High-Sensitivity Cardiac Troponin in Suspected ACS

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1 15 th Annual Biomarkers in Heart Failure and Acute Coronary Syndromes STATE-OF-THE-ART High-Sensitivity Cardiac Troponin in Suspected ACS David A. Morrow, MD, MPH Director, Levine Cardiac Intensive Care Unit Director, TIMI Biomarker Program Senior Investigator, TIMI Study Group Professor of Medicine Brigham & Women s Hospital Harvard Medical School

2 Disclosures D Morrow has received Research grant support from Abbott, Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GlaxoSmithKline, Medicines Co, Merck & Co, Roche, Novartis, and Takeda. Served as a consultant for Abbott, Aralez, AstraZeneca, Bayer, InCarda, and Roche. Some of the high sensitivity assays for cardiac troponin & applications discussed are not approved by the US FDA.

3 High Sensitivity Assays for ctn 1. hstn 101 Can measure ctn in >50% of normal population 2. The good Better assays deliver better overall dx accuracy Leverage sensitivity in hstn for NPV 3. The bad Capture many other conditions with injury 4. The path forward Use approach fr/ 4 th UDMI: #1 Acute? #2 Ischemia? Use the delta to separate acute from chronic

4 Global Adoption of High Sensitivity ctn Anand A et al. Clin Chem 2019 epub ahead of print

5 High-sensitivity ctn 101

6 Defining High-Sensitivity Assay designation Level 4 (third generation, hs) Measurable normal values below the 99th percentile, % 95 Level 3 (second generation, hs) 75 to <95 Level 2 (first generation, hs) 50 to <75 Level 1 (contemporary) <50 1. Switch to new units ng/l 0.04 ng/ml 40 ng/l 2. Use sex-specific cut-points (99 th percentile URL) Apple FS. Clin Chem 2009; 7: Thygesen et al. 4 th Universal Definition of MI. JACC 2018; epub ahead of print

Independent determinants of hstnt 25% of individuals hstnt >99 th %ile Variable Wald Chi- OR 95% CI P value Square Model 1 Male sex 114.7 4.4 3.4-5.8 <0.001 Age (per year) 65.2 1.06 1.05-1.08 <0.

7 Independent determinants of hstnt 25% of individuals hstnt >99 th %ile Variable Wald Chi- OR 95% CI P value Square Model 1 Male sex <0.001 Age (per year) <0.001 Diabetes <0.001 Log egfr <0.001 LV mass (per g)* <0.001 Black Race <0.001 Hypertension <0.001 History of Heart Failure <0.001 **Prior MI, Angina, and CAC not independently associated de Lemos JA et al. JAMA 2010;304:

8 Mechanisms of Release of Cardiac Troponin in Conditions Outside ACS Myocardial ischemia Oxidative stress Inflammatory Cytokines Catecholamine excess Myocardial wall stress Infiltrative processes Direct Trauma Cell turnover Apoptosis Increased membrane permeability Release of ctn degradation products Reversible cell injury Cell necrosis After Morrow DA. AACC 2013 Eggers and Lindahl. Clin Chem 2017:63: Release of Cardiac Troponin Morrow DA. AACC 2017

Biomarkers in T2DM: SAVOR-TIMI 53 Distribution of hstnt 3 0.3 40.

9 Biomarkers in T2DM: SAVOR-TIMI 53 Distribution of hstnt hstnt (ng/l) Undetectable 3-< >50 Scirica BM et al. JAMA Cardiology 2016;1:

10 What works well w/ hstn

11 Clinical Probability of ACS and Diagnostic Performance of hstnt Diagnostic N = 7115Performance for acute MI (NSTEMI) Predictive Values based on hstnt Result Low Prob Med Prob High Prob ng/l ng/l ng/l ED MD Clinical Probability by Visual Analog Scale (VAS) Badertscher P et al. Clin Chem 2018; 64: NPV PPV NPV PPV hstnt 14 ng/l hstnt 52 ng/l

