Does serial troponin measurement help identify acute ischemia/ischemic events?

Transcription

1 Does serial troponin measurement help identify acute ischemia/ischemic events? Allan S. Jaffe, MD.* Consultant - Cardiology & Laboratory Medicine Professor of Medicine and Laboratory Medicine & Pathology 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 Amgen. CP

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4 Elevations of Troponins without Overt Ischemic Heart Disease Trauma (including contusion, ablation, pacing, ICD firings including atrial defibrillators, cardioversion, endomyocardial biopsy, cardiac surgery, after interventional closure of ASDs) Congestive heart failure acute and chronic Aortic valve disease and HOCM with significant LVH Hyper and hypotension, especially with arrhythmias Postoperative noncardiac surgery patients who seem to do well Renal failure Critically ill patients, with respiratory failure, gastrointestinal bleeding, sepsis, heat stroke 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 eg. 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% Cardiomyopathies including Infiltrative diseases such as amyloidosis, hemachromatosis, sarcoidosis and scleroderma, non compaction syndrome Acute neurological disease, including CVA, subarchnoid bleeds Rhabdomyolysis with cardiac injury Transplant vasculopathy CP Vital Exhaustion

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

6 Point of Care Assays Contemporary Assays High Sensitive Assays Comparison of Normals Detected With Various Assays Singulex hstnl ARCHITECT hstnl Siemens hstnl Beckman Access hstnl Roche hstnt Beckman Tnl Siemens Tnl Ultra (Centaur) Siemens Tnl (Immulite) AxSYM Tnl ARCHITECT Tnl OCD Tnl Siemens Tnl (Dimension) Roche Tnl Siemens Tnl (Vista) IL ctnl Abbott ISTAT Siemens Stratus Alere BioMerleux Detected (%) Apple et al: Clin Chem 58(11):56, 2012 CP

7 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

8 Distribution of hs-ctnl (Siemens) in Entire Population Female (n=961) Male (n=882) Combined (n=1843) Arrows 95% % Triangles 99% Troponin I (ng/l) Clin Chem 59:7, 2013 CP

9 Distribution of hs-ctnl (Siemens) in Normals Female (n=306) Male (n=259) Combined (n=565) Arrows 95% % Triangles 99% Troponin I (ng/l) Clin Chem 59:7, 2013 CP

10 Hs-cTnT (ng/l) Hs-cTnT Reference Values According to Age and Gender Male Female Age (years) Mechanisms of Aging and Development 2013 CP

11 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

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

13 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

14 Determining Assay Values Are Different 1. Determine the standard deviation around the values 2. With elevated troponin values, this is a coefficient of variation of 5-7% 3. The 95% confidence limit for a significant difference between the values is +/- 1.96*sqrt(2)*SDa = 2.77*SDa Thus 3 SDs of the variance between values should ensure that one is measuring a true difference CP

15 Determining Assay Values are Different CP

16 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

17 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

18 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

19 Delta Guidance Must use fixed timing All assays are different The greater the change, the more likely AMI The lesser the change, the less likely AMI CP

20 Reasons for Difficulty Calcuating the Proper Delta Value Problems with the gold standard diagnosis CP

21 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

22 Mean increase in hsctnt (ng/l) Delta for the Diagnosis of AMI with hsctnt Based on The Gold Standard (T0-T3hr) % CV 99th % hsctnt TUSCA, AJM in press 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 CP

24 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 Spontaneous changes in those without AMI CP

25 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

26 Myocarditis Pericarditis Heart failure Cardiac dysrhythmia Hypertensive urgency/emergenc y Other presentation (Ug/l) hsctnt at Baseline Hs-cTnT at AMI CNCD Haaf et al: Circulation, 2012 CP

27 Myocarditis Pericarditis Heart failure Cardiac dysrhythmia Hypertensive urgency/emergenc y Other hs-ctnt 0h- 6h abs max (Ug/l) Absolute Changes Over 6 Hours AMI CNCD Haaf et al: Circulation, 2012 CP

28 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

29 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 Spontaneous changes in those without AMI Late presenters CP

30 Median relative change (%) Median absolute change (ng/l) Relative change (%) Absolute change (ng/l) Hs-cTnT Changes in Patients With Non-STEMI n=1178 n= Max hs-ctnt (ng/l) Max hs-ctnt (ng/l) % ng/l Median max hs-ctnt (ng/l) Bjurman et al: JACC 62(14):1231, 2013 <20% <9 ng/l Median max hs-ctnt (ng/l) CP

31 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 Spontaneous changes in those without AMI Late presenters What metric is desired to optimize clinical performance; i.e. sensitivity vs specificity CP

32 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

33 Additional Problems to Consider What to call those who have elevated hsctn with symptoms compatible with angina but a less than significant defined delta? Unstable angina with structural heart disease? Missed AMI? Do we need different deltas for men and women? CP

34 Rate of CV death or MI (%) Relationship Between 30-Day CV Death and/or AMI with Gender Specific hs-ctnl Values <99 th 99 th <16 16 to <26 26 Adj OR 3.7 (2.3, 5.7) P Adj OR 3.2 (2.1, 4.9) P Adj OR 3.2 (1.5, 6.7) P= Adj OR 3.6 (2.0, 6.3) P Adj OR 2.0 (0.5, 7.3) P=0.3 n= 703 3, ,986 n= , ,779 hs-ctnl (percentile) hs-ctnl (ng/l) Bohula May et al: Clin Chem 2013 CP

35 Use of Gender Specific Cut Offs fortype 1 Myocardial Infarction Contemporary Assay High-Sensitivity Assay % Men Women Single Single Sex-specific Sensitivity 77 (69-83) 47 (38-56) 87 (80-92) 68 (59-77) 86 (80-91) 95 (89-98) Mills, ESC 2013 CP

36 Outcome of Women With Suspected Acute Coronary Syndrome Survival free from death or recurrent MI (%) Troponin I concentration <16 ng/l Troponin I concentration ng/l Troponin I concentration 50 mg/l P<0.001 Days Mills, ESC 2013 CP

37 Additional Problems to Consider What to call those who have elevated hsctn with symptoms compatible with angina but a less than significant defined delta? Unstable angina with structural heart disease? Missed AMI? Do we need different deltas for men and women? Relative or Absolute deltas? CP

38 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

39 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