STATE-OF-THE-ART

High-SensitivityCardiac Troponin in

Suspected ACS

David A. Morrow, MD, MPHDirector, Levine Cardiac Intensive Care Unit

Director, TIMI Biomarker ProgramSenior Investigator, TIMI Study Group

Professor of MedicineBrigham & Women’s Hospital

Harvard Medical School

15th Annual Biomarkers in Heart Failure and Acute Coronary Syndromes

DisclosuresD 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.

High Sensitivity Assays for cTn1. 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/ 4th UDMI: #1 Acute? #2 Ischemia?• Use the “delta” to separate acute from chronic

Global Adoption of High Sensitivity cTn

Anand A et al. Clin Chem 2019 epub ahead of print

High-sensitivity cTn“101”

Defining “High-Sensitivity”

Apple FS. Clin Chem 2009; 7:1303-6Thygesen et al. 4th Universal Definition of MI. JACC 2018; ePub ahead of print

Assay designation Measurable normal values below the 99th percentile, %

Level 4 (third generation, hs) ≥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/L2. Use sex-specific cut-points (99th percentile URL)

Independent determinants of hsTnT

de Lemos JA et al. JAMA 2010;304:2503-12.

Variable Wald Chi-Square

OR 95% CI P value

Model 1Male sex 114.7 4.4 3.4-5.8 <0.001Age (per year) 65.2 1.06 1.05-1.08 <0.001Diabetes 24.4 2.2 1.6-3.0 <0.001Log eGFR 17.4 0.36 0.22-0.58 <0.001LV mass (per g)* 13.7 1.01 1.00-1.01 <0.001Black Race 12.0 1.5 1.2-1.9 <0.001Hypertension 6.0 1.4 1.1-1.7 <0.001History of Heart Failure 4.5 1.9 1.1-3.5 <0.001

**Prior MI, Angina, and CAC not independently associated

25% of individuals hsTnT >99th %ile

Mechanisms of Release of Cardiac Troponin in Conditions Outside ACS

After Morrow DA. AACC 2013Eggers and Lindahl. Clin Chem2017:63:223-235

Inflammatory Cytokines

Oxidative stress Catecholamine

excess

Myocardial wall stress

Myocardial ischemia

Infiltrative processes

Direct Trauma

Release ofCardiac Troponin

Cellturnover Apoptosis

Increasedmembrane

permeability

Cellnecrosis

Reversiblecell injury

Release of cTndegradation

products

Morrow DA. AACC 2017

Biomarkers in T2DM: SAVOR-TIMI 53

0.3

56

40.7

3

Distribution of hsTnT

Undetectable3-<1414-50>50

hsTnT (ng/L)

Scirica BM et al. JAMA Cardiology 2016;1:989-998

What works wellw/ hsTn …

Clinical Probability of ACS and Diagnostic Performance of hsTnT

Badertscher P et al. Clin Chem 2018; 64:515-525

N = 7115Diagnostic Performance for acute MI (NSTEMI)

Predictive Valuesbased on hsTnT Result

1. ≥14 ng/L2. ≥28 ng/L3. ≥52 ng/L

ED MD Clinical Probabilityby Visual Analog Scale (VAS)

100

9

99

26

98

33

92

63

90

7369

92

0

10

20

30

40

50

60

70

80

90

100

NPV PPV NPV PPV

Low Prob Med Prob High Prob

hsTnT ≥14 ng/L hsTnT ≥52 ng/L

ResultsAccelerated Evaluation with 1hr hsTnT Algorithm: TRAPID-AMI

Mueller C et al. Annals of Emerg Med 2016; 68:76-87

NPV 99.1 (98.2-99.7)

1282 pts w/ acute chest pain

0h <12 ng/L& 1h Δ <3 ng/L

Other 0h ≥52 ng/Lor 1h Δ ≥5 ng/L

Rule out 813 (63%)

Gray-zone285 (22%)

“Rule-in”184 (14%)

PPV 77.2 (70.4-83.0)

Prevalence MI22.5%

30d Mortality0.1%

30d Mortality2.7%

30d Mortality0.7%

Application of hsTn in the US

Peacock WF et al. JAMA-Car 2018:3:104-111

• 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%

Vigen et al. Circulation 2018:138:2061-2063

Application of a hsTnT-based Accelerated Diagnostic Protocol in US (1)

Application of a hsTnT-based Accelerated Diagnostic Protocol in US (2)

N = 536

66%

Vigen et al. Circulation 2018:138:2061-2063

Impact of hsTn on Use of Stress Testing, Coronary Angio

Twerenbold R. EHJ 2016;37:3324-32

29

12

1719

10 9

0

5

10

15

20

25

30

35

All cardiacstress tests

CardiacSPECT

Exercise ECG

Pre Post

23

13

23

13

0

5

10

15

20

25

30

35

CoronaryAngio

PCI

p<0.001

p<0.001

p = ns

p = ns

p = ns

Cardiac Stress Testing Invasive Testing

Introduction of hsTnT

Morrow DA. AACC 2017

What are the challengesw/ hsTn …

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

0h/1h vs. 0h/3h hsTn-BasedAccelerated Diagnostic Protocol

Badertscher et al. Circulation 2018;137:2536–2538

N = 2547

Chapman AR et al. JAMA 2017; 318:1913-24

Single hsTnI at Presentation & 30d Outcome: Pooled Analysis in 19 Cohorts

N = 22,457 w/ suspected ACS (19 Cohorts)• MI/cardiac death 12.4%• hsTnI (Abbott)

