Use of Biomarkers for Detection of Acute Myocardial Infarction

Size: px

Start display at page:

Download "Use of Biomarkers for Detection of Acute Myocardial Infarction"

Sydney Russell
5 years ago
Views:

1 Use of Biomarkers for Detection of Acute Myocardial Infarction 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. CP

2 Biomarkers for Detection of Myocardial Infarction Preferably Detection of rise and/or fall of Troponin (I or T) with at least one value above the 99 th percentile of the upper reference limit measured with a coefficient of variation 10%. CP

3 Biomarkers for Detection of Myocardial Infarction Preferably Detection of rise and/or fall of Troponin (I or T) with at least one value above the 99 th percentile of the upper reference limit measured with a coefficient of variation 10%. CP

4 GUSTO-IV (Death and MI) % Death Myocardial infarction > > % 10%CV ROC Evaluated cutoff points for troponin T (µg/l) James et al: Am J Med 115:182, CP CP

5 Table 1. Analytical characteristics of commercial and research cardiac troponin I and T assays declared by the manufacturer. Commercially available assays - Company/ platform(s)/ assay LoB # (ng/l) LoD* (ng/l) 99 th % (ng/l) %CV at 99 th % 10% CV (ng/l) Risk Stratificati on Epitopes recognised by Antibodies Abbott AxSYM ADV Yes C 87-91, 41-49; D ALP Detection Antibody Tag Abbott ARCHITECT < Yes (No in US) C 87-91, 24-40; D: Acridinium Abbott i-stat Yes C: 41-49, 88-91; D: 28-39, ALP Alere Triage SOB 50 NAD NA NA No C: NA; D: Fluorophor Alere Triage Cardio 3 (r) 10 NAD 17.0 (at 20) NA No NA Fluorophor Beckman Coulter Access Accu Yes C: 41-49; D: ALP biomerieux Vidas Ultra 10 10** No C: 41-49, 22-29; D: 87-91, 7B9 ALP Mitsubishi Chemical PATHFAST No C: 41-49; D: , ALP Ortho Vitros ECi ES Yes C: 24-40, 41-49; D: HRP Radiometer AQT90 FLEX TnI NA C: 41-49, ; D: Europium Radiometer AQT90 FLEX TnT NA C: ; D: Europium Response Biomedical RAMP 30 NAD 18.5 (at 50) 210 No C: 85-92; D: Fluorophor CP

6 IFCC_Troponin_Table_vDec_2010_ FINAL_ng_L_28Jan11.pdf CP

7 Table 1. Analytical characteristics of commercial and research cardiac troponin I and T assays declared by the manufacturer. Commercially available assays - Company/ platform(s)/ assay Abbott AxSYM ADV 20 LoB # (ng/l) Lo D* (ng /L) th % (ng/l) %CV at 99 th % 10% CV (ng/l) Risk Stratificati on Epitopes recognised by Antibodies Yes C 87-91, 41-49; D ALP Detection Antibody Tag Abbott ARCHITECT < Yes (No in US) C 87-91, 24-40; D: Acridinium Abbott i-stat 20 Alere Triage SOB NAD Yes C: 41-49, 88-91; D: 28-39, ALP NA NA No C: NA; D: Fluorophor Alere Triage Cardio 3 (r) 10 NAD 17.0 (at 20) NA No NA Fluorophor Beckman Coulter Access Accu 10 biomerieux Vidas Ultra 10 Mitsubishi Chemical PATHFAST 8 Ortho Vitros ECi ES ** Yes C: 41-49; D: ALP No C: 41-49, 22-29; D: 87-91, 7B9 ALP No C: 41-49; D: , ALP Yes C: 24-40, 41-49; D: HRP Radiometer AQT90 FLEX TnI Radiometer AQT90 FLEX TnT NA C: 41-49, ; D: Europium NA C: ; D: Europium Response Biomedical RAMP 30 NAD 18.5 (at 50) 210 No C: 85-92; D: Fluorophor CP

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.