12 Accelerated Results Evaluation with 1hr hstnt Algorithm: TRAPID-AMI 1282 pts w/ acute chest pain 0h <12 ng/l & 1h Δ <3 ng/l Rule out 813 (63%) Other Gray-zone 285 (22%) 0h 52 ng/l or 1h Δ 5 ng/l Rule-in 184 (14%) NPV 99.1 ( ) 30d Mortality 0.1% Prevalence MI 22.5% 30d Mortality 0.7% PPV 77.2 ( ) 30d Mortality 2.7% Mueller C et al. Annals of Emerg Med 2016; 68:76-87

13 Application of hstn in the US 1355 pts with suspected ACS in 15 EDs in the US (0h/3h) Overall MI rate 9.8%; 30-day ACE MI/urg rev/death 1.2% Diagnosis: NPV 0h hstnt <6 ng/l 99.4% NPV 0h/3h hstnt 19 ng/l 99.2% Prognosis: NPV 0h/3h hstnt 19 ng/l 99.3% Peacock WF et al. JAMA-Car 2018:3:

14 Application of a hstnt-based Accelerated Diagnostic Protocol in US (1) Vigen et al. Circulation 2018:138:

15 Application of a hstnt-based Accelerated Diagnostic Protocol in US (2) N = % Vigen et al. Circulation 2018:138:

16 Impact of hstn on Use of Stress Testing, Coronary Angio Cardiac Stress Testing Invasive Testing p< Pre Post Introduction of hstnt p = ns p = ns 10 p< p = ns All cardiac stress tests Cardiac SPECT Exercise ECG 0 Coronary Angio PCI Twerenbold R. EHJ 2016;37: Morrow DA. AACC 2017

17 What are the challenges w/ hstn

18 Implementation of hstn 1. What timing of samples? 0h/1h, 0h/2h, 0h/3h, 3-6h Do you incorporate a one-and-done 0h option? 2. What cut-points (absolute & )? Sex-specific? 3. Incorporate formal clinical risk-stratification? Other stuff Inpatient vs. ED What to do with grey zone pts Morrow DA. UCSD Biomarkers 2019

19 0h/1h vs. 0h/3h hstn-based Accelerated Diagnostic Protocol N = 2547 Badertscher et al. Circulation 2018;137:

20 Single hstni at Presentation & 30d Outcome: Pooled Analysis in 19 Cohorts FN per 1000 NPV, % NPV 99.5% N = 22,457 w/ suspected ACS (19 Cohorts) MI/cardiac death 12.4% hstni (Abbott) 99 th %ile URL 26 ng/l <5 ng/l 49.1% <2 ng/l 13.7% Chapman AR et al. JAMA 2017; 318:

Sex-specific cut-offs 3. Incorporate clinical risk score 4.

21 BWH/MGH ED Algorithm Development Decisions 1. 0/1h algorithm w/ time from sx onset criterion 2. Sex-specific cut-offs 3. Incorporate clinical risk score 4. 0h R/O possible 5. Inpatient delta 7 ng/l Sx >3h, HEART 0-3, hstnt<6 ng/l Sx >3h Baugh C et al. Crit Pathways in Cardiol 2019;18: 1 4)

22 High Sensitivity ctn in 377 Patients w/ Low-Intermediate Probability of ACS Diagnostic N = 7115Performance for Acute Coronary Synd Correlates of +hstnt (N=38) in pts without ACS (N=340) N = 37 w/ ACS hstnt + hstnt Sens Spec PPV NPV Januzzi J et al. Circulation 2010; 121: DM Hx CAD RWMA CTA Result Segments w/ Plaque

23 Distribution of hstnt Concentration in the ED Based on Final Diagnosis patients with acute chest pain presenting to ED AMI UA Non-CAD Cardiac Series 1 Reichlin T et al. Arch Int Med 2012; 172: Non-cardiac Unknown

Clinical Probability of ACS and Diagnostic Performance of hstnt Diagnostic N = 7115Performance for acute MI (NSTEMI) Predictive Values based on hstnt Result Low Prob Med Prob High Prob 1. 14 ng/l 2.

24 Clinical Probability of ACS and Diagnostic Performance of hstnt Diagnostic N = 7115Performance for acute MI (NSTEMI) Predictive Values based on hstnt Result Low Prob Med Prob High Prob ng/l ng/l ng/l ED MD Clinical Probability by Visual Analog Scale (VAS) Badertscher P et al. Clin Chem 2018; 64: NPV PPV NPV PPV hstnt 14 ng/l hstnt 52 ng/l

BIOMARKER PROGRAM Low Concentration of hstni Identifies Gradient of Risk 12 LoD 99 th %ile 10 9.7 CV Death or MI (%) 8 6 4 3.2 4.