• 99th %ile URL 26 ng/L• <5 ng/L 49.1%• <2 ng/L 13.7%

99.5%

NPV

FN p

er 1

000

NPV

, %

BWH/MGH ED Algorithm

Sx >3h, HEART 0-3,hsTnT<6 ng/L

Baugh C et al. Crit Pathways in Cardiol 2019;18: 1–4)

Sx >3h

Development Decisions1. 0/1h algorithm w/ time from sx

onset criterion2. Sex-specific cut-offs3. Incorporate clinical risk score4. 0h R/O possible5. Inpatient delta 7 ng/L

High Sensitivity cTn in 377 Patients w/ Low-Intermediate Probability of ACS

Januzzi J et al. Circulation 2010; 121:1227-1234

N = 7115

0

10

20

30

40

50

60

70

80

90

100

Sens Spec PPV NPV0

5

10

15

20

25

30

DM Hx CAD RWMA

Diagnostic Performance for Acute Coronary Synd

Correlates of +hsTnT (N=38) in pts without ACS (N=340)

N = 37 w/ ACS hsTnT + hsTnT -

1.7

4.8

CTA ResultSegments w/

Plaque

Distribution of hsTnT Concentration in the ED Based on Final Diagnosis

872 patients with acute chest pain presenting to ED

0

20

40

60

80

100

AMI UA Non-CADCardiac

Non-cardiac Unknown

Series 1Reichlin T et al. Arch Int Med 2012; 172:1211-18

Clinical Probability of ACS and Diagnostic Performance of hsTnT

Badertscher P et al. Clin Chem 2018; 64:515-525

N = 7115Diagnostic Performance for acute MI (NSTEMI)

Predictive Valuesbased on hsTnT Result

1. ≥14 ng/L2. ≥28 ng/L3. ≥52 ng/L

ED MD Clinical Probabilityby Visual Analog Scale (VAS)

100

9

99

26

98

33

92

63

90

7369

92

0

10

20

30

40

50

60

70

80

90

100

NPV PPV NPV PPV

Low Prob Med Prob High Prob

hsTnT ≥14 ng/L hsTnT ≥52 ng/L

1.6

3.2

4.4

9.7

0

2

4

6

8

10

12LoD

hsTnI Concentration (ng/L)

≥26<1.5 ≥6 - <11 ≥11-<26

99th %ile

≥1.5 - <6

No pts with undetectable

hsTnI

CV

Dea

th o

r MI (

%)

n = 257 N = 217 n = 229 n = 3992

Low Concentration of hsTnI Identifies Gradient of Risk

Bohula May E et al. Clin Chem 2014 60:158-64

BIOMARKERPROGRAM

Implementation of a High Sensitivity cTnI Assay: High-STEACS RCT

Mills N et al. Lancet 2018; 392: 919–28

Stepped-wedge, cluster randomized design

Reclassified by hsTnI Abnormal w/

old assay

n=42,282

10 hosp in Scotland

21% (10,360) had elevated cTnI

17% (1,771; 4% overall) ‘reclassified’ by hsTnI

Primary comparisonadj-HR 1.10 (0.75, 1.61, p=0.62)

Time since presentation (days)

Surv

ival

w/o

ut M

I or C

V de

ath

Path forward to practical clinical use of hsTn …

The Central Concept of Myocardial Injury

Thygesen K et al. EHJ 2018; 40: 237-69.

4th Universal Definition of MIApproach to Interpreting cTn

Thygesen K et al. EHJ 2018; 40: 237-69.

Prognosis in Patients with Type 2 MI and Non-ischemic Myocardial Injry

Chapman A et al. Circulation 2018;137:1236-45.

21.624.2

27.8

17.8

10

6.7

13.2

35.7

41.8

8.85.8

9.2

0

5

10

15

20

25

30

35

40

45

Type 1 MI Type 2 MI Injury

Adverse Outcomes by Cause of Myocardial InjuryCV death NFMI HF Non-CV death

N = 2122 pts with elevated cTn• 55.2% Type 1 MI• 20.2% Type 2 MI• 24.6% Myocardial injury

cTn and Prognosis in Pts Discharged without a Specific Diagnosis

Eggers, Jernberg, Lindahl. JACC 2019;73:1-9.

N = 48,872 w/ suspected ACS but d/c w/out specific dx in SWEDEHEART• 20.1% >99th %ile• Tertiles of ↑ cTn• Age, sex-adjusted

HR (95% CI) for T3 CV death

3.27 (2.9-3.7) Non-CV death

2.37 (2.1-2.7)

cTn <99th %ile(n=39,072)

T3 (n=2,137)

T1 (n=5,137)

T2 (n=2,490)

Death, MI, stroke, readmission for HF

Biomarkers in T2DM: SAVOR-TIMI 53 (4)

Scirica BM et al. JAMA Cardiology 2016;1:989-998

Primary Endpoint According to Biomarker Quartile

NT-

pro

BN

Ph

s-T

nT

0%

5%

10%

15%

20%

25%

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Overall PopulationEstablished Cardiovascular

Disease Multiple Risk Factors

High Sensitivity Assays for cTn1. 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/ 4th UDMI: #1 Acute? #2 Ischemia?• Use the “delta” to separate acute from chronic

Discussion

hsTn: My Seven Key Points for Practitioners to Know

1. cTn ≠ myocardial infarction2. hsTn will be measurable in majority of CV pts3. Use in the ED is based on a probabilistic

assessment not a definitive dx algorithm4. Use the Δ to identify acute myocardial injury5. hsTn improves dx accuracy & prognostication6. Use of hsTn may decrease the amount of non-

invasive and invasive testing and cost7. Don’t dismiss stably elevated hsTn

Recognize the increase in long-term riskMorrow DA. AACC 2017