CARDIOLOGY GRAND ROUNDS

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1 CARDIOLOGY GRAND ROUNDS Presentation: Speaker: Date: Location: Troponin State of the Art: Past, Present and Future Yader Sandoval, MD Cardiovascular Disease Fellow Minneapolis Heart Institute at Abbott Northwestern Hospital & Hennepin County Medical Center Research Associate Cardiac Biomarkers Trials Laboratory, Minneapolis Medical Research Foundation Monday, April 27, 2015, 7:00 8:00 AM ANW Education Building, Watson Room OBJECTIVES At the completion of this activity, the participants should be able to: 1. Recognize the analytical characteristics of cardiac troponin assays. 2. Describe the differences between contemporary and high-sensitivity cardiac troponin assays. 3. Describe the relation between cardiac troponin and the Universal Definition of MI with an emphasis on type 1 and 2 myocardial infarction. 4. Explain future directions of cardiac troponin. ACCREDITATION Physicians: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Allina Health and Minneapolis Heart Institute Foundation. Allina Health is accredited by the ACCME to provide continuing medical education for physicians. Allina Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: This activity has been designed to meet the Minnesota Board of Nursing continuing education requirements for 1.2 hours of credit. However, the nurse is responsible for determining whether this activity meets the requirements for acceptable continuing education. Others: Individuals representing other professional disciplines may submit course materials to their respective professional associations for 1.0 hours of continuing education credit. DISCLOSURE STATEMENTS Speaker: Dr. Sandoval has declared he does not have any conflicts of interest to disclose. Planning Committee: Dr. Michael Miedema, and Eva Zewdie have declared that they do not have any conflicts of interest associated with the planning of this activity. Dr. Robert Schwartz declared the following relationships - stockholder: Cardiomind, Interface Biologics, Aritech, DSI/Transoma, InstyMeds, Intervalve, Medtronic, Osprey Medical, Stout Medical, Tricardia LLC, CoAptus Inc, Augustine Biomedical; scientific advisory board: Abbott Laboratories, Boston Scientific, MEDRAD Inc, Thomas, McNerney & Partners, Cardiomind, Interface Biologics; options: BackBeat Medical, BioHeart, CHF Solutions; speakers bureau: Vital Images; consultant: Edwards LifeSciences. PLEASE SAVE A COPY OF THIS FLIER AS YOUR CERTIFICATE OF ATTENDANCE

2 MHIF Grand Rounds 2015 Yader Sandoval, M.D. Co-Chief Cardiovascular Disease Fellow, HCMC/ANW. Co-Investigator, Cardiac Biomarker Trials Laboratory, MMRF. April 27 th, Disclosures No financial relationships with industry. 1

3 Objectives 1. Introduction. 2. Understanding ctn assays: Analytical characteristics. 3. Clinical correlation: A) ctn in the emergency department. B) Myocardial infarction. 4. New directions. Why are we talking about this? More than 8 million patients present annually to the ED with acute CP. Cardiac biomarker testing (CK-MB, ctni and ctnt) occurs in 16.9% of all ED visits million out of million ED visits in the United States ( ). Makam AN et al. JAMA Intern Med 2015; 175: Hoffmann U et al. Am Heart J 2012; 163:

4 Evolution of Cardiac Biomarkers PAST PRESENT FUTURE * 1950s 1960s 1970s 1980s 1990s Late 1990s 2000s Today AST SGOT Total CK CKMB LDH CKMB mass assays Early ctnt ctni POC Contemporary ctnt ctni High sensitivity hs-tnt hs-ctni Lewandroski KB. Clin Lab Med Ladenson JH. Clin Chem Evolution of Cardiac Biomarkers PAST PRESENT FUTURE * 1950s 1960s 1970s 1980s 1990s Late 1990s 2000s Today AST SGOT Total CK CKMB LDH CKMB mass assays Early ctnt ctni POC Contemporary ctnt ctni High sensitivity hs-tnt hs-ctni * Please note that the the US Future is the rest of the developed world s present. 3