8 AUC More Diagnoses with Higher-Sensitivity Assays 1.0 Sensitive troponin I 99 th % value Troponin T 10%CV value NEJM 361:868, to <3 3 to <6 6 to <9 9 to < All Time of chest-pain onset (hr) Diagnosis of AMI (no.) Single determination (no.) Sensitive troponin I >0.04 ng/ml Troponin T >0.03 ng/ml CP

9 Area under the ROC curve Accuracy by Time of Admission th % value NEJM 361:858, 2009 Mostly same assays but < 99 th % value cut off used Abbott-architect troponin I Roche high-sensitive troponin T Roche troponin I Siemens troponin I ultra Standard assay All patients Hours since onset of symptoms CP

Sensitivity Sensitivity Diagnostic Accuracy of Biomarkers at the Time of Admission 1.0 All Patients 1.0 Chest-Pain Onset <3 Hr 0.8 0.6 0.4 0.2 0.0 1.0 0.8 Troponin I (0.96) Troponin T (0.

10 Sensitivity Sensitivity Diagnostic Accuracy of Biomarkers at the Time of Admission 1.0 All Patients 1.0 Chest-Pain Onset <3 Hr Troponin I (0.96) Troponin T (0.85) Myoglobin (0.82) Creatine kinase MB (0.73) Creatine kinase (0.70) Chest-Pain Onset <6 Hr Troponin I (0.95) Troponin T (0.76) Myoglobin (0.83) Creatine kinase MB (0.64) Creatine kinase (0.62) Chest-Pain Onset <12 Hr NEJM 361:868, specificity Troponin I (0.95) Troponin T (0.79) Myoglobin (0.83) Creatine kinase MB (0.67) Creatine kinase (0.63) specificity Troponin I (0.96) Troponin T (0.81) Myoglobin (0.83) Creatine kinase MB (0.70) Creatine kinase (0.65) CP

20 10 0 <1 1-3 4-6 7-9 >9 Reduction in time to

11 Reduction in Time with a 3 Compared to a 6-9 Hour Sampling Schedule Relative frequency (%) < >9 Reduction in time to diagnosis (hr) Clin Chem 52(5):812, 2006 CP CP

12 Biomarkers for Detection of Myocardial Infarction Preferably Detection of rise and/or fall of Troponin (I or T) with at least one value above the 99 th percentile of the upper reference limit measured with a coefficient of variation 10%. CP

All-Cause Mortality by Cardiac Troponin T (n=733) Cumulative survival (%) 100 80 60 40 20 0 Time since blood

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.

13 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

ctnt Determinants of Elevation in the Community* 40 P<0.

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

15 CV (%) Elecsys Troponin T: Functional sensitivity (trend analysis) 50,0 40,0 20% CV: ng/ml 10% CV: ng/ml 5% CV: ng/ml 30,0 20,0 10,0 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) Data from the multicenter evaluation; each dot corresponds to a day to day imprecision data set of at least 11 runs (August March 1999 in 8 labs on 2010 and 1010) CP

16 DETERMINING ASSAY VALUES ARE DIFFERENT CP

17 Baseline Elevations in Patients Without AMI 2 Roche high-sensitive troponin T Siemens troponin I ultra Abbott-Architect troponin I 1 0 >70 years 70 years Reiter M et al: EHJ 32: , 2011 CP

Short- and Long-term Bio variation in hsctnt Analytical variation Short Term Long term CVA, % 53.

18 Short- and Long-term Bio variation in hsctnt Analytical variation Short Term Long term CVA, % Biological Variation CVI, % 48.2 CVG, % 85.9 Index of Individuality 84.5 RCV, log-normal increase, % CP

19 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 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 CP White HD; AHJ 2010

20 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

a setting where coronary supply is at least some part of the problem,

21 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. CP

22 ctnt and Angiographic Measures Stenosis (%) Thrombus (%) TFG 0/1 (%) TMPG 0/1 (%) 74 P< P= P= P< Prog Cardiovasc Dis 47(3), 2004 TnT (<0.01) TnT (>0.01) CP CP

Subsets of the Population with ACS Studied 200 150 Culprit lesion No Yes P<0.001 168 Pt (no.

