleveland Clinic

2. Biomarker? What is a biomarker? – An expensive lab test – Commonly Protein with levels that correspond to Diagnosis Prognosis – Most common method of measurement ELISA

3. Lab-test-ology Sensitivity TP/(TP+FN) Specificity TN/(TN+FP)

4. Lab-test-ology LOB LOD CV 99 th %ile

5. CV vs LOD Assay w LOD 5 pg/mL LOD 99 th %ile

6. CV and 99 th %ile 99% of the normal range for cTnI 99% Cutoff 7 pg/ml 10% CV The box of undetectableness Where is the 99 th %ile?

7. CV and 99 th %ile 99% of the normal range for cTnI 99% Cutoff 7 pg/ml 10% CV 20% CV 30% CV

8. Historical timing of cardiac necrosis markers

9. TIMI IIIB: Troponin I Levels Predict Mortality In UA/NSTEMI 1.0 1.7 3.4 3.7 6.0 7.5 0 2 4 6 8 0 to <0.40.4 to <1.01.0 to <2.02.0 to <5.05.0 to <9.0>9.0 8311741481346750 Risk Cardiac Troponin I (ng/ml) Ratio 1.0 1.83.5 3.96.27.8 Mortality at 42 Days (% of Patients) Antman EA, et al. N Engl J Med. 1996;335:1342-1349

10. 2000 Emergency docs – This crap is useless in almost all patients – Only helpful if positive Rarely positive, <5% of chest pain – The rest of chest pain requires other testing Cardiologists own troponin – Tactics-TIMI 18 – IF it is detectable, it is an MI, otherwise forget it – If positive, don’t even bother thinking, just call the cath lab

11. C Statistic AUC = C Statistic C Stat = 50% REALLY BAD TEST C Stat = 1.0 A PERFECT Test C Stat = 75 C Stat = 0.69 OK test Area Under the Receiver Operator Characteristic (ROC) Curve

12. Reichlin T. N Engl J Med 2009;361:858-67. 718 consecutive ED suspect AMI MI/USA 238 (33.1%)

13. ACEP Marker Recommendations Level A recommendations Don’t use markers to exclude non-AMI ACS (ie, unstable angina) Level B recommendations Use any of the following to exclude NSTEMI 8-12 hours after symptom onset –A single (-) CK-MB mass, TnI, or TnT Serial measures if < 8 hours after symptom onset –Baseline and 90 mins »A (-) myoglobin with a (-) CKMB, or (-) Tn –(-) 2-hour delta »CK-MB and Tn Can you trust them?

14. Historical timing of cardiac necrosis markers hsTnI

16. If It Moves, It Is Bad MarkerComparatorOR for 30 day MACE 95% CI  ing Tn vs. stable Troponin 2.251.42-3.55  ing Tn 3.041.94-4.75  ing CKMB vs. stable CKMB 0.670.48-0.95  ing CKMB 0.960.57-1.60 Logistic regression models showing the odds ratios for predicting ACS MACE: MI, revascularization (PCI or CABG), or positive testing (>70% stenosis at catheterization, [+] MPI or non-invasive stress testing) within 30 days of index visit. McMullin N. AJEM 2009.

17. Event Free vs cTnT Values Days after admission to the hospital AJC 93:278, 2004 Normal <0.01  g/L Marginal <0.01-0.09  g/L Frank elevation >0.01  g/L Cumulative proportion free of events P=0.004

18. STRIVE ® You can’t have it both ways…

19. Tn, its not just for AMI anymore

20. Tn Elevation w/o Overt Cardiac Ischemia Trauma contusion, ablation, pacing, ICD firings, cardioversion, endomyocardial biopsy, cardiac surgery, interventional closure of ASDs CHF Aortic valve disease and HOCM with significant LVH HTN Hypotension, often with arrhythmias Postoperative noncardiac surgery patients who seem to do well Renal failure Critically ill patients, esp with diabetes, respiratory failure, gi bleeding, sepsis Drug toxicity, eg adriamycin, 5 FU, herceptin, snake venoms, carbon monoxide poisoning Hypothyroidism Abnormalities in coronary vasomotion, including coronary vasospasm Apical ballooning syndrome Inflammatory diseases – myocarditis, eg. Parvovirus B19, Kawasaki disease, sarcoid, smallpox vaccination, or myocardial extension of BE Post PCI patients who appear to be uncomplicated Pulmonary embolism, severe pulmonary hypertension Sepsis Burns, esp if TBSA > 30% Infiltrative diseases including amyloidosis, hemachromatosis, sarcoidosis and scleroderma Acute neurological disease – CVA, subarchnoid bleeds Rhabdomyolysis with cardiac injury Transplant vasculopathy Vital Exhaustion