5 Objectives 1. Introduction. 2. Understanding ctn assays: Analytical characteristics. 3. Troponin and myocardial infarction. 4. New directions. Troponin Assays: Understanding test results. - Limit of blank (LoB) - Limit of detection (LoD) -99 th percentile upper-reference limit (URL) - Coefficient of variation (CV) total imprecision. 4

6 Troponin Assays: Understanding test results. - Limit of blank (LoB) - Limit of detection (LoD) -99 th percentile upper-reference limit (URL) - Coefficient of variation (CV) total imprecision. Limit of blank (LoB) Limit of Detection (LoD) Smallest concentrations of a measurand that can be reliably measured by an analytical procedure. Armbruster DA, Pry T. Clin Biochem Rev

7 Case Example: Abbott Architect ctni Assay <0.010 ng/ml LoD Limit of Detection Manufacturer s Package: - LoD: µg/l Troponin Assays: Understanding test results. - Limit of blank (LoB) - Limit of detection (LoD) -99 th percentile upper-reference limit (URL) - Coefficient of variation (CV) total imprecision. 6

8 Cardiac Troponin and the 99 th percentile URL DEFINITION OF MYOCARDIAL INFARCTION The term acute MI should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI: Detection of a rise and/or fall of cardiac biomarker values [preferably ctn] with at least one value above the 99 th percentile URL and with at least one of the following: 1. Ischemic symptoms 2. New or presumed new ST-T changes or new LBBB 3. Development of pathological Q waves in the ECG 4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. 5. Identification of an intracoronary thrombus by angiography or autopsy. Thygesen et al. Third Universal Definition of MI. JACC 2012 Case Example: Abbott Architect ctni Assay ng/ml NOT the 99 th percentile <0.010 ng/ml LoD Limit of Detection Manufacturer s Package: - LoD: µg/l or ng/ml - 99 th percentile URL: µg/l or ng/ml - 10% CV concentration: µg/l or ng/ml 7

9 NORMALITY Questionnaires Surrogate biomarkers Imaging Physical examination Sandoval Y, Apple FS. Clin Chem Selection Criteria 99 th percentile URL No patient selection 29.9 ng/l Questionnaire alone 20.0 ng/l Questionnaire BP egfr 14.4 ng/l Imaging Collinson P, Apple FS Clin Chem

10 SUBSTANTIAL VARIABILITY BETWEEN LABORATORIES IN TROPONIN DECISION LEVEL FOR DIAGNOSIS OF MYOCARDIAL INFARCTION AND ASSAY 99TH PERCENTILE: FINDINGS FROM THE INTERNATIONAL STUDY OF COMPARATIVE HEALTH EFFECTIVENESS WITH MEDICAL AND INVASIVE APPROACHES (ISCHEMIA) TRIAL J Am Coll Cardiol. 2014;63(12_S). doi: /s (14) Significant variability exists in the ctn MI decision level used by hospital laboratories relative to the assay ctn 99th percentile. Only one-third of labs follow the Third Universal Definition of MI. These data have important implications for the diagnosis of MI in clinical practice and adjudicating MI endpoints in clinical trials. Copyright The American College of Cardiology. All rights reserved. Troponin Assays: Understanding test results. - Limit of blank (LoB) - Limit of detection (LoD) -99 th percentile upper-reference limit (URL) - Coefficient of variation (CV) total imprecision. 9

11 Total Imprecision Coefficient of Variation (CV) Fierdoz O. Essential laboratory knowledge for the clinician. Continuing Medical Education, [S.l.], v. 30, n. 7, p , jun Total Imprecision Coefficient of Variation (CV) Apple FS. Clin Chem

12 What is a high-sensitivity ctn assay? What is a high-sensitivity ctn assay? Contemporary ctn Assay Measure cardiac troponin values above the LoD in LESS than 50% of a reference population. High Sensitivity ctn Assay Measure cardiac troponin values above the LoD in 50% of a reference population. CV <10% at the 99 th URL 11

