Cardiac Troponin Testing and Chest Pain Patients: Exploring the Shades of Gray

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1 Cardiac Troponin Testing and Chest Pain Patients: Exploring the Shades of Gray Nichole Korpi-Steiner, PhD, DABCC, FACB University of North Carolina Chapel Hill, NC

2 Learning Objectives Describe the acute coronary syndrome continuum Define the 3 rd universal definition of myocardial infarction Explore analytical and post-analytical considerations for cardiac troponin testing Discuss similarities and differences between contemporary and high-sensitivity troponin assays

3 Case Study 3 days ago, patient AW (65 y female) exhibited an episode of chest pain while exercising, the pain resolved upon rest. Today, she was at a basketball game and developed acute crushing chest pain with radiation to her neck while cheering. Her husband brings her to the ED for evaluation. AW patient assessment and treatment in the ED: o Cardiac biomarker testing ordered, collected, sent to lab o Refractory nitroglycerin and morphine treatment o Normal ECG findings What is the likelihood of acute coronary syndrome and adverse clinical outcome?

4 Pathophysiology of Acute Coronary Syndrome Pathophysiology: Plaque rupture Reduced blood flow Myocardial necrosis Unstable plaque Intracoronary thrombus Myocardial ischemia Clinical Presentation: Acute Coronary Syndrome Asymptomatic Unstable Angina Acute myocardial infarction (NSTEMI or STEMI)

5 Acute Coronary Syndrome & Clinical Triage In US, estimated that >780,000 persons will experience an acute coronary syndrome (ACS) per year o ~ 70% NSTE-ACS Twerenbold R et al. Eur Heart J. 2012; 33: AHA/ACC NSTE ACS Guideline

6 Third Universal Definition of Myocardial Infarction ESC/ACCF/AHA/WHF Expert Consensus Both are required for a diagnosis of myocardial infarction: 1. Detection of a rise and/or fall of cardiac biomarkers (preferably troponin) with at least 1 value above the 99th percentile of the upper reference limit 2. Evidence of myocardial ischemia from symptoms, electrocardiogram, or cardiac imaging Thygesen et al. Circulation. 2012; 126(16):

7 Chest Pain Center Accreditation Society of Cardiovascular Patient Care (SPSC) o Lab quality metrics TAT!

8 Chest Pain Patient: Shades of Gray Thrombolysis in Myocardial Infarction (TIMI) Risk score

9 Cardiac Troponin Subunits Regulatory protein complex of thin myofilament contraction Ca 2+ troponin complex TnC TnI TnT tropomyosin The ctn complex = 3 different proteins (TnC, TnI, and TnT) that regulate Ca mediated striated muscle contraction actin Troponin consists of 3 subunits: ctnt: 37 kda, binds to tropomyosin (inhibitory complex) Cardiac specificity ctni: 22 kda, binds to actin in thin myofilament Holds troponin-tropomyosin complex in place Cardiac specificity ctnc: 18 kda, calcium binding subunit Non-specific

10 Cardiac Troponin (ctn) Detection Pattern in Acute Myocardial Infarction Wu and Christenson. Clin Biochem 46 (2013)

11 Creatine Kinase (CK) MB CK is a dimer composed of 2 subunits (M and/or B) Three cytosolic isoenzymes: MM, MB, BB; Two mitochondrial isoenzymes CK-MB is NOT unequivocally specific for myocardium Tissue distribution: CK 1 (BB) CK 2 (MB) CK 3 (MM) Skeletal 0% 1% 99% Cardiac 1% 20% 79% Brain 97% 3% 0%

