Detection and Risk Stratification of Myocardial Damage: The Troponin Story

1
Detection and Risk Stratification of Myocardial
Damage The Troponin Story
E. Magnus Ohman, MB, FRCPI, FESC, FACC Professor
of Cardiovascular Medicine Director, Program for
Advanced Coronary Disease Duke University Medical
Center Duke Clinical Research Institute Durham,
North Carolina
AIMBE 15th Annual Event National Academy of
Sciences Washington, DC March 2, 2006
2
The Troponin Story

• Conflict of interest
• Research grants -
• Berlex, Sanofi-Aventis, Schering-Plough, Bristol
  Meyer Squibb, and Millennium.
• Stock ownership -
• Medtronic
• Consultant -
• Response Biomedical, Liposcience and Inovise
  Medical

3
The Troponin Story
Outline

• What is Troponin and how does it relate to
  myocardial infarction (MI heart attack)
• Observations on changing a Gold Standard
• Skeptics and push-back by the clinical community
• Diagnostic and therapeutic linkage
• Adoption in practice lessons learned

4
Striated Muscle Contraction Apparatus The Actin
Tropomyosin Complex

• The Troponins

Troponin Complex
TnT
Actin
Tropomyosin
TnC
TnI
5
Cardiac Markers Ability To Diagnose MI (Heart
Attack)
Myocardial Cell

• Troponin
• Bound
• Soluble

• Troponin
• Bound
• Soluble

• Creatine Kinase MB
• myocardial enzyme

TnT
CK-MB
TnT
Blood vessel
6
Microvascular Obstruction with Troponin Elevation
Following Plaque Rupture
- Newby Ohman, JACC 2003
7
The Troponin Story
Outline

• What is Troponin and how does it relate to
  myocardial infarction (MI heart attack)
• Observations on changing a Gold Standard
• Skeptics and push-back by the clinical community
• Diagnostic and therapeutic linkage
• Adoption in practice lessons learned

8
(No Transcript)
9
Incidence of Death or MI Following Acute Coronary
Syndromes
10
The Troponin Story Evolution of a Cardiac Marker
of MI

• Initially identified as Troponin T by Dr Hugo
  Katus in Heidelberg, Germany in 1992 (Clin Chem)
• Cardiac specificity defined in man
• Early experience suggested poor specificity
  compared with CK-MB 1992-1995
• Troponin I assays developed to mimic CK-MB
  characteristcs
• Linkage with ultimate outcome (death) was missing

11
Changing a Gold Standard
- Ohman et al, NEJM 1996
12
Long Term Survival and TnT Status
GUSTO-IIa Study
Mortality Rates TnT Pos 14 TnT Neg 5
p TnT -
TnT
- Ohman et al, NEJM 1996
13
GUSTO-IIa TnT Study
Predictors of 30-Day Mortality
Unadjusted Adjusted Variable X2 p X2 p Tr
oponin T 21 0.027 ECG 14 0.003 12
0.009 CK-MB 11 0.004 0.7
0.7 Adjusted for the other 2 variables

- Ohman et al, NEJM 1996
14
Combining Clinical, ECG and Cardiac Markers in
ACS
Predictors of 1-Year Mortality Variable ?2
p-value Hazard Ratio Age
55 elevation 15 0.0001 3.42 Previous
CABG 12 0.0005 3.80 Baseline TnT 10 0.007 1.44 C
hronic renal failure 7 0.008 4.73 10-year
increment 0.1 ng/ml increment
Newby, Circ 1998
15
Changing The Gold Standard For MI
- ESC/ACC, JACC 2000
16
New Definition of AMI ESC/ACC The Switch to a
Troponin Standard

• Criteria for acute, evolving or recent MI
• Typical rise and gradual fall (Tn) or more rapid
  rise and fall (CK-MB) of biochemical markers of
  myocardial necrosis with at least one of the
  following
• ischemic symptoms
• Development of pathologic Q waves on ECG
• ECG changes indicative of ischemia
• Coronary artery intervention
• Pathologic findings of an acute MI

ESC/ACC Committee, JACC 2000.
17
- Christenson Ohman 1998
18
(No Transcript)
19
The Troponin Story
Outline

• What is Troponin and how does it relate to
  myocardial infarction (MI heart attack)
• Observations on changing a Gold Standard
• Skeptics and push-back by the clinical community
• Diagnostic and therapeutic linkage
• Adoption in practice lessons learned

20
Reasons For Unusual Troponin Results

• Assay performance
• Cut-off not standardized
• Detection of myocardial necrosis in non-ACS
  setting
• Too much reliance on a single test

