Peri-operative Troponin Measurements - Pathophysiology and Prognosis 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 and Amgen. CP887679-0
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 CP887679-1 Vital Exhaustion
Survival Postop Survival by ctni Values 1.0 0.9 0.8 0.7 ctn-i 0.6 and ctn-t 0.03 0.6< ctn-i 1.5 and/or 0.03 <ctn-t 0.1 P=0.047 P=0.007 0.6 0.5 0.4 1.5< ctn-i 3.1 and/ or 0.1 <ctn-t 0.2 ctn-i >3.1 and/or ctn-t >0.2 P<0.001 0.3 0 1 2 3 4 5 Years after surgery J Am Coll Cardiol 42:1551, 2003 CP887679- CP1133453-8 2
Survival Postop Survival by ECG Changes 1.0 0.9 ST-dep ischemia 15 min 0.8 0.7 0.6 0.5 15 min < ST-dep ischemia 30 min P=0.08 P=0.08 0.4 0.3 ST-dep ischemia 30 min 0.2 0 1 2 3 4 5 J Am Coll Cardiol 42:1551, 2003 Years after surgery CP1133453-10 CP887679-3
Association of Longest Ischemia Duration with Biochemical Markers of MI Total No. % No. % No. % No. % No. % CK >170 IU and 34 6.7 17 50.0 14 41.2 12 35.3 7 20.5 MB >5% CK >170 IU and 14 2.9 8 57.1 7 50.0 7 50.0 5 35.7 MB >10% ctn-i >0.6 ng/ml 107 23.9 34 31.8 29 27.1 21 19.6 19 17.7 and or ctn-t >0.03 ng/ml ctn-i >1.5 ng/ml 41 8.7 38 87.8 24 58.3 19 46.3 18 43.9 and or ctn-t >0.1 ng/ml ctn-i >3.1 ng/ml 21 4.2 19 90.5 17 81.0 17 81.0 13 61.9 and or ctn-t >0.2 ng/ml J Am Coll Cardiol 42:1549, 2003 Ischemia >15 min Ischemia >30 min Ischemia >60 min Symptoms attributable to MI CP887679- CP1133453-7 4
A 67-year-old man - abdominal aortic aneurysm repair Landesberg G et al. Circulation 2009;119:2936-2944 CP887679-5
Differentiation between MI Types according to the Condition of the Coronary Arteries Plaque rupture with clot MI Type 1 Vasospasm or endothelial dysfunction Fixed Atherosclerosis and Supply-demand imbalance MI Type 2 MI Type 2 Supply-demand imbalance alone MI Type 2 CP887679-6
CHARACTERISTICS OF TYPE 1 AND TYPE 2 AMIS Type 1 Type 2 Spontaneous around known triggers Higher ctn Some evidence of increased demand Lower ctn Persistent ECG changes, especially ST segment depression More transient ECG changes Out patients Procedure related often More procoagulant activity Procoagulation related inadequate perfusion CP887679-7
Cumulative hazard ratio Prognosis Over Time After Surgery (POISE) 0.20 0.15 Asymptomatic MI 0.10 0.05 Symptomatic MI Isolated cardiac biomarker or enzyme level elevation 0.00 0 5 10 15 20 25 Devereaux et al: Ann Intern Med 154:523, 2011 Time after surgery (days) Pt at risk (no.) Symptomatic MI 144 130 126 118 106 Asymptomatic MI 271 238 234 226 214 Isolated cardiac biomarker 697 665 658 645 624 or enzyme level elevation CP887679-8
Risk (%) Risk (%) Risk (%) Risk (%) Outcomes in POISE 0.08 Primary Outcome (CV Death or Nonfatal AMI or Cardiac Arrest) 0.08 AMI 0.06 Placebo Metoprolol 0.06 Placebo 0.04 0.04 Metoprolol 0.02 0.02 0.00 0.00 No. at risk No. at risk Placebo 4,177 3,915 3,873 3,854 Placebo 4,177 3,919 3,873 3,859 Metoprolol 4,174 3,958 3,908 3,878 Metoprolol 4,174 3,966 3,917 3,888 0.020 Stroke 0.03 Death Metoprolol 0.015 0.02 Metoprolol Placebo 0.010 0.005 0.01 Placebo 0.000 0.00 0 10 20 30 0 10 20 30 No. at risk Days No. at risk Days Placebo 4,177 4,105 4,078 4,060 Placebo 4,177 4,119 4,093 4,074 Metoprolol 4,174 4,084 4,038 4,012 Metoprolol 4,174 4,112 4,066 4,039 Lancet 371:1839, 2008 CP887679-9