12 Biomarker Detection Patterns in Acute Myocardial Infarction

13 CK MB, To Test or Not To Test? ctn the preferred biomarker and has advantages over CK MB Higher clinical sensitivity for AMI Higher clinical specificity for AMI Better late indicator of AMI 2014 AHA/ACC NSTE ACS guideline: With contemporary ctn assays, CK MB is not useful for diagnosis of ACS CK MB may be used to estimate infarct size Detection of re infarction after percutaneous coronary intervention remains controversial 2012 ESC/ACCF/AHA/WHF 3 rd Definition of MI and 2007 NACB guideline: If ctn assay is not available, the best alternative is CK MB (mass assay)

14 CK MB Mass Assay Immunoassay measures mass (ng/ml) not activity Confers analytical specificity for CK-MB

15 Case Study (Continued) Patient has symptoms of myocardial ischemia Lab findings: Patient Results 17:00 (presentation) 18:16 Reference Range ctni < ng/ml (34 ng/l) CK MB 0.4 < 6.0 ng/ml Diagnosis: Non-ST elevated myocardial infarction (NSTEMI) TIMI Score: 6 (High-risk) Treatment Plan: Percutaneous coronary intervention o Found 100% occlusion of obtuse marginal coronary artery o Stent was placed

16 Cardiac Troponin Assays Methods are automated immunometric immunoassays Anti ctn Signal Ab* ctni or ctnt *Antibodies (Ab) in excess Anti ctn Capture Ab* Roche Diagnostics is the sole manufacturer of ctnt assays Other vendor (Abbott, Beckman, Ortho, etc ) assays measure ctni Qualitative and quantitative POCT methods available

17 ctni or ctnt Assay, Does it Matter? Clinical Practice Guidelines do not recommend one (ctni or ctnt) assay over the other Equivalent diagnostic utility and risk stratification for ACS ctn elevations in patients with kidney disease are common ctnt elevations more prevalent compared with ctni 2014 AHRQ Cardiac Troponins Used as Diagnostic and Prognostic Tests in Patients with Kidney Disease: Both ctni and ctnt are useful in risk stratification of ESRD patient receiving dialysis Elevations are associated with increased risk of mortality 2014 AHRQ Publication No. 14 EHC030 EF Jaffe. Heart. 2011; 97: Apple and Collinson. Clin Chem. 2012; 58(1):54 61

18 What ctn Cutoff Should be Used? ESC/ACCF/AHA/WHF 3 rd Universal Definition of MI o Recommend 99 th percentile URL with optimal precision (CV 10%) as cutpoint for considering myocardial necrosis Facilitates detection of changing troponin values o ctn assays with CV > 20% at the 99 th percentile URL should NOT be used Evidence-based data support acceptable CV 20% at 99 th percentile URL o No significant misclassification of ACS patients in diagnostic or risk-assessment management Thygesen et al. Circulation. 2012; 126(16): Apple et al. Clin Chem. 2005; 51(11): Apple and Collinson. Clin Chem. 2012; 58(1):54 61

19 ctni Assay Heterogeneity Analytical sensitivity and 99 th Percentile URL reference values are assay-dependent Apple and Collinson. Clin Chem. 2012; 58(1):54 61

20 Can ctni Assays Be Standardized? IFCC standardization efforts for ctni assays are ongoing Goal is to establish metrological traceability of manufacturer s ctni calibrations Stable region of ctni (amino acids ) is target for development of secondary reference measurement procedures NIST SRM 2921 contains purified intact troponin ITC complex Wu and Christenson. Clin Biochem 46 (2013)

21 What about Point of Care ctn Assays? 2007 NACB LMPG Evidence-based Practice for POCT o Collect to report ctn test TAT should be < 1 h, optimally < 30 min o Institutions that cannot achieve TAT < 1 h should consider POCT o Unclear if use of POC ctn assays improve clinical outcomes 2014 AHA/ACC NSTE-ACS guideline: o POC troponin values may provide initial diagnostic information, although their sensitivity is substantially below that of central laboratory methods 2014 review of manufacturer s package inserts: o 7 of 10 POC assays indicated CV 20% at 99 th percentile URL o 4 POC assay indicated CV 10% at 99 th percentile URL o No POC ctn device is FDA-approved for risk stratification Amundson and Apple. Clin Chem Lab Med. 2014; DOI

