Defining rise and fall of cardiac troponin values

Defining rise and fall of cardiac troponin values Doable but Not Simple Allan S. Jaffe, MD.* Consultant - Cardiology & Laboratory Medicine Professor of Medicine Chair, CCLS Division, Department of Laboratory Medicine and Pathology Mayo Clinic and Medical School Rochester, Minnesota Chair, Biomarker Subcommittee of the Global Task Force *Dr. Jaffe is a has been a consultant to most of the major diagnostic companies as well as Amgen. CP887679-0

ctnt Determinants of Elevation in the Community* 40 P<0.0001 30 % with elevated ctnt 20 10 0 0 1 2 >3 Risk determinants present (no.) No. 2,087 478 120 22 *Circulation, 113: 1958 1965, 2006 CP1219620-13 CP887679-1

Prevalence of Detectable ctnt & levels > 99 th Percentile URL. ctnt Level, ng/ml.. 0.003.. 0.014. Sample Sample Sample Weight-Adjusted Weight-Adjusted Size, Prevalence, % Prevalence, Group No. No. (%) (95% Cl) No. (%) 95% Cl) Overall population 3546 957 (27.0) 25.0 (22.7 27.4) Restricted population Without CHD 3428 891 (26.0) 24.2 (21.8 26.5) Without cardiovascular disease 3277 813 (24.8) 23.7 (21.3 26.1) Without cardiovascular disease or CKD a Without cardiovascular disease, CKD, subclinical heart disease, diabetes, or hypertension b 3222 773 (24.0) 23.1 (20.7 25.5) 2554 510 (20.0) 19.3 (16.8 21.8) 122 (3.4) 103 (3.0) 2.0 (1.5 2.6) 1.8 (1.2 2.4) 82 (2.5) 1.9 (1.0 2.0) 65 (2.3) 1.2 (0.8 1.7) 43 (1.7) 1.1 (0.6 1.7) CP887679-2

All-Cause Mortality by Cardiac Troponin T (n=733) Cumulative survival (%) 100 80 60 40 20 0 Time since blood draw (years) ctnt <0.01 g/l ctnt 0.04 g/l ctnt 0.04 to 0.10 g/l ctnt 0.10 g/l 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Patients at risk (no.) Baseline 1 yr 2 yr 2.5 yr ctnt <0.01 g/l 132 106 25 12 ctnt 0.01 to <0.04 g/l 214 166 41 15 ctnt 0.04 to <0.10 g/l 239 180 63 18 ctnt 0.10 g/l 148 93 20 8 Circulation 106:2944, 2002 CP1090800-14 CP887679-3

TnT (ng/l) TnT (ng/l) Above cutpoint (%) Age Dependence of hsctnt Values 120 100 ED Patients n=651 120 100 Population Cohort 50 40 ED Pt Above Given Cut Off Values (%) Age >65 yr 80 60 40 80 60 40 99th 30 20 20 0 20 0 10 0 Age <65 yr Age (yr) Age (yr) TnT cutpoint (ng/l) Hammarsten et al: Clin Chem, 2012 CP887679-4

99 th Percentile Values in Normal Subjects Measured By Contemporary, Sensitive and High-Sensitivity Cardiac Troponin Assays High Sensitivity 99 th Percentile Percent Measurable Male 99 th Percentile Female 99 th Percentile LoD N ng/l >LoD ng/l ng/l ng/l Abbott ARCHITECT Beckman Access Siemens Dimension Vista Singulex Erenna 23.4 95.0 35.8 15.1 1.2 524 32.2 87.4 52.2 23.1 3.0 524 57.5 85.3 81.0 42.3 0.5 503 31.4 100.0 36.3 30.3 0.009 523 Roche ctnt 14.5 25.4 20.3 12.9 5.0 523 Apple et al: CLINCHEM/2012/186874 CP887679-5

Changes in ctnt in Dialysis Patients with ACS ctnt (µmol/l) 30 25 20 15 3 2 1 0 0 1 2 Nephron Clin Prac 98:c87, 2004 Days CP887679- CP1232536-1 6

Delta Guidance Must use fixed timing The greater the change, the more likely AMI The lesser the change, the less likely AMI CP887679-7

CV (%) Cardiac Troponin T Precision Profile 50,0 99 th % value = <0.01 ng/ml 40,0 10% CV value = 0.035 ng/ml 30,0 20,0 10,0 ROC value = 0.1 ng/ml 0,0 0,00 0,02 0,04 0,06 0,08 0,10 0,12 0,14 0,16 0,18 Concentration (µg/l) CP887679-8

Determining Assay Values are Different CP887679-9

Use of High Sensitivity Troponin T to Diagnose Myocardial Infarction Clinical setting consistent with myocardial ischemia Baseline <14 ng/l 14-52 ng/l 53 ng/l Retest hstnt 3 hours after symptom onset or if timing of symptom onset is unclear at 6 hours after presentation Change <50% 14-52 ng/l 53 ng/l Change 50% Change <20% Change 20% 14 ng/l rules out MI with >90% probability If 14 ng/l then proceed to middle part of algorithm Adverse prognosis Retest hstnt at 6, 12 hr White HD; AHJ 2010 Myocardial infarction Evidence-based treatments CP887679-10

ug/l Absolute and Relative Changes of ctn Over 1- and 2-hours 0.400 0.300 Hs-cTnT 1h absolute changes Hs-cTnT 2h absolute changes ctnl Ultra 1h absolute changes ctnl Ultra 2h absolute changes 300 Hs-cTnT 1h relative changes Hs-cTnT 2h relative changes ctnl Ultra 1h relative changes ctnl Ultra 2h relative changes 0.300 0.200 200 0.200 % 100 0.100 0.100 0 0.000 0.000 AMI Unstable angina Cardiac but not CAD Non- Unknown cardiac chest pain -100 AMI Unstable angina Cardiac but not CAD Non- Unknown cardiac chest pain Reichlin et al: Circulation 124:135, 2011 CP887679-11

Absolute and Relative Changes in Patients with AMI, Unstable Angina and Non-Cardiac Chest Pain 10000.000 1000.000 100.000 10.000 1.000 0.100 0.010 0.001 100000.000 10000.000 1000.000 100.000 10.000 1.000 0.100 0.010 0.001 Non-STEMI UAP Non-ACS Non-STEMI UAP Non-ACS Absolute change (log) Relative change (log) Mueller et al: Clinical Chemistry 58:1 (2011) CP887679-12

Sensitivity ROC Analysis by Deltas % Change [(y-x)/x *100] Absolute value of % Change Change (y-x) Absolute value of Change 100-specificity Apple FS et al: Clin Biochem (2012) CP887679-13

Sensitivity Diagnostic Increases in ctn (Christchurch ED Trial) 1.0 Baseline Total 0.8 0.6 0.4 0.2 Hs TnT Abbott TnT CKMB Reference line 0.0 0.00 0.02 0.04 0.06 0.08 0.10 1-specificity 0.00 0.02 0.04 0.06 0.08 0.10 1-specificity Aldous et al: Ann Clin Biochem 48:241, 2011 CP887679-14

Reasons for Difficulty Calculating the Proper Delta Value Problems with the gold standard diagnosis Inclusion of patients with large infarctions diagnosed with less sensitive assays will increase deltas Inclusion of patients based on elevations of ctn alone based on adjudication criteria will reduce deltas CP887679-15

Sensitivity High sensitive troponin T (pg/ml) Sensitivity Relationship of hsctnt and Plaque Characteristics 100 Detection of Non-Calcified Plaque 45 40 35 30 25 20 15 10 Classified by Plaque Composition P<0.001 P<0.001 P<0.001 P=NS 80 60 40 20 0 Hs TnT>10.5 * AUC=0.79 100-specificity SE=0.04 95% CI=0.71-0.86 0 20 40 60 80 100 Detection of 5 0 Normal vessels (n=46) Only calcified plaque (n=26) Non- Calcified Plaque (n=44) Remodeled Plaque (n=8) 100 80 60 40 Remodeled Plaque * Hs TnT>21.8 20 AUC=0.90 SE=0.07 * Using a cut-off value of hstnt=14 pg/ml Korosoglou et al: Heart 97:2011 0 95% CI=0.84-0.95 0 20 40 60 80 100 100-specificity CP887679-16