23 Subsets of the Population with ACS Studied Culprit lesion No Yes P< Pt (no.) STEMI (n=108) NSTEMI (n=196) UAP (n=184) Ong et al: JACC 52:523, 2008 CP CP

24 Response to Acetylcholine Reproduction of symptoms No Yes 42 Pt (no.) Ong et al: JACC 52:523, >75 Vasoconstriction to acetylcholine (%) CP CP

25 Cum survival All-Cause Mortality No Yes P< ,000 1,200 Culprit lesion Culprit lesion Ong et al: JACC 57(2):147, 2011 CP

26 Myocardial Infarction Type 4a PCI-related increase of biomarkers (assuming a normal troponin baseline) > 3 X 99th percentile of the upper reference limit (URL) is by convention defined as myocardial infarction. R CP

27 Values ctn CK-MB Upper reference value Upper reference value Time (hr) Time (hr) CP

28 CK-MB (ng/ml) Magnitude of CK-MB Elevations at Each Time Point Baseline ctnt Elevation None 8-hour peak 16-hour peak Miller, Jaffe, EHJ 27:1061, 2006 CP CP

29 CK-MB (ng/ml) Magnitude of CK-MB Elevations at Each Time Point No Baseline ctnt Elevation None 8-hour peak 16-hour peak Miller, Jaffe, EHJ 27:1061, 2006 CP CP

Death or MI (%) Pre-PCI Troponin and Long-Term Mortality 40 35 30 25 20 15 10 5 0 <0.01 0.01-0.03 >0.03-0.1 >0.1-0.5 >0.5-1.

30 Death or MI (%) Pre-PCI Troponin and Long-Term Mortality < > > > >1.0 P< Months from PCI Prasad et al: Circ Cardiovasc Intervent 1:10, 2008 CP CP

Mortality (%) 30-Day Mortality According to Periprocedural ctnt Levels 2.5 2.0 P<0.001 Kaplan-Meier Estimates Pre 0.01 2.3% 1.5 1.0 0.5 0.

31 Mortality (%) 30-Day Mortality According to Periprocedural ctnt Levels P<0.001 Kaplan-Meier Estimates Pre % /13 events non cardiac Pre <0.01, post > % Pre <0.01, post < % Days from PCI Prasad, Jaffe et al: Circ Cardiovasc Intervent 1:10, 2008 CP CP

Mortality (%) Long-Term Mortality According to Periprocedural ctnt Levels 30 25 20 15 10 5 P<0.001 Pre 0.01 Pre <0.01, post >0.

32 Mortality (%) Long-Term Mortality According to Periprocedural ctnt Levels P<0.001 Pre 0.01 Pre <0.01, post >0.01 Pre <0.01, post < Months from PCI Prasad, Jaffe et al: Circ Cardiovasc Intervent 1:10, 2008 CP CP

$11 1.69, 2.65 <0.001 Body mass index 25.5 * <0.001 Chronic renal failure 22.5 2.256 1.61, 3.16 <0.001 Diabetes 19.4 1.60 1.30, 1.97 <0.001 Ejection fraction 11.3 * 0.010 Cerebrovascular disease 9.3 1.$

33 Multivariable Cox Model for Long-Term Risk of Death 95% hazard Variable 2 Hazard ratio ratio CL P Pre-PCI ctnt elevation , 2.39 <0.001 Age 83.0 * <0.001 Congestive heart failure , 2.65 <0.001 Body mass index 25.5 * <0.001 Chronic renal failure , 3.16 <0.001 Diabetes , 1.97 <0.001 Ejection fraction 11.3 * Cerebrovascular disease , Smoking , Isolated post-pci ctnt elevation , Prasad, Jaffe et al: Circ Cardiovasc Intervent 1:10, 2008 CP CP

34 Event-free survival Survival with by ctn post PCI 1.00 Troponin 0.45 ng/ml Troponin >0.45 ng/ml P= After covariate correction, p = ns Follow-up (days) Cavallini et al: Circ Cardio Interv 3:431, CP

35 Criteria for Type 4A when baseline values are elevated but stable Use reinfarction criteria 20% rise from the baseline value CP

High Sensitivity Troponin Improves Management. But Not Yet

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