13 Comparing Contemporary vs. hs-ctn Assays Selected examples. Manufacturer assay Measurable values >LoD, % CV Total Imprecision (according to Manufacturer) Abbott ARCHITECT hs-ctni 96% 3% Abbott ARCHITECT ctni 2% 14% Beckman Access 2 hs-ctni 80% 8.6% Beckman Access 2 ctni 35% 14% Siemens Dimension Vista hs-ctni 100% 3% Siemens Dimension Vista - ctni 1% 10% Apple FS, Collinson PO. Clin Chem Apple FS, Ler R, Murakami MM. Clin Chem Impact of Analytical Variation on MI Diagnosis Sandoval Y, Smith SW, Schulz KM, Murakami MM, Love SA, Nicholson J, Apple FS. Clin Chem

14 Objectives 1. Introduction. 2. Understanding ctn assays: Analytical characteristics. 3. Troponin: Clinical correlation Part I ctn in the emergency department. 4. New directions. EMERGENCY PHYSICIANS CARDIOLOGISTS Can t miss ACS. Not another trop leak please NEGATIVE PREDICTIVE VALUE ED OVERCROWDING DX. SPECIFICITY EMPHASIS ON ACS 13

15 Chest Pain in the ED US Data >8 million patients present annually to the ED with acute CP. 2 10% are diagnosed with ACS. Cost in excess of $8 billion. Unnecessary hospitalization and testing. Current strategies often require hospital admission from hours in most US hospitals (>90%) and include serial ECGs and biomarker measurements, observation and some of functional testing to exclude myocardial ischemia. Hoffmann U et al. AHJ 2012 Limitations of Contemporary ctn Assays Delays in Excluding Disease Delays in rule-out interferes with evaluation of alternative diagnoses and contributes to expensive overcrowding in the ED (~ increased in medical errors, public health problem). Delays in Diagnosing Disease Delays in rule-in hold back prompt use of evidencebased therapies. Delayed increase of circulating levels for 3-4 hours, often requiring sampling for 6-12 hours. Reichlin et al. Arch Intern Med

16 Symptoms Suggestive of ACS Non cardiac diagnosis Chronic stable angina Possible ACS Definite ACS Treatment as indicated by alternative diagnosis. ACC/AHA Guidelines for Chronic Stable Angina. Non-diagnostic ECG and normal initial biomarkers Guidelines for NSTEMI/UA Observe, serial ECGs, cardiac biomarkers Consider MPI to identify rest ischemia Guidelines for STEMI If negative If positive If negative If positive Study to provoke ischemia or detect anatomic CAD Admit to hospital Outpatient Follow Up Admit to hospital If negative If positive Outpatient follow up Admit to hospital Amsterdam EA et al. Testing of low-risk patients presenting to the emergency department with chest pain. Circulation Symptoms Suggestive of ACS Non cardiac diagnosis Chronic stable angina Possible ACS Definite ACS Treatment as indicated by alternative diagnosis. ACC/AHA Guidelines for Chronic Stable Angina. Non-diagnostic ECG and normal initial biomarkers Guidelines for NSTEMI/UA Observe, serial ECGs, cardiac biomarkers Consider MPI to identify rest ischemia Guidelines for STEMI If negative If positive If negative If positive Study to provoke ischemia or detect anatomic CAD Admit to hospital Outpatient Follow Up Admit to hospital If negative If positive Outpatient follow up Admit to hospital Amsterdam EA et al. Testing of low-risk patients presenting to the emergency department with chest pain. Circulation

17 Rule-out Strategies Use of undetectable hs-ctn levels. (Below <LoD or <LoB) Accelerated Serial hs-ctn sampling (0h and 1-3h) Hs-cTn in combination with a risk score (ADPs) Rule-out strategies with hs-ctn: Using LoD/LoB Author - Journal - Year ctn Assay Cutoff value used % qualifying for NPV strategy Body R et al. Roche <3 ng/l 195 out of % JACC 2011 hs-ctnt (LoB) (28%) (6 month) Bandstein N et al. Roche <5 ng/l 8,907 out of 14,636. NPV for MI: JACC 2014 hs-ctnt (LoD) (61%) 99.8% (30 d) 99.4% (1 year) NPV for death: 100% (30 d) 99.6% (1 year) Thelin J et al. Roche <5 ng/l 160 out of 478 NPV for NSTEMI: Eur Heart J ACC hs-ctnt (LoD) (33%) 100% NPV for ACS/UA: 94% 16

