Utilization of Cardiac Serum Marker Measurements to Identify and Exclude Acute Myocardial Infarction

1
Utilization of Cardiac Serum Marker Measurements
to Identify and Exclude Acute Myocardial
Infarction

• Francis M. Fesmire, MD, FACEP
• Assistant Professor, UT College of Medicine
• Director, Heart-Stroke Center
• Erlanger Medical Center, Chattanooga, Tn
• ffesmire_at_comcast.net

2
Do You Want A Piece of Me?
3
Ready, Aim..
4
Fire!!!!
5
Overview

• Which is the best marker of AMI?
• CK-MB activity
• CK-MB mass
• CK-MB subform ratio
• Myoglobin
• cTnT
• cTnI
• Newer assays?????

6

• 2000 Clinical Policy of the American College of
  Emergency Physicians reviewed 50 articles
  comparing serum markers
• CK-MB activity 7 cutoff values (5-23 IU/L)
• CK-MB mass 14 (4-20 ng/ml)
• CK-MB subform ratio 2 (1.5 2.3)
• Myoglogin 9 (35-110 ng/ml)
• cTnT 5 (0.06-0.2 ng/ml)
• cTnI 5 (0.1-2.5 ng/ml)

7
Bias

• Multitude of Experimental Bias
• Positive value of assay also defines AMI
• Use the ROC curve optimum value of newer assay to
  compare against gold standard for older assay
• Differing patient populations
• ICU vs general ED
• Early symptom onset versus late symptom onset

8
Valid Comparison?

• Conditions for a valid study
• The diagnosis of AMI needs to be independent of
  positive value of marker under investigation
• Statistical Analysis of ROC curve area
• Sensitivity and specificity comparison should be
  performed at a point on the individual ROC curves
  where likelihood ratios are equivalent and
  clinically meaningful

9
Likelihood Ratios

• Bayes Theorem
• Pretest odds of the disease X likelihood ratio
  Posttest odds of the disease
• Positive LR sensitivity/(1-specificity)
• Negative LR (1-sensitivity)/specificity
• In general, a LR gt 10 or lt 0.1 should influence
  clinical decision making
• The ideal marker of AMI should both identify and
  exclude AMI

10
Definition

• Reliably Identifies
• sensitivity gt 90 with LR gt 10
• Reliably Excludes
• specificity gt 90 with -LR lt 0.1

ACEP Clinical Policy Suspected AMI or Unstable
Angina Annals of Emergency Medicine 2000 Ann
Emerg Med 200035521-544.
11
Diagnostic Marker Cooperative Study

• Prospective double-blind study comparing CK-MB
  activity, CK-MB mass, CK-MB subforms, myoglobin,
  cTnT, and cTnI
• 955 patients, 119 with AMI
• Conclude that CK-MB subforms and myoglobin are
  the most sensitive for early diagnosis of AMI

Zimmerman et al Circulation 1999991671-1677
12
AMI Definition

• The diagnostic standard for myocardial
  infarction was a CK-MB mass gt 7 ng/ml and CK-MB
  index gt 2.5 in greater than 2 samples or in one
  sample if only one sample was available for
  analysis
• CK-MB mass gt 7 ng/ml both defines AMI and a
  positive value of CK-MB
• No WHO criteria for AMI utilized

13
ROC Curve Area Data

• 6 Hours CK-MB subform (0.95) cTnT (0.95) gt
  CK-MB activity (0.94) gt myoglobin (0.92) gt cTnI
  (0.89)
• 14 Hours CK-MB activity (0.99) gt cTnI (0.97) gt
  CK-MB subform (0.94) gt cTnT (0.91) gt myoglobin
  (0.84)
• Area of CK-MB mass not given???
• No statistical analysis of ROC curves
• No comparison at equal likelihood ratios

14
6 Hour Data
15
6 Hour Data
16
14 Hour Data
17
14 Hour Data
Reliably identifies and reliably excludes
18
Ideal Marker ??