Meta-Analysis of -Blocker Trials Relative risk -blocker Control (99% CI) Total mortality Pre-POISE 33/1,080 36/1,070 0.89 (0.49-1.64) POISE 129/4,174 97/4,177 1.33 (0.95-1.87) Total 162/5,254 133/5,247 1.21 (0.90-1.63) P=0.10, I 2 =37% Nonfatal myocardial infarction Pre-POISE 25/958 42/919 0.58 (0.32-1.06) POISE 152/4,174 215/4,177 0.71 (0.54-0.92) Total 177/5,132 257/5,096 0.69 (0.54-0.87) P<0.0001, I 2 =31% Nonfatal stroke Pre-POISE 12/972 3/967 2.98 (0.74-12.0) POISE 27/4,174 14/4,177 1.93 (0.83-4.50) Total 39/5,146 17/5,144 2.19 (1.06-4.50) P=0.005, I 2 =0% 0.10 1 2 4 8 16 Relative risk (99% CI) Lancet 371:1839, 2008 CP887679-10
Survival in Postoperative Patients With and Without Coronary Revascularization Probability of survival 1.0 0.8 0.6 0.4 0.2 0.0 No. at risk Coronary artery revascularization No coronary artery revascularization P=0.92 0 1 2 3 4 5 6 Years after randomization Revascularization 226 175 113 65 18 7 No revascularization 229 172 108 55 17 12 McFalls et al: NEJM 351(27):2795, 2004 CP887679-11
Patient Flow in the Vision Study 23,693 Patients fulfilled VISION eligibility criteria 1,084 Not identified in time to enroll 22,609 Screened in time 6,522 Excluded 5,262 Did not consent 251 Cognitive impairment 134 Surgeon did not approve 875 Other source 16,087 Enrolled in VISION 954 Excluded from the fourth-generation Troponin T Prognostic Study 779 No troponin assay measured after surgery 29 Died before a troponin assay was measured 750 No troponin assay measured before discharge 146 Had peak troponin measurement reported as <0.04, <0.03, or <0.02 instead of the absolute value 29 Missing data 15,133 Included in the VISION fourth-generation Troponin T Prognostic Study 15,093 Completed the 30-day follow-up 40 Did not complete the 30-day follow-up and were censored at the time of last contact 15,133 Patients included in the final analyses JAMA. 2012;307(21):2295-2304 CP887679-12
Cumulative hazard Mortality Analysis by Peak ctnt Value (VISION) Peak troponin T (ng/ml) 0.30 0.03-0.29 0.02 0.01 Days after surgery No. at risk Peak troponin T (ng/ml) 0.30 142 136 129 127 121 118 117 0.03-0.29 1121 1103 1075 1058 1036 1030 1018 0.02 494 492 489 485 480 477 473 0.01 13,376 13,348 13,300 13,271 13,250 12,230 13,209 JAMA. 2012;307(21):2295-2304 CP887679-13
Relationship of -Blockers and 30-Day Mortality All surgery No. of patients No. of deaths Exposed Not exposed Exposed Not exposed All patients 37,805 37,805 426 583 Revised cardiac risk index predictors (no.) 0 12,250 12,250 67 53 1 16,057 16,057 166 186 2 6,795 6,795 111 176 3 2,090 2,090 59 110 >4 613 613 23 58 Favors exposure Favors nonexposure Vascular surgery No. of patients No. of deaths Exposed Not exposed Exposed Not exposed All patients 3,999 3,999 55 62 Revised cardiac risk index predictors (no.) 0 857 857 5 6 1 1,593 1,593 20 21 2 1,033 1,033 11 18 3 403 403 13 12 >4 113 113 6 5 0.2 1.0 5 Relative risk (95% CI) Favors exposure Favors nonexposure London et al: JAMA 309(16):1704, 2013 0.2 1.0 5 Relative risk (95% CI) CP887679-14
Relationship of -Blockers and 30-Day Cardiac Morbidity All surgery No. of patients No. of deaths Exposed Not exposed Exposed Not exposed All patients 37,662 37,662 225 336 Revised cardiac risk index predictors (no.) 0 12,228 12,228 23 35 1 16,004 16,004 83 104 2 6,761 6,761 63 105 3 2,063 2,063 36 59 >4 606 606 20 33 Favors exposure Favors nonexposure Vascular surgery No. of patients No. of deaths Exposed Not exposed Exposed Not exposed Favors exposure All patients 3,973 3,973 34 49 Revised cardiac risk index predictors (no.) 0 852 852 0 4 1 1,590 1,590 5 14 2 1,024 1,024 15 13 3 395 395 9 11 >4 112 112 5 7 London et al: JAMA 309(16):1704, 2013 0.2 1.0 5 Relative risk (95% CI) Favors nonexposure 0.2 1.0 5 Relative risk (95% CI) CP887679-15