18 Rule-out strategies with hs-ctn: Serial Sampling Author - Journal - Year Total ctn Assay Sampling % qualifying for NPV patients algorithm strategy Reichlin T et al. n=1320 Roche 0h and 1h 786 out of 1320 NPV AMI: 99.9% CMAJ 2015 (APACE) hs-ctnt 59.5% Rubini Gimenez et al. AJM 2015 n=1811 Abbott hs-ctni 0h and 1h 50.5% 99.6% Reichlin T et al. DC=436 Roche 0h and 1h 259 out of % Arch Int Med 2012 VC=436 hs-ctnt 60% Reichlin et al. N=1665 Roche 0h and 2h DC=60% 99.9% AJM 2015 DC=1148 hs-ctnt VC=78% 99.5% VC=517 Thelin J et al. n=478 Roche Oh and 3-4h 309 out of 478 NPV ACS: 91% Eur H J ACC 2014 hs-ctnt 65% NPV NSTEMI: 99% 2011 ESC Guidelines A rapid rule-out protocol (0h and 3h) is recommended when highly sensitive troponin tests are available (Class I LOE: B). Eur Heart J 2011; 32:

19 Rule-out strategies hs-ctn: Accelerated Diagnostic Protocols (ADPs) Author - Journal - Total ctn Protocol % qualifying NPV Year patients Assay for strategy Cullen L et al. ADAPT=1635 Abbott 0h and 2h ADAPT=41.5% NPV MACE* JACC 2013 APACE=909 hs-ctni TIMI 1, nl ECG, nl hs-ctni (<99 th URL) APACE=38.6% ADAPT= 99.7% APACE= 99.7% Carlton EW et al. Heart 2015 N=960 Roche hs-ctnt TRUST ADP Low Risk: Goldman 1 Non-ischemic ECG 382 of 960 (39.8%) 99.7% Single hs-ctnt < 99 th URL (14 ng/l) * Cullen et al. MACE (30 days): death (excluding clearly noncardiac, cardiac arrest, acute MI, emergency revascularization procedure, cardiogenic shock, ventricular arrhythmia requiring intervention and high degree AV block requiring intervention. Regardless of the achieved NPV, ctn should always be used in conjunction with full clinical assessment, including patient history and exam, and 12-lead ECG. Reichlin T et al. CMAJ

20 Distinguishing between acute and chronic ctn elevations: DELTA TROPONIN Korley F, Jaffe AS. JACC 2013 Keller T et al. JAMA 2011 Reichlin T et al. Circulation

21 Objectives 1. Introduction. 2. Understanding ctn assays: Analytical characteristics. 3. Troponin: Clinical correlation Part II Myocardial infarction. 4. New directions. Non ST-Elevation MI ACS Unstable Angina ST-Elevation MI Classical Acute Coronary Syndromes (ACS) Classification. 20

22 2014 NSTEMI Guidelines STE/ACS MI is not synonymous with ACS (plaque disruption with thrombosis), since ischemia can occur via a number of other mechanisms. ACS MI UA/ACS NSTE/ACS ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations. Newby K et al. JACC

23 Myocardial Injury vs. Myocardial Infarction Type 1 vs. Type 2 MI Thygesen. Circulation Thygesen K et al. Third Universal Definition of MI. JACC

24 MI subtypes Type 1 Type 2 Type 3 Type 4A Type 4B Type 5 Spontaneous MI (atherosclerotic plaque rupture) (>1x URL) MI secondary to an ischemic imbalance. (>1x URL) MI resulting in death when biomarker values are unavailable. MI related to PCI (>5x URL) MI related to stent thrombosis. MI related to CABG (>10x URL) Thygesen. Circulation T3MI T2MI T1MI T5MI T4MI MI is not synonymous with ACS (plaque disruption with thrombosis), since ischemia can occur via a number of other mechanisms. ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations. Newby K et al. JACC

