Defining rise and fall of cardiac troponin values

Transcription

1 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. CP

2 ctnt Determinants of Elevation in the Community* 40 P< % with elevated ctnt >3 Risk determinants present (no.) No. 2, *Circulation, 113: , 2006 CP CP

3 Prevalence of Detectable ctnt & levels > 99 th Percentile URL. ctnt Level, ng/ml Sample Sample Sample Weight-Adjusted Weight-Adjusted Size, Prevalence, % Prevalence, Group No. No. (%) (95% Cl) No. (%) 95% Cl) Overall population (27.0) 25.0 ( ) Restricted population Without CHD (26.0) 24.2 ( ) Without cardiovascular disease (24.8) 23.7 ( ) Without cardiovascular disease or CKD a Without cardiovascular disease, CKD, subclinical heart disease, diabetes, or hypertension b (24.0) 23.1 ( ) (20.0) 19.3 ( ) 122 (3.4) 103 (3.0) 2.0 ( ) 1.8 ( ) 82 (2.5) 1.9 ( ) 65 (2.3) 1.2 ( ) 43 (1.7) 1.1 ( ) CP

4 All-Cause Mortality by Cardiac Troponin T (n=733) Cumulative survival (%) 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 Patients at risk (no.) Baseline 1 yr 2 yr 2.5 yr ctnt <0.01 g/l ctnt 0.01 to <0.04 g/l ctnt 0.04 to <0.10 g/l ctnt 0.10 g/l Circulation 106:2944, 2002 CP CP

5 TnT (ng/l) TnT (ng/l) Above cutpoint (%) Age Dependence of hsctnt Values ED Patients n= Population Cohort ED Pt Above Given Cut Off Values (%) Age >65 yr th Age <65 yr Age (yr) Age (yr) TnT cutpoint (ng/l) Hammarsten et al: Clin Chem, 2012 CP

6 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 Roche ctnt Apple et al: CLINCHEM/2012/ CP

7 Changes in ctnt in Dialysis Patients with ACS ctnt (µmol/l) Nephron Clin Prac 98:c87, 2004 Days CP CP

8 Delta Guidance Must use fixed timing The greater the change, the more likely AMI The lesser the change, the less likely AMI CP

9 CV (%) Cardiac Troponin T Precision Profile 50,0 99 th % value = <0.01 ng/ml 40,0 10% CV value = 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) CP

10 Determining Assay Values are Different CP

11 Use of High Sensitivity Troponin T to Diagnose Myocardial Infarction Clinical setting consistent with myocardial ischemia Baseline <14 ng/l 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% 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 CP

12 ug/l Absolute and Relative Changes of ctn Over 1- and 2-hours 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 % 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 CP

13 Absolute and Relative Changes in Patients with AMI, Unstable Angina and Non-Cardiac Chest Pain Non-STEMI UAP Non-ACS Non-STEMI UAP Non-ACS Absolute change (log) Relative change (log) Mueller et al: Clinical Chemistry 58:1 (2011) CP

14 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) CP

15 Sensitivity Diagnostic Increases in ctn (Christchurch ED Trial) 1.0 Baseline Total Hs TnT Abbott TnT CKMB Reference line specificity specificity Aldous et al: Ann Clin Biochem 48:241, 2011 CP

16 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 CP

17 Sensitivity High sensitive troponin T (pg/ml) Sensitivity Relationship of hsctnt and Plaque Characteristics 100 Detection of Non-Calcified Plaque Classified by Plaque Composition P<0.001 P<0.001 P<0.001 P=NS Hs TnT>10.5 * AUC= specificity SE= % CI= Detection of 5 0 Normal vessels (n=46) Only calcified plaque (n=26) Non- Calcified Plaque (n=44) Remodeled Plaque (n=8) Remodeled Plaque * Hs TnT> AUC=0.90 SE=0.07 * Using a cut-off value of hstnt=14 pg/ml Korosoglou et al: Heart 97: % CI= specificity CP

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 CP

19 Sensitivity Specificity Defining the Optimal Delta: The Tension Between Sensitivity and Specificity Sensitivity Specificity Relative change in hstni concentration Data from Keller et al (20) CP

20 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 CP

21 Short-Term Analytical and Biological Variation by hs-ctnl Assays Abbott a Beckman a Roche (E170) b Siemens a Singulex c CV-A (%) d CV-I (%) CV-G (%) NA Index of individuality NA RCV (%) e NA NA 47.0 NA NA RCV increase (%) f NA RCV decrease (%) f NA Within-individual mean (ng/l) NA 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 CP

22 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 ( ) 14.1 ( ) 866 Heart failure 10 ( 9-12) 51 (38-65) 3.1 ( ) 30 ( ) 204 Stable angina pectoris 10 ( 9-1 2) 67 (34-99) 1.4 ( ) 13.6 ( ) 343 Atrial fibrillation 9 ( 6-12) 66 (29-104) 1.1 ( ) 9.1 ( ) 86 Noncardiac chest pain 12 (10-15) 64 (46-82) 1.2 (1-1.5) 7.5 ( ) 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) CP

23 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? CP

24 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 CP

25 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. CP

26 It is not the Data but How You Intepret it that is Important CP