21. What now? Cardiologists are in a tizzy Cardiologists are in a tizzy All these “false positives” All these “false positives” Emergency docs think this is great Emergency docs think this is great There is no such thing as a false positive when your talking about being DEAD There is no such thing as a false positive when your talking about being DEAD

22. Reichlin T. N Engl J Med 2009;361:858-67. Do we really gotta be doing serial troponin’s anymore???

23. 2012 The decade of 2000-10 –Will be remembered as when the cardiologists owned troponin Used to be an MI marker –Those days are gone Emergency Medicine –Taking troponin back from the cardiologists! –IT IS NOT AN AMI MARKER ANYMORE Now it’s a 14 day death marker –I don’t care about 30 days or 180 days from now –I REALLY don’t care about a year from now

24. Myocardial Infarction It’s a changing world An MI used to be – >40 and sweating with chest pain – Positive markers in 8-12 hours Now – It aint >40 – It aint sweating – It aint even chest pain

25. It would be really great if they had it written on their forehead!!

26. In 2011, you will miss 423,600 Acute Myocardial Infarction’s 1/3 have no chest pain Canto JG et al. JAMA. 2000;283:3223-3229 If you think this is the way they look…

27. STRIVE ® % With Chest Pain During AMI Stratified by Age SOB W&D N/V Syncope Confused

28. STRIVE ® 28 When your laying naked around the ER, they all look the same…… This one is having an AMI

29. STRIVE ® Closing Time You don’t have to go home, but you can’t stay here…. –Semisonic

30. STRIVE ® The ER docs challenge Admit them all: and let the insurance company sort them out… Discharge them all and let God sort them out…

31. STRIVE ® Emergency Medicine Roulette What % are discharged from the ED??

32. 14 Asia-Pacific region EDs >18yo with >5 mins CP Risk stratification (blinded to care team) –TIMI<1, ECG non-dx, –Negative 0 & 2hr POC Tn, CKMB, myo Endpoint: 30 day MACE Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3

33. STRIVE ® 33 TIMI Risk Score Risk factors: –Age  65 years –  3 risk factors for CAD –Prior coronary stenosis  50% –ST-segment deviation on ECG –  2 anginal events in last 24 hours –Use of ASA in last 7 days –Elevated serum cardiac markers CK-MB or troponin Each risk factor is assigned 1 point, and the total represents a given patient’s TIMI Risk Score 1 Event rates (all-cause mortality, MI, or urgent revascularization) increase with each 1-point increase in score (P<0.001 by chi square test for trend) 1 Number of Risk Factors 1 Rate of Composite Endpoint (Days 1-14), % 1.Antman EM et al. JAMA. 2000;284:835-842.

34. N=3582 –30 day MACE in 421 (11·8%) –Most often NSTEMI ADP identified 9·8% (352/3582) as low risk –3 (0·9%) had 30 day MACE Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3

35. Potential costs savings in low risk negative ADP patients Hospital LOS –Median 26·0 h (IQR 9·9–37·0) –Mean 43·2 h (95% CI 36·2–51·2) Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3

36. STRIVE ® He is a 67 year old, hypertensive, obese man. He took an aspirin this morning, he still smokes and has high cholesterol. Many of his family have CAD. He has been a diabetic for 15 years, and 4 years ago he had an MI. Age > 65, 3 risk factors, H/O MI, took asa: TIMI Risk score = 4 19.9% chance of death, MI, or UTVR in the next 14 days George is sitting in his bar at his restaurant across the street from the Emergency Department

37. STRIVE ® He is a 67 year old, hypertensive, obese man. He took an aspirin this morning, he still smokes and has high cholesterol. Many of his family have CAD. He has been a diabetic for 15 years, and 4 years ago he had an MI. TIMI Risk score = 4 19.9% chance of death, MI, or UTVR in the next 14 days George is laying in the ED, diaphoretic, with crushing CP, nauseated, BP = 100/70