• The ideal marker should reliably identify
  (sensitivity gt90 LR gt 10) and reliably exclude
  (specificity gt 90 and -LR lt 0.1)
• No marker fulfills this criteria at 2, 4, 6 hours
• CK-MB activity 10, 14, 18 hours
• CK-MB mass 10, 14, 18, 22 hours
• cTnI 10, 18 hours
• CK-MB subform, myoglobin, cTnT never

19
ACEP Evidence-Based Standards

• No single determination of one serum biochemical
  marker of myocardial necrosis reliably identifies
  or reliably excludes AMI less than 6 hours of
  symptom onset.
• No serum biochemical marker identifies or
  excludes unstable angina at any time after
  symptom onset.

ACEP Clinical Policy Suspected AMI or Unstable
Angina Annals of Emergency Medicine 2000
35521-544.
20
ACEP Guidelines

• In patients presenting with acute chest pain and
  a negative baseline serum marker level, consider
  repeat testing at the following time intervals
  from symptom onset prior to making an
  exclusionary diagnosis of AMI

ACEP Clinical Policy Suspected AMI or Unstable
Angina Annals of Emergency Medicine 2000 In
Press
21
ACEP Guidelines
22
ACEP Guidelines

• The exact timing of the repeat serum marker
  should take into account the sensitivity,
  precision, and institutional norms of the assay
  being utilized, as well as the release kinetics
  of the marker being measured.
• cTnT and cTnI are the preferred serum markers in
  patients presenting greater than 24 hours after
  symptom onset.
• Myoglobin does not reliably identify or exclude
  AMI at any time after symptom onset.

23
Footnote

• If time of symptom onset is unknown, unreliable,
  or more consistent with preinfarctional angina,
  then time of symptom onset should be referenced
  to the time of ED presentation.

ACEP Clinical Policy Suspected AMI or Unstable
Angina Annals of Emergency Medicine 2000
35521-544.
24
WHO Diagnostic Criteria for AMI

• WHO Criteria Two of three characteristics
• Typical symptoms
• Typical rise and fall in cardiac markers
• New Q waves on ECG

25
ESC/ACC Diagnostic Criteria

• Typical rise and fall of cardiac markers
  accompanied by one of the following
• Ischemic symptoms
• New Q waves
• Ischemic ECG changes
• Coronary intervention

J Am Col Cardiol 200036959-969
26
ESC/ACC Diagnostic Criteria

• An increased value for cardiac troponin should
  be defined as a measurement exceeding the 99th
  percentile of a reference control group.
  Acceptable imprecision at the 99th percentile for
  each assay should be defined as lt 10

J Am Col Cardiol 200036959-969
27
ESC/ACC Cutoff Values
99 (ng/ml) 10 CV (ng/ml)
Abbott Axsym 0.5 0.8
Bayer Immuno 0.1 0.35
Beckman-Coulter 0.04 0.06
Biosite 0.19 0.5
Dade RXL 0.07 0.14
Dade Stratus CS 0.07 0.06
Ortho Vitros 0.08 0.12
Roche Elecys 0.01 0.035
Am Heart J 2002144981-986.
28
Implications

• Estimated that number of patients with diagnosis
  of AMI utilizing new definition will increase
  by???
• Ferguson et al (Heart 2002 88343-347)
• 80 admitted chest pain patients
• 29 fulfilled WHO criteria
• 40 fulfilled ESC/AHA criteria

29
Implications

• Global Registry of Acute Coronary Events (GRACE
  Registry)
• 3420 patients
• Redefining AMI based on new troponin cutoff
  recommendations
• 25 increase in number of patients classified as
  AMI

Gooman et al J Am Coll Cardiol 200137358A
30
The Future !!!

• Utilization of Second Generation cTnI Assays for
  the Early Identification of Acute Coronary
  Syndromes

31
Stratus CS 2-Hour cTnI
32
Stratus CS Delta cTnI
33
What is the best marker of AMI?

• Troponins by default become best marker of AMI
  (incorporation bias)
• Multiple causes of troponin elevations confusing
  physicians and researchers
• New definitions on AMI need to focus on measuring
  changes in troponin values as opposed to absolute
  values

34
Proud Card Member Since 1981
35
Breakfast of Champions !!
36
No Excuses!
37
Utilization of Cardiac Serum Marker Measurements
to Identify and Exclude Acute Myocardial
Infarction
Just Do It!!!
Francis M. Fesmire, MD, FACEP Director
Heart-Stroke Center, Erlanger Medical
Center Associate Professor, UT College of Medicine