21
Conditions Associated with Myocardial Necrosis
Detected by Troponin assays

• Congestive Heart Failure
• Hypertensive Crisis
• Multi-organ failure in ICU
• PCI/CABG
• Myocarditis
• Auto-immune Heart Disease

22
Outcomes (Death or Hospitalization) Among Stable
CHF Patients
TnT vs. TnT- ?2 17.51 P
Proportion without death /HF
Hudson, AHJ 2004
23
Christenson et al Clin Chem 200147431-437
Variation in 13 Troponin I Assays

• 10 ng/mL troponin CIT standard material,
  value-assigned by NIST, was measured by 13
  participating cTnI assays, in duplicate

Mean 28.1 SD 36.4 CV 130
Within assay reproducibility good, but
measurement of 10 ng/mL material yielded results
that were 30-fold different!
24
Improvement in Troponin Assay Harmony
- R Christenson, National Institute of Standards
and Technology 2005
25
The Troponin Divide
The Troponin Enthusiast
The Troponin Ignorer

• Academic Cardiologist
• Invasive/Interventional
• Young
• Troponin provides risk stratification and aids
  treatment selection

• Community Cardiologist
• Non-invasive
• Old
• 20 years in practice
• Unreliable test with unclear association with
  mortality

Broad use of anti-thrombotics
Narrow use of anti-thrombotics
- A Hiller, Personal Communication
26
The Troponin Story
Outline

• What is Troponin and how does it relate to
  myocardial infarction (MI heart attack)
• Observations on changing a Gold Standard
• Skeptics and push-back by the clinical community
• Diagnostic and therapeutic linkage
• Adoption in practice lessons learned

27
PARAGON B TnT Study
TnT Positive
TnT Negative Placebo GP2b/3a Placebo
GP2b/3a 30-Day N237 N227
N349 N344 Death 5.1 3.1
2.1 1.2 Death MI 19.0
11.0 10.3 9.6 Death/MI/RI 19.4
11.0 11.2 10.8 p 0.29
p 0.018 p0.013
Newby, Circ 2001
28
GP2b/3a and Troponin status Reduction in
Death/MI in Trop
PARAGON-B
PRISM
CAPTURE
Combined
Troponin T-Positive
Troponin T-Negative
Interaction
Newby Ohman, Circ 2001
29
The Troponin Story
Outline

• What is Troponin and how does it relate to
  myocardial infarction (MI heart attack)
• Observations on changing a Gold Standard
• Skeptics and push-back by the clinical community
• Diagnostic and therapeutic linkage
• Adoption in practice lessons learned

30
Mortality by Peak Troponin
ULN
Roe et al, Arch Intern Med 2005
31
Troponin Testing in theCRUSADE CQI Project
Tn Pos Tn NegTherapy (n 11,455) (n
3,444) p-value Aspirin 91 90 0.0001 b-blocker 78 73 0.0001 Cath 66 59 0.0001 Mortality 6.5 1.1
Roe et al, Arch Intern Med 2005
32
Lessons Learned in Risk StratificationInsights
from CRUSADE
GP IIb/IIIa Use Early Invasive
In-Hospital Mortality
Roe, Arch Intern Med 2005
33
Adjusted Mortality by Early GP IIb-IIIa
Inhibitor Results from CRUSADE, Clinical Trials,
and NRMI
95 CI Odds Ratio
CRUSADE ACS (n40,808)
0.94 (0.83, 1.06)
CRUSADE Trop (n27,184)
0.88 (0.76, 1.05)
6 RCTs ACS (n31,402)
0.91 (0.81, 0.99)
NRMI NSTEMI (N60,770)
0.88 (0.79, 0.97)
1.0
2.0
0.5
Early GP IIb-IIIa Inhibitor Better
No Early GP IIb-IIIa Inhibitor Better

• Boersma 2002 Lancet359189-98
• Peterson 2003 JACC

34
Testing and treating as a function of probability
of diagnosis Young vs Old
Test threshold
Treatment threshold
Diagnosis established
Diagnosis uncertain
Diagnosis excluded
Test further
Young
0
1.0
Diagnosis uncertain
Old
1.0
0
Probability of diagnosis
- Grimes Schulz, Lancet 2005
35
The Troponin Story Lessons Learned

• Changing a Gold Standard takes a long time
• A decade to change (1990 2000)
• Lack of standardization causes confusion and
  pushback
• Adoption in CRUSADE 95 2002
• Collaborations (MD/PhD) essential
• Therapeutic linkage essential
• Why bother with this new test
• Innovative targets and markers challenges
  medical school concepts
• Troponin was able do detect small amount of
  myocardial necrosis in non-ACS settings