22 What Is a Significant Change (Delta) in ctn Values? ctn is a biomarker of myocardial injury and not specific for acute myocardial infarction o Detection of a rise and/or fall in ctn concentration suggests acute myocardial injury as opposed to chronic ctn elevation from non-acs etiologies 2014 AHA/ACC NSTE-ACS guideline: o For any ctn values below or close to the 99th percentile, change of 3 standard deviations of the variation around the initial value as determined by the individual laboratory o Evidence for a serial increase or decrease 20% is required if the initial value is elevated o Clinical laboratory reports should indicate whether significant changes in cardiac troponin values for the particular assay have occurred

Not As Complex As It Sounds ctn Assay Example: o Reference range 0.01 ng/ml (99 th percentile URL) o 3 SD = 0.03 ng/ml o Delta value is calculated/reported between 0-3 and 0-6 h o If baseline ctn 0.

23 Not As Complex As It Sounds ctn Assay Example: o Reference range 0.01 ng/ml (99 th percentile URL) o 3 SD = 0.03 ng/ml o Delta value is calculated/reported between 0-3 and 0-6 h o If baseline ctn 0.20 ng/ml, a change of +/ ng/ml or greater suggests clinically significant change o If baseline ctn > 0.20 ng/ml a change of +/- 20% or greater is suggests clinically significant change Courtesy of Dr. Jaffe, Mayo Clinic

24 When Should Samples be Collected? Serial sample timing is essential Lack of consensus on what frequency samples should be collected for troponin testing o 2007 NACB LMPG Clinical Characteristics & Utilization of Biochemical Markers in ACS guideline: At presentation and 6-9 h after symptom onset o 2012 ESC/ACCF/AHA/WHF 3 rd Universal Definition of MI At presentation and 3-6 h post-presentation o 2014 AHA/ACC NSTE-ACS guideline: At presentation and 3-6 h after symptom onset Optimal timing depends on assay performance characteristics and is currently institution-dependent

25 What is a High Sensitivity Troponin Assay? ctn assays with improved ( high ) analytical sensitivity Heterogeneous nomenclature: high performance, highly sensitive, high-sensitive, ultrasensitive, novel highly sensitive, etc. Recommended nomenclature: high-sensitivity

26 Cardiac Troponin Assay Scorecard gen = generation; hs = high sensitivity Apple FS et al. Clin Chem. 2009; 55(7):1303

27 Why All the Hype for High Sensitivity ctn Assays? High-sensitivity ctn assay potential: o Improved analytical sensitivity may permit detection and definition of 99 th percentile of normal population o Improved precision will enhance detection of a significant serial change Potential Clinical Practice Benefits: o Permit earlier diagnosis of myocardial injury and infarction o Improve/enhance risk stratification o Expedite patient triage o Reduce morbidity and mortality Earlier identification of ACS patients allowing earlier treatment Rapid rule-out of patients decreasing ED overcrowding Twerenbold R et al. Eur Heart J. 2012; 33:579

28 Summary ctn is a biomarker of myocardial necrosis ctn is the preferred biomarker to facilitate diagnosis of ACS and risk stratify patients < 99 th percentile URL is recommended reference value with CV < 20% (ideally CV < 10%) o Assay-specific! Detection of a rise and/or fall pattern (significant delta) in ctn concentration is required and improves clinical specificity for acute myocardial necrosis High-sensitivity ctn assays have improved analytical sensitivity with potential to support earlier diagnosis of acute myocardial infarction and improve risk stratification of patients

Impact of Troponin Performance on Patient Care

Impact of Troponin Performance on Patient Care Linda C, Rogers PhD, DABCC, FACB Agenda Introduction Diagnosis of MI Guidelines Troponin Assay differences Classification of troponin assays Guideline acceptable