High Sensitivity Troponin Improves Management But Not Yet 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 *Dr. Jaffe is or has been a consultant to most of the major diagnostic companies as well as Pfizer and Amgen. CP887679-0
AUC More Diagnoses with Higher-Sensitivity Assays 1.0 Sensitive troponin I 99 th % value 0.8 0.6 0.4 Troponin T 10%CV value 0.2 0.0 NEJM 361:868, 2009 0 to <3 3 to <6 6 to <9 9 to <12 12-15 All Time of chest-pain onset (hr) Diagnosis of AMI (no.) 227 97 44 29 17 528 Single determination (no.) Sensitive troponin I 184 100 38 32 25 534 >0.04 ng/ml Troponin T >0.03 ng/ml 81 56 19 21 12 305 CP887679-1
Area under the ROC curve Accuracy by Time of Admission 1.000 0.950 0.900 99 th % value 0.850 0.000 NEJM 361:858, 2009 Mostly same assays but < 99 th % value cut off used 0.800 0.750 0.700 Abbott-architect troponin I Roche high-sensitive troponin T Roche troponin I Siemens troponin I ultra Standard assay 2 4 6 10 All patients Hours since onset of symptoms CP887679-2
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 CP887679-3
Diagnosis of NSTEMI and Unstable Angina 120 100 80 60 10% CV 99 th % hsctnt 85.5 100 100 40 20 0 4.6 0 0 0 Non-ACS (n=174) 0 UA (n=101) 23.8 NSTEMI (n=83) Ordonez, TUSCA CP887679-4
Diagnostic Increases in ctn (Christchurch ED Trial) hs TnT Tnl 3 TnT 100 Baseline 100 Total 80 80 60 60 40 40 20 20 0 0-2 2-4 4-6 6-8 8-10 >10 n=20 n=26 n=9 n=8 n=7 n=18 Aldous et al: Ann Clin Biochem 48:241, 2011 0 0-2 2-4 4-6 6-8 8-10 >10 CP887679-5
Prevalence of Detectable Cardiac Troponin T ( 3 ng/l) and levels greater the 99 th percentile value ( 14 ng/l). 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) CP887679-6
Cumulative incidence of overall death (%) Total Mortality by ctnt Values All-Cause Mortality 40 30 ctnt Detectable Undetectable 40 30 ctnt category, ng/ml 0.0014 0.0066-<0.0014 0.0041-0.00657 0.003-0.00440 <0.003 (undetectable) 20 20 10 10 0 0 12 24 36 48 60 72 No. at risk Months ctnt Detectable 957 945 933 914 903 887 651 Undetectable 2,589 2,584 2,576 2,570 2,554 2,552 1,995 0 0 12 24 36 48 60 72 Months No. at risk 0.0014 122 117 115 109 101 94 64 0.0066-<0.0014 278 273 267 261 258 254 182 0.00441-0.00657 279 278 276 271 271 268 209 0.003-0.00440 278 277 275 273 273 271 196 <0.003 2,589 2,584 2,576 2,570 2,554 2,552 1,995 P<0.001 for all between-group comparisons by the log-rank test; detectable cardiac troponin T (ctnt) levels are 0.003 ng/ml or greater by the highly sensitive assay; Y-axes shown in blue indicate the range from 0% to 20% JAMA 304(22):2503, 2010 CP887679-7
hsctnt and Chronic CAD hsctnt in Men vs Women 16 14 hs-ctnt (ng/l) 12 10 8 6 4 No CAD Mild Moderate Severe Multi Laufer et al: Arterioscler Thromb Vasc Biol 30:1272, 2010 CP887679-8
Death and Hospitalization and hstnt at Baseline 10 Mortality Hospitalization for HF Hazard ratio (95% CI) 1 Latini et al: Circ 116, 2007 0 1 2 3 4 5 6 7 8 9 10 Deciles CP887679-9