38. Can we discharge you?? Derivation by blinded sampling (N= 703) 130 (18.5%) AMI –None w initially undetectable hs-cTnT –Sn 100.0%, NPV 100.0% 27.7% would have ‘ruled out’ for AMI –2 (1.0%) died or had AMI w/in 6 months » (1 peri-procedural AMI, 1 non-cardiac death) Validation by standard practice (N= 915) –1 patient (0.6%) with initially undetectable hscTnT developed subsequent elevation (to 17ng/L) Sn 99.8% (99.1-100.0) NPV 99.4% (96.6-100.0). Body, et al. JACC, 2011

39. European Society of Cardiology A Tn @ presentation cannot R/O NSTEMI –Repeated Tn 3 hours after admit or more CP. –LOE 1B Tn is preferred over CKMB Myoglobin is not specific or sensitive enough –Is not recommended.

40. STRIVE ® ESC Guidelines Due to improved analytical sensitivity, low troponin levels can be detected in stable angina and in healthy patients. The mechanisms of this troponin release are not yet explained, but ANY measurable troponin is associated with an unfavourable prognosis.

41. Low Level Troponins One Cut-off or Two? 0 2 4 6 8 10 12 14 16 1357911131517192123252729More pg/ml cTNI Frequency Myocardial necrosis AMI Sp=99% Wait and see, do more tests AMI Sp=85%

42. The Now and Then of High Sensitivity Troponins Last decade Detectable Tn –99 th %ile cutpoint Great specificity Better sensitivity –No real clinical disposition impact for the ER Serial testing of less necessary Next decade Good bye specificity 2 cutpoints? Second marker –copeptin, ST-2, MPO, IMA, etc Hello sensitivity Exclude ischemia? Challenges –The role of cardiology consults –EDUCATION…………

43. So next time you want to get a troponin…. Risk stratify (after decide it might be ACS) You want to send that patient home? –Put on your thinking cap! –AMI? Something else? Can always repeat

44. Results 25 participating hospitals N=1,360 patients Overall Mean DTBT 115.7  70.1 minutes Median 100; IQR=73,138 Central lab Mean DTBT 119.2  70.5 minutes Median 103; IQR=76,141 Point of Care Mean DTBT 68.2  40.8 minutes Median 62.5, IQR=43,83.5 Peacock WF et al. Acad Emerg Med. 2004;11:569–570. Saves about 1 hour

45. Delay = Death N= 13,934,542 Adverse events increase with the mean LOS in similar patients in the same ED shift OR for Death if LOS ≥6 v <1 hr cohorts –Hi Acuity 1.79 Low Acuity 1.71 BMJ 2011; 342:d2983

46. Overcrowding = Long waits Long waits = Death N= 62,495 Risk ratio for DEATH –Per hour of ED stay = 1.1 (p < 0.001) –Per hour of ED wait = 1.2 (p=0.01) MJA 2006; 184: 208–212

47. Delay = Bad Care N=42,780 Long ED stays less often received guideline-recommended NSTEMI therapies Ann Emerg Med. 2007; 50; 489-96

48. Delay = Bad Care N=694 patientsDelayed/No antibiotics –OR 1.05 for each additional WR patient –OR 1.14 for each additional WR hour Ann Emerg Med. 2007;50:510-516

49. Delay = Bad Care N=13,758 Nontreatment of pain associated with waiting room number OR = 1.03 for each additional waiting patient Ann Emerg Med. 2008;51:1-5.]

50. Delay = Bad Care N=162 “boarded” patients (waiting for room) Undesirable event Missed meds, lab results, arrhythmias, or other adverse events 27.8% had an undesirable event Ann Emerg Med. 2009;54:381-385.]

51. 14,054,431 patients: waiting = bad outcomes or death

52. What business intentionally kills its customers? The era of POC needing to justify itself is over. We are now in the era where the central lab must prove it is not killing our patients. If you had a way of getting data quickly, wouldn’t you?

53. POC vs Lab Singulex 295 MIDAS patients 155 (52.5%) NCCP 67 (22.7%) USA 61 (20.7%) NSTEMI 12 (4.1%) STEMI SensitivitySpecificity Negative Predictive Value Positive Predictive Value Area Underneath ROC curve (C-Statistic) Point of Care Alere 8694958294 Central Lab Singulex 9086966894 SnSpNPVPPVAUC POC8694958294 Lab9086966894