25 Type 2 MI Frequency Based on Total MI Denominator Sandoval et al. JACC

26 Adjudication Studied Population Definition T2MI Frequency ctn Assay and utilized cutoff value Sandoval et al. JACC 2014 Mortality in Type 1 vs. Type 2 MI Author - Journal Sandoval et al. Eur Heart J ESC Total N Type 1 MI Type 2 MI Follow up P value % 11.4% 180 days 0.4 * Post DC Saaby et al. Am % 49% 2.1 years <0.001 J Med In-hospital: 7% In-hospital: 19% 30d: 9% 30d: 24% 1y: 17% 1y: 44% Bonaca et al. Circulation % 7.3% 180 days NR 25

27 MI Subtypes in Clinical Practice TYPE 1 MI ACC/AHA Guidelines Focused on STE/ACS and NSTE/ACS. ACS directed therapies. Possible revascularization NSTE/ACS: conservative vs. early strategies. STE/ACS: revascularization TYPE 2 MI No guidelines exist. Treat underlying etiology / correct underlying trigger. If underlying fixed CAD contributing, consider ASA and statins. If related to underlying CAD, consider additional invasive or non-invasive imaging and consider outpatient follow up. Sandoval et al JACC 2014 What will happen when high-sensitivity troponin assays are approved for clinical use in the US? 26

28 MI Frequency: ctni vs. hs-ctni Adjudication Method by 99 th percentile MI Type 1 Type 2 Assay Total n=310 URL (ng/l) n (%) n (%) n (%) MIs adjudicated using contemporary assay (14%) (4.5%) (9.4%) MIs adjudicated using hs-ctni (11%) (3.5%) (7.1%) MIs adjudicated using F:16; M: hs-ctni with GS cutoffs (10%) (3.2%) (7.1%) 127 (41%) had at least 1 value above the sex-specific 99 th percentile. Most common etiologies are not related to primary myocardial ischemia. Sandoval Y, Smith SW, Schulz KM, Murakami MM, Love SA, Nicholson J, Apple FS. Clin Chem 2015; 61: * Roche hs-ctnt (n=1124) AMI: 18% (198) 22% (242) New AMI: n=35, Type 1 MI * e.g. myocarditis, SCM, acute HF, tachyarrhythmias. ctnt >99 th URL: 22% hs-ctnt >99 th URL: 36% Reichlin T et al. AJM

29 Total N = 1124 Moderate Large MI (+ ctnt and + hs-ctnt) = 198 Small MIs (only + hs) = 44 30m CV Mortality No MI: 2.6% Small MIs: 13.5% Mod-Large MIs: 17.9% Reichlin T et al. AJM 2012 Coronary angiography within 30-days Revascularization within 30-days Moderate Large AMI Detected with Both ctni and hs-ctnt) (n=198) Small AMI (Detected with only hs-ctnt) (n=44) P value 77% 50% < % 36% <0.001 Those undergoing coronary angiography. Moderate Large AMI Detected with Both ctni and hs-ctnt) (n=198) Small AMI (Detected with only hs-ctnt) (n=22) P value Stenosis <75% 2% 0% 0.6 Stenosis 75-95% 16% 25% 0.34 Stenosis 95-99% 35% 69% 0.01 Stenosis 100% 47% 6% Reichlin T et al. AJM

30 1-YEAR MORTALITY SWEDEHEART Groups stratified according to maximum hs-ctnt value during hospitalization. Study Population 48,594 patients Most would have had a negative ctnt using old assay Most would have a positive ctnt even suing the old ctnt assay Group 1 Group 2 Group 3 Group 4 hs-ctnt <6 ng/l hs-ctnt 6-13 ng/l hs-ctnt ng/l hs-ctnt 50 ng/l 5,790 patients 6,491 patients 10,476 patients 25,837 patients (11.9%) (13.4%) (21.6%) (53.2%) 95 (1.6%) 158 (2.4%) 1,078 (10.3%) 4,422 (17.1%) Melki D et al. JACC 2015; 65: Group 3: Increased hs-ctnt (previously negative ctnt) MEDICATIONS ADMISSION MEDICATIONS DISCHARGE ASPIRIN (%) 52% 71% PY2 12 RECEPTOR BLOCKER (%) 15% 39% BETA-BLOCKER (%) 56% 77% STATIN (%) 49% 69% ACEI-ARB (%) 51% 66% GROUP 3: - Diagnosis at discharge: ACS (62%) - MI (18%) - UA (44%) Revascularization: - PCI: 2421 (23% all or 50% CA) - CABG: 411 (4% all or 8.5% CA) Coronary angiography: 4,808 (46%) vessel disease: 2,222 (46%) - Left main or 3V disease: 1,194 (25%) Melki D et al. JACC 2015; 65:

31 Implementation Validation Validation phase (reported 0.20 ng/ml) (Total n=1038) Implementation phase (reported ng/ml) (Total n=1054) Mills NL et al. JAMA 2011; 305: Objectives 1. Introduction. 2. Understanding ctn assays: Analytical characteristics. 3. Troponin: Clinical correlation 4. New directions. 30

32 hs-ctn and ccta: ROMICAT II Patients presenting with symptoms suggesting ACS Measure hs-ctn hs-ctni <LoD Between LoD and 99 th percentile hs-ctni 99 th percentile Calcium score, median: 0 Any CAD: 11% Stenosis >50%: 0% Stenosis >70%: 0% Calcium score, median: 0 Any CAD: 58% Stenosis >50%: 19% Stenosis >70%: 13% Calcium score, median: 111 Any CAD: 83% Stenosis >50%: 75% Stenosis >70%: 58% Januzzi JL et al. Am Heart J 2015; 169: hs-ctni as a Predictor of Vascular Events in Primary Prevention: Impact of Statin Therapy JUPITER trial (Rosuvastatin 20 mg daily vs. Placebo). Without known CVD, DM, LDL <130 mg/dl 12,596 (73%) with baseline samples available. Primary endpoint: 1 st major vascular event defined as the composite of non fatal MI, non-fatal stroke, hospitalization for UA, arterial revascularization or death from CV causes. Everett BM, Zeller T, Glynn RJ, Ridker PM, Blankenberg S. Circulation 2015 [In press] 31

33 hs-ctni as a Predictor of Vascular Events in Primary Prevention: Impact of Statin Therapy ARCHITECT STAT hs-ctni assay. Median hs-ctni: 3.4 ng/l 92% had concentrations > LoD (1.9 ng/l) Everett BM, Zeller T, Glynn RJ, Ridker PM, Blankenberg S. Circulation 2015 [In press] hs-ctni as a Predictor of Vascular Events in Primary Prevention: Impact of Statin Therapy Everett BM, Zeller T, Glynn RJ, Ridker PM, Blankenberg S. Circulation 2015 [In press] 32

34 hs-ctni as a Predictor of Vascular Events in Primary Prevention: Impact of Statin Therapy Tertiles Rosuvastatin Placebo hs-ctni N events/ Incidence N events/ Incidence ARR N at risk Rate N at risk Rate 1 18 / / / / / / Lowest tertile hs-ctni: 5-year NNT of 67 Highest tertile hs-ctnt: 5-year NNT of 18 Rosuvastatin offered similar relative reductions of risk of major vascular events across baseline hs-ctni levels. In the highest category baseline ctni, rosuvastatin was associated with the most substantial reduction in absolute risk of CV events and therefore the lowest NNT. Everett BM, Zeller T, Glynn RJ, Ridker PM, Blankenberg S. Circulation 2015 [In press] 33

35 TAKE-HOME POINTS 1. Understanding and mastering basic ctn concepts NOW (prior to the introduction of high-sensitivity ctn assays) is critical. 2. LoD 99 th percentile URL CV (imprecision) 3. Rule-out and rule-in strategies. Delta troponin. 4. Type 1 vs. Type 2 MI. 5. Future: Complementary approaches (e.g. cardiac CT, cardiac MRI) in selected cohorts. 6. Future: Prevention. Thank you for your attention. Acknowledgements: - Fred S. Apple, PhD. - Stephen W. Smith, M.D. - All the staff, research associates, and co-investigators at the (CBTL), MMRF. 34