Survival Cumulative Survival (A= Stress testing, B = Angiography) 1.0 Group B (n=105) 0.8 0.6 Group A (n=103) 0.4 0.2 0.0 P=0.01 Group A n= 81 41 12 Group B n= 99 52 17 0 1 2 3 4 5 6 7 8 Years from randomization JACC 54(11):989, 2009 CP887679-16
Freedom from MACE Freedom from Major Adverse Cardiac Events (A= Stress testing, B = Angiography) 1.0 0.8 Group B (n=105) 0.6 0.4 0.2 0.0 Group A (n=103) P=0.003 Group A n= 79 39 12 Group B n= 97 51 15 0 1 2 3 4 5 6 7 8 Years from randomization JACC 54(11):989, 2009 CP887679-17
Frequency (%) Distribution of Preoperative hsc-tnt Values in Vision 45 40 Published 99 th 14 ng/l VISION 95 th 33 ng/l VISION 99 th >72 ng/l 35 30 25 20 15 10 5 0 TnT-hs (ng/l) Kavsak et al: Clin Biochem 44:1021, 2011 CP887679-18
Frequency (%) 50 Frequency of Elevated hsc-tnt Postoperative Values 40 30 20 10 Published 99 th TnT hs VISION 95 th TnT hs VISION 99 th TnT hs >85% change in TnT hs from preop >242% change in TnT hs from preop TnT 4 th gen >0.03 g/l 0 Day 1 Day 2 Day 3 Postoperative days Kavsak et al: Clin Biochem 44:1021, 2011 CP887679-19
Preoperative hsctnt and Myocardial Infarction 25 20 Myocardial infarction Postop Troponin I elevation >0.07 g/l % 15 10 5 0 <14 ng/l >14 ng/l Preoperative hs-ctnt concentration AHJ, 2013, (in press) CP887679-20
All-cause mortality (%) All-Cause Mortality based on Preopeartive hsctnt 30 25 >14 ng/l 20 15 10 <14 ng/l 5 0 0 1 2 3 4 5 Survival time (years) AHJ, 2013, (in press) CP887679-21
All-cause mortality (%) All-cause mortality (%) All-Cause Mortality based on Sex-Specific 99 th Percentiles for Preoperative hsctnt 25 20 Women >10 ng/l 30 25 Men >15 ng/l 15 10 <10 ng/l 20 15 10 <15 ng/l 5 5 0 0 1 2 3 4 5 0 0 1 2 3 4 5 Survival time (years) Survival time (years) AHJ, 2013, (in press) CP887679-22
All-cause mortality (%) All-Cause Mortality Grouped by Preoperative hsctnt Quartiles 35 30 25 20 15 10 5 Quartile (ng/l) 4 (>19.3) 3 (12.0-19.3) 1 (<8.3) 2 (8.3-12.0) 0 0 1 2 3 4 5 Survival time (years) AHJ, 2013, (in press) CP887679-23
Mortality (%) Predictive Accuracy of Biomarkers to Presage Mortality 8 P<0.001 6.9 6 P=0.002 4.8 P=0.01 4.8 4.6 4 2.4 2 1.4 1.2 0.7 0 <300 pg/ml 300 pg/ml 14 ng/l >14 ng/l 0 1 2 3 n=644 n=355 n=746 n=233 n=277 n=450 n=187 n=65 NT-proBNP hs-tnt Lee index Weber et al: Eur Heart J 34:853, 2013 CP887679-24
Combined endpoint (%) Combining Lee Index and hsctnt to Predict CV Events 14 12 hs-tnt 14 ng/l hs-tnt >14 ng/l 13 10 8 8.5 6 4 2 0 3.8 2.9 2.2 0.4 Lee score = 0 Lee score = 1 Lee score > 2 n=243 n=34 n=352 n=98 n=151 n=101 Weber et al: Eur Heart J 34:853, 2013 CP887679-25
Mortality (%) Combining Lee Index and hsctnt to Predict Mortality 10 8 hs-tnt 14 ng/l hs-tnt >14 ng/l 8.7 6.6 6 4 2 2.9 1.4 2.3 0 0.4 Lee score = 0 Lee score = 1 Lee score > 2 n=243 n=34 n=352 n=98 n=151 n=101 Weber et al: Eur Heart J 34:853, 2013 CP887679-26
Comparative Incidence of Plaque Rupture Author Postop cases Cohen Dawood et al Combined Non-postop cases Constantanides Hori et al Quiao et al Burke et al Combined Point estimate with 95% CI 46% 36% 49% 0 25 50 75 100 % 50% 51% 55% 64% Cohen and Aretz: Cardiovasc Pathol 8(3):133, 1999 83% CP887679-27
Angiographic Characteristics PACS no. (%) SACS no. (%) Stable CAD no. (%) P Complex lesion 68 (56.7) 95 (79.2) 76 (31.8) <0.001 Ambrose s type II lesions 54 (45.0) 68 (56.7) 44 (16.4) <0.001 Thrombus 9 (7.5) 39 (32.5) 21 (8.8) <0.001 Ulceration 15 (12.5) 18 (15.0) 16 (6.7) 0.03 Haziness 45 (37.5) 54 (45.0) 39 (16.3) <0.001 TIMI flow <3 27 (22.5) 61 (50.8) 48 (20.1) <0.001 Gualandro DM et al: Atherosclerosis, 2012 (in press) CP887679-28