36
(No Transcript)
37
GUSTO-IIa Angiographic Substudy
Baseline Troponin T
status 1-year mortality TnT pos TnT neg
p value No cath 36.6
11.1 0.0001 Cath medical 19.7
6.1 0.085 Cath PTCA 6.3
6.2 0.78 Cath CABG 5.8
5.9 0.71 Goldmann, AHA 1999
38
POC TnT in STEMI GUSTO-3 Experience
12,666 patients with ST elevation from 807
hospitals in 11 countries
Independent predictor of 30-day mortality
Higher 30-day mortality irrespective of symptom
duration
- Ohman, AJC 1999
39
PARAGON B TnT Study
5225
Patients
1160 (22) Troponin T Substudy Lamifiban Placebo
Pos TnT 0.1 mg/ml 48-72
40 Heparin Hours Heparin N561 N586
Newby, Circ 2001
40
TnT Results in CHF Patients
TnT Concentration (ng /ml) 0.02 0.02-0.059 0.06-0.099 0.1 N (136) 103
23 4 7 75 17 3 5
Elevated TnT in 34/ 136 (25) of heart failure
outpatients
Hudson, AHJ 2004
41
Clinical Outcomes and TnT
TnT Concentration (ng/ml) Risk P- (103) (34) (95
CI) value Death/ HF Hosp. 21.4 58.8 2.7
(1.7-4.3) 0.001 Death 7.8 32.4 4.2
(1.6-9.5) 0.001 HF Hospitalization 16.5 41.2
2.5 (1.4-4.5) 0.004 MI 4.9 20.6 4.2
(1.5-12.7) 0.01 Stroke 1.9 8.8 4.5 (0.8-26.3)
0.10 PTCA/ CABG 6.8 5.9 0.9 (0.2-4.0)
1.0 Cardiac Txp 2.9 3.0 1.0 (0.1-9.4) 1.0
Increased death HF hospitalization in TnT
patients
Hudson, AHJ 2004
42
Baseline Characteristics/Lab Results
TnT Concentration (ng/ml) ml P- (103) (34) value TnT(ng/ml) 0.002
?.005 0.062?0.1
.3

P value compares (-)TnT (0.02)
Hudson, AHJ 2004
43
(No Transcript)
44
Thresholds for testing and treating as a function
of probability of diagnosis
Test threshold
Treatment threshold
Diagnosis established
Diagnosis uncertain
Diagnosis excluded
Test further
0
1.0
Probability of diagnosis
- Grimes Schulz, Lancet 2005
45
Meta-analysis of Troponin Among Chest Pain Unit
(CPU) Patients Risk of Death or AMI
56.77 (19.5, 165)
Tn and CK-MB ()
7.45
Tn only ()
2.28
MB only ()
1.0
- Rao et al, AJC 2003
46
Predicting Late Rise in Troponin TIMI-11b and
GUSTO-2b
Performance of score
Multivariate predictors of a Positive TnI (0.4
ng/ml)
Januzzi et al, AHJ 2006
47
Mortality and Troponin
Cath and Troponin
Presence and Risk of AMI not Affecting Cath
Strategy in CRUSADE
Roe et al, Arch Intern Med 2005
48
Odds ratio (95 confidence interval)
GUSTO-4 ACS MI in first 30 days
Age65 years
Current smoking
- James, Circ 2003
Angina Pectoris
Previus MI
Heart failure
Crea. cl. Diabetes mellitus
ST-depression 0.5 mm
CRP 10 mg/L
Troponin T 0.01 ug/L
NT-proBNP NT-proBNP 237- 669 ng/L
NT-proBNP 669-1869 ng/L
NT-proBNP 1869 ng/L
49
Odds ratio (95 CI)
GUSTO-4 ACS 1-Year Mortality
0
1
2
3
4
5
6
7
Age65 years
Current smoking
Angina Pectoris
- James, Circ 2003
Previus MI
Heart failure
Crea. cl. Diabetes mellitus
ST-depression 0.5 mm
CRP 10 mg/L
Troponin T 0.01 ug/L
NT-proBNP NT-proBNP 237- 669 ng/L
NT-proBNP 669-1869 ng/L
NT-proBNP 1869 ng/L
50
GUSTO-4 ACS Mortality 1 year
22,4
25
18,3
20
15,7
12,8
15

9,3
6,9
7
7,9
10
NT-proBNP, quartiles ng/L
4,1
3,8
4,1
5
1869
3,5
2,7
669- 1869
2,7
1,2
237- 669
0
1,6
0.47
0.12 - 0.47
0.01 - 0.12
Troponin T, quartiles ug/l
- James, Circ 2003