Utilization of Cardiac Serum Marker Utilization of Cardiac Serum Marker Measurements to Identify and Measurements to Identify and

Exclude Acute Myocardial InfarctionExclude Acute Myocardial Infarction

Francis M. Fesmire, MD, FACEP

Assistant Professor, UT College of Medicine

Director, Heart-Stroke Center

Erlanger Medical Center, Chattanooga, Tn

ffesmire@comcast.net

Do You Want A Piece of Me?

Ready, Aim…..

Fire!!!!

OverviewOverview

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

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)

BiasBias

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

Valid Comparison?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 ratio’s are equivalent and clinically meaningful

Likelihood RatiosLikelihood 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 > 10 or < 0.1 should influence clinical decision making

The ideal marker of AMI should both identify and exclude AMI

DefinitionDefinition

Reliably Identifies:– sensitivity > 90% with +LR > 10

Reliably Excludes:– specificity > 90% with -LR < 0.1

ACEP Clinical Policy: Suspected AMI or Unstable Angina; Annals of Emergency Medicine 2000; Ann Emerg Med 2000;35:521-544.

Diagnostic Marker Cooperative StudyDiagnostic 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 AMIConclude that CK-MB subforms and

myoglobin are the most sensitive for early diagnosis of AMI

Zimmerman et al: Circulation; 1999;99:1671-1677

AMI DefinitionAMI Definition

“The diagnostic standard for myocardial infarction was a CK-MB mass > 7 ng/ml and CK-MB index > 2.5% in greater than 2 samples or in one sample if only one sample was available for analysis”– CK-MB mass > 7 ng/ml both defines AMI and

a positive value of CK-MB– No WHO criteria for AMI utilized

ROC Curve Area DataROC Curve Area Data 6 Hours: CK-MB subform (0.95) = cTnT (0.95) >

CK-MB activity (0.94) > myoglobin (0.92) > cTnI (0.89)

14 Hours: CK-MB activity (0.99) > cTnI (0.97) > CK-MB subform (0.94) > cTnT (0.91) > myoglobin (0.84)– Area of CK-MB mass not given???– No statistical analysis of ROC curves– No comparison at equal likelihood ratio’s

6 Hour Data6 Hour Data

Sens Spec MB Activity (9 IU/L) 74.5 97.5 MB Mass (7 ng/ml) 66.0 100 MB Subforms (1.6 ratio) 91.5 89.0 Myoglobin (85 ng/ml) 78.7 89.4 TnT (0.1 ng/ml) 61.7 96.1 TnI (1.5 ng/ml) 57.5 94.3

6 Hour Data6 Hour Data

+LR -LR MB Activity (9 IU/L) 29.8 0.26 MB Mass (7 ng/ml) 0.34 MB Subforms (1.6 ratio) 8.3 0.10 Myoglobin (85 ng/ml) 6.8 0.13 TnT (0.1 ng/ml) 15.8 0.39 TnI (1.5 ng/ml) 10.1 0.45

14 Hour Data14 Hour Data

Sens Spec MB Activity (9 IU/L) 98.1 96.1 MB Mass (7 ng/ml) 90.5 98.9 MB Subforms (1.6 ratio) 90.6 90.0 Myoglobin (85 ng/ml) 62.3 88.3 TnT (0.1 ng/ml) 84.9 96.1 TnI (1.5 ng/ml) 90.6 92.2

14 Hour Data14 Hour Data +LR -LR MB Activity (9 IU/L)* 25.1 0.02 MB Mass (7 ng/ml)* 82.3 0.02 MB Subforms (1.6 ratio) 9.1 0.1 Myoglobin (85 ng/ml) 5.3 0.43 TnT (0.1 ng/ml) 21.8 0.16 TnI (1.5 ng/ml)* 11.6 0.02

*Reliably identifies and reliably excludes

Ideal Marker ?? Ideal Marker ?? The ideal marker should reliably identify

(sensitivity >90%; +LR > 10) and reliably exclude (specificity > 90% and -LR < 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

ACEP ACEP Evidence-Based Evidence-Based StandardsStandards

“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; 35:521-544.

ACEP ACEP GuidelinesGuidelines

“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

ACEP ACEP GuidelinesGuidelines

CK-MB Activity 8-12 Hours

CK-MB Mass 6-10 Hours

CK-MB Subforms 6-10 Hours

TnT 8-12 Hours

TnI 8-12 Hours

ACEP ACEP GuidelinesGuidelines “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.”

FootnoteFootnote

“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; 35:521-544.

WHO Diagnostic Criteria for AMIWHO Diagnostic Criteria for AMI

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

ESC/ACC Diagnostic CriteriaESC/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 2000;36;959-969

ESC/ACC Diagnostic CriteriaESC/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 < 10%”

J Am Col Cardiol 2000;36;959-969

ESC/ACC Cutoff ValuesESC/ACC Cutoff Values99% (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 2002;144:981-986.

ImplicationsImplications

Estimated that number of patients with diagnosis of AMI utilizing new definition will increase by???

Ferguson et al (Heart 2002; 88:343-347)– 80 admitted chest pain patients

29% fulfilled WHO criteria 40% fulfilled ESC/AHA criteria

ImplicationsImplications

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

AMIGooman et al: J Am Coll Cardiol 2001;37:358A

The Future !!!The Future !!!Utilization of Second Generation

cTnI Assays for the Early Identification of Acute Coronary

Syndromes

Stratus CS: 