25 BIOMARKER PROGRAM Low Concentration of hstni Identifies Gradient of Risk 12 LoD 99 th %ile CV Death or MI (%) No pts with undetectable hstni < <6 6 - <11 11-<26 26 n = 257 N = 217 n = 229 n = 3992 Bohula May E et al. hstni Concentration (ng/l) Clin Chem :158-64

Implementation of a High Sensitivity ctni Assay: High-STEACS RCT Stepped-wedge, cluster randomized design n=42,282 10 hosp in Scotland 21% (10,360) had elevated ctni 17% (1,771; 4% overall)

26 Implementation of a High Sensitivity ctni Assay: High-STEACS RCT Stepped-wedge, cluster randomized design n=42, hosp in Scotland 21% (10,360) had elevated ctni 17% (1,771; 4% overall) reclassified by hstni Survival w/out MI or CV death Reclassified by hstni Abnormal w/ old assay Primary comparison adj-hr 1.10 (0.75, 1.61, p=0.62) Mills N et al. Lancet 2018; 392: Time since presentation (days)

27 Path forward to practical clinical use of hstn

28 The Central Concept of Myocardial Injury Thygesen K et al. EHJ 2018; 40:

29 4 th Universal Definition of MI Approach to Interpreting ctn Thygesen K et al. EHJ 2018; 40:

30 Prognosis in Patients with Type 2 MI and Non-ischemic Myocardial Injry Adverse Outcomes by Cause of Myocardial Injury CV death NFMI HF Non-CV death N = 2122 pts with elevated ctn 55.2% Type 1 MI 20.2% Type 2 MI % Myocardial injury Type 1 MI Type 2 MI Injury Chapman A et al. Circulation 2018;137:

31 ctn and Prognosis in Pts Discharged without a Specific Diagnosis N = 48,872 w/ suspected ACS but d/c w/out specific dx in SWEDEHEART 20.1% >99 th %ile Tertiles of ctn Age, sex-adjusted HR (95% CI) for T3 CV death 3.27 ( ) Non-CV death 2.37 ( ) Death, MI, stroke, readmission for HF T3 (n=2,137) T2 (n=2,490) T1 (n=5,137) ctn <99 th %ile (n=39,072) Eggers, Jernberg, Lindahl. JACC 2019;73:1-9.

32 Biomarkers in T2DM: SAVOR-TIMI 53 (4) Primary Endpoint According to Biomarker Quartile 25% Overall Population Q1 Established Cardiovascular Disease 25% Q1 25% Multiple Risk Factors Q1 NT-proBNP 20% 15% 10% Q2 Q3 Q4 20% 15% 10% Q2 Q3 Q4 20% 15% 10% Q2 Q3 Q4 5% 5% 5% hs-tnt 0% 25% 20% 15% 10% Q1 Q2 Q3 Q4 0% 25% 20% 15% 10% Q1 Q2 Q3 Q4 0% 25% 20% 15% 10% Q1 Q2 Q3 Q4 5% 5% 5% 0% % % Scirica BM et al. JAMA Cardiology 2016;1:

33 High Sensitivity Assays for ctn 1. hstn 101 Can measure ctn in >50% of normal population 2. The good Better assays deliver better overall dx accuracy Leverage sensitivity in hstn for NPV 3. The bad Capture many other conditions with injury 4. The path forward Use approach fr/ 4 th UDMI: #1 Acute? #2 Ischemia? Use the delta to separate acute from chronic

34 Discussion

35 hstn: My Seven Key Points for Practitioners to Know 1. ctn myocardial infarction 2. hstn will be measurable in majority of CV pts 3. Use in the ED is based on a probabilistic assessment not a definitive dx algorithm 4. Use the Δ to identify acute myocardial injury 5. hstn improves dx accuracy & prognostication 6. Use of hstn may decrease the amount of noninvasive and invasive testing and cost 7. Don t dismiss stably elevated hstn Recognize the increase in long-term risk Morrow DA. AACC 2017

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