Reasons for Difficulty Calcuating the Proper Delta Value Problems with the gold standard diagnosis Flow dependence of release High sensitivity means small changes make big differences What metric is desired to optmize clinical performance; i.e. sensitivity vs specificity CP887679-17

Sensitivity Specificity Defining the Optimal Delta: The Tension Between Sensitivity and Specificity 100 100 80 80 60 60 40 20 Sensitivity Specificity 40 20 0 0 0 50 100 150 200 250 Relative change in hstni concentration Data from Keller et al (20) CP887679-18

Reasons for Difficulty Calcuating the Proper Delta Value Problems with the gold standard diagnosis Flow dependence of release High sensitivity means small changes make big differences What metric is desired to optmize clinical performance; i.e. sensitivity vs specificity Spontaneous changes in those without AMI CP887679-19

Short-Term Analytical and Biological Variation by hs-ctnl Assays Abbott a Beckman a Roche (E170) b Siemens a Singulex c CV-A (%) d 13.8 14.5 7.8 13.0 8.3 CV-I (%) 15.2 6.1 15.0 12.9 9.7 CV-G (%) 70.5 34.8 NA 12.3 57.0 Index of individuality 0.22 0.46 NA 0.11 0.21 RCV (%) e NA NA 47.0 NA NA RCV increase (%) f 69.3 63.8 NA 57.5 46.0 RCV decrease (%) f -40.9-38.9 NA -36.5-32.0 Within-individual mean (ng/l) 3.5 4.9 NA 5.5 2.8 a Apple et al (38); b Vasile et al (36); c Wu et al (35) d CV-A, analytical CV; CV-I, within-individual CV; CV-G, between individual CV; NA, not available; RCV, relative change value; e REC percentage applies to parametric data f RCV increase and decrease percentages refer to nonparametric data and are log-transformed Apple et al: Clin Chem 58:1, 2012 CP887679-20

PERCENTILES OF CHANGE IN ctnt CONCENTRATION IN CORONARY CARE UNIT PATIENTS WITHOUT MI. Relative change, %.. Absolute change, ng/l. Diagnosis 50 th (95% Cl) 97.5 th (95% Cl) 50 th (95% Cl) 97.5 th (95% Cl) n a All diagnoses 10 (10-11) 59 (48-71) 1.6 (1.4-1.7) 14.1 (10.1-18) 866 Heart failure 10 ( 9-12) 51 (38-65) 3.1 (2.5-3.7) 30 (17.3-42.5) 204 Stable angina pectoris 10 ( 9-1 2) 67 (34-99) 1.4 (1.2-1.6) 13.6 (9.4-17.8) 343 Atrial fibrillation 9 ( 6-12) 66 (29-104) 1.1 (0.8-1.4) 9.1 (6.4-11.8) 86 Noncardiac chest pain 12 (10-15) 64 (46-82) 1.2 (1-1.5) 7.5 (5.9 0-9.1) 229 a Number of ctnt measurements included in calculations. b NA, not applicable, because the absolute change in ctnt concentration differed among diagnosis groups (heart failure vs atrial fibrillation, stable angina pectoris, and noncardiac chest pain, all P <0.02, and atrial fibrillation vs stable angina pectoris, P = 0.017, for difference in medians. Reference Clin Chem 2012;58(3) CP887679-21

Reasons for Difficulty Calcuating the Proper Delta Value Problems with the gold standard diagnosis Flow dependence of release High sensitivity means small changes make big differences What metric is desired to optmize clinical performance; i.e. sensitivity vs specificity Spontaneous changes in those without AMI What to call those who have elevated hsctn but a less than significant defined delta? CP887679-22

MUST USE FIXED TIMING Near 99 th % URL value Delta Guidance The greater the change, the more likely AMI The lesser the change, the less likely AMI Percentages and absolute values may provide similar information At higher levels Absolute values may be better CP887679-23

Delta Guidance MUST USE FIXED TIMING Near 99 th % URL value At higher levels Avoid The greater the change, the more likely AMI The lesser the change, the less likely AMI Percentages and absolute values may provide similar information Absolute values may be better Extrapolating the data from one assay to another assay The idea that release is continuous so that one can use a one or 2 hour delta by dividing by the delta found at 5 or 6 hours. CP887679-24

It is not the Data but How You Intepret it that is Important CP887679-25