SENSITIVITIES AND SPECIFICITIES INCORPORATING DELTA TROPONINS n = 332, (%) Number positive Sensitivity Specificity hstnt > 99 th centile at peak 143 (43.1) 90.9 (85.2 94.8) 80.6 (77.8 82.5) + 20% delta 93 (28.0) 71.8 (66.0 76.2) 93.7 (90.8 95.9) + 50% delta 75 (22.6) 61.8 (56.7 64.9) 96.8 (94.3 98.4) Tnl 3 > 99 th centile at peak 129 (38.9) 90.0 (84.4 88.4) 86.5 (83.7 88.4) + 20% delta 100 (30.1) 74.5 (68.5 79.3) 91.9 (88.9 94.3) + 50% delta 88 (26.5) 68.2 (62.4 72.5) 94.1 (91.3 96.3) TnT > 99 th centile at peak 108 (32.5) 83.6 (78.1 87.9) 92.8 (90.0 94.9) + 20% delta 91 (27.4) 72.7 (67.2 76.7) 95.0 (92.3 97.0) + 50% delta 79 (23.8) 65.5 (60.4 68.8) 96.8 (94.3 98.4) Reference: Ann Clin Bioch 2011;48(3):241-248. CP887679-10
SENSITIVITIES AND SPECIFICITIES INCORPORATING DELTA TROPONINS n = 332, (%) Number positive Sensitivity Specificity hstnt > 99 th centile at peak 143 (43.1) 90.9 (85.2 94.8) 80.6 (77.8 82.5) + 20% delta 93 (28.0) 71.8 (66.0 76.2) 93.7 (90.8 95.9) + 50% delta 75 (22.6) 61.8 (56.7 64.9) 96.8 (94.3 98.4) Tnl 3 > 99 th centile at peak 129 (38.9) 90.0 (84.4 88.4) 86.5 (83.7 88.4) + 20% delta 100 (30.1) 74.5 (68.5 79.3) 91.9 (88.9 94.3) + 50% delta 88 (26.5) 68.2 (62.4 72.5) 94.1 (91.3 96.3) TnT > 99 th centile at peak 108 (32.5) 83.6 (78.1 87.9) 92.8 (90.0 94.9) + 20% delta 91 (27.4) 72.7 (67.2 76.7) 95.0 (92.3 97.0) + 50% delta 79 (23.8) 65.5 (60.4 68.8) 96.8 (94.3 98.4) Reference: Ann Clin Bioch 2011;48(3):241-248. CP887679-11
SENSITIVITIES AND SPECIFICITIES INCORPORATING DELTA TROPONINS n = 332, (%) Number positive Sensitivity Specificity hstnt > 99 th centile at peak 143 (43.1) 90.9 (85.2 94.8) 80.6 (77.8 82.5) + 20% delta 93 (28.0) 71.8 (66.0 76.2) 93.7 (90.8 95.9) + 50% delta 75 (22.6) 61.8 (56.7 64.9) 96.8 (94.3 98.4) Tnl 3 > 99 th centile at peak 129 (38.9) 90.0 (84.4 88.4) 86.5 (83.7 88.4) + 20% delta 100 (30.1) 74.5 (68.5 79.3) 91.9 (88.9 94.3) + 50% delta 88 (26.5) 68.2 (62.4 72.5) 94.1 (91.3 96.3) TnT > 99 th centile at peak 108 (32.5) 83.6 (78.1 87.9) 92.8 (90.0 94.9) + 20% delta 91 (27.4) 72.7 (67.2 76.7) 95.0 (92.3 97.0) + 50% delta 79 (23.8) 65.5 (60.4 68.8) 96.8 (94.3 98.4) Reference: Ann Clin Bioch 2011;48(3):241-248. CP887679-12
Short-Term Biological Variability in ctnl Participant no. 1 2 3 4 5 6 7 8 9 10 11 12 Clin Chem 55:1, 2009 0.0 1.0 2.0 3.0 4.0 5.0 6.0 ctnl (ng/l) CP887679-13
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 Retest hstnt 3 hours later Change < 50% Change 50% Retest hstnt 3 hours later Change < 20% Change 20% 14ng/L rules out MI with >90% probability If 14ng/L then proceed to middle part of algorithm. Adverse Prognosis Retest hstnt at 6,12 hr Evidence based treatments Myocardial infarction CP887679-14 White HD; AHJ 2010
Short- and Long-term Bio variation in hsctnt Analytical variation Short Term Long term CVA, % 53.5 98 Biological Variation CVI, % 48.2 CVG, % 85.9 Index of Individuality 84.5 RCV, log-normal increase, % 84.6 94 94 19.6 315 CP887679-15
sensitivity ROC Analysis for 1- and 2-Hour Change 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 0.0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1-specificity 1-specificity hs-ctnt 1h absolute change ( ) AUC 0.93 ctnl Ultra 1h absolute change ( ) AUC 0.94 hs-ctnt 1h relative change ( %) AUC 0.66 ctnl Ultra 1h relative change ( ) AUC 0.64 hs-ctnt 2h absolute change ( ) AUC 0.95 ctnl Ultra 2h absolute change ( ) AUC 0.95 hs-ctnt 2h relative change ( %) AUC 0.76 ctnl Ultra 2h relative change ( ) AUC 0.72 Reichlin et al: Circulation 124:135, 2011 CP887679-16
CP887679-17
Myocardial Infarction Type 2 Myocardial infarction secondary to ischemia due to either increased oxygen demand or decreased supply in a setting where coronary supply is at least some part of the problem, e.g. spasm, fixed coronary artery disease, endothelial dysfunction. CP887679-18
TACTICS (TIMI 18) Cardiac troponin T Conservative Invasive No. treatment treatment Primary endpoint <0.1 ng/ml 840 5.6 6.0 0.1 - <0.4 137 16.2 8.7 0.4 - <1.5 101 12.2 3.9 1.5 748 16.8 8.3 Favors invasive treatment Favors Conservative treatment Death or MI <0.1 ng/ml 810 3.1 2.9 0.1 - <0.4 137 13.2 7.3 0.4 - <1.5 101 4.1 1.9 1.5 748 11.0 5.5 JAMA 286:2405, 2001 0.01 0.1 1.0 10 Odds ratio CP1036852-10 CP887679-19
30 20 Any Marker Positive (n=442) P=0.03 Outcomes by Gender Women TACTICS-TIMI 18 No Marker Positive (n=173) Rehosp Death/MI P=0.02 Any Marker Positive (n=885) P=0.002 Men No Marker Positive (n=297) P=NS % 10 0 Invasive P=NS Conservative Invasive P=NS Conservative Invasive P=0.07 Conservative P=NS Invasive Conservative Circ 109:584, 2004 CP887679- CP1143360-11 20
Short-Term Events Gusto IV ACS 20 15 hs-ctnt neg/ctnt neg hs-ctnt pos/ctnt pos hs-ctnt pos/ctnt neg P<0.001 P=0.52 P<0.001 P=0.001 P=0.85 P=0.001 P<0.001 % 10 P=0.08 P=0.07 5 0 AHJ 160:224, 2010 Death at 1 yr Death/AMI at 30 days PCI at 30 days CP887679-21
DIAGNOSTIC PERFORMANCE OF THREE MODELS INCORPORATING hstnt AND ECG FINDINGS FOR EARLY EXCLUSION OF AMI Model Sensitivity Specificity PPV NPV (95% Cl) (95% Cl) (95%Cl) (95% Cl) A 100.0 (97.1 100.0) 30.1 (26.3 34.0) 23.7 (20.2 27.6) 100.0 (97.9 100.0) B 95.2 (89.9 98.2) 69.4 (65.5 73.2) 40.4 (34.8 46.2) 98.5 (96.8 99.5) C 100.0 (97.1 100.0) 66.4 (63.1 69.5) 30.3 (25.9 35.0) 100.0 (99.4 100.0) Model A: hstnt <3 ng/l and no ECG ischaemia; Model B: hstnt <14 ng/l and no ECG ischaemia; Model C: (hstnt <3 ng/l and no ECG ischaemia) OR (hstnt <14 ng/l and no ECG ischaemia and symptom onset <6h) Reference: Body CP887679-22
RULING OUT AMI 1. May require different criteria to do this early. 2. No data that sending people home with elevations and non ACS diagnoses is safe. 3. Using other markers will be associated with false positive elevations of that marker which will require some attention. CP887679-23
Post PCI and hsctn NO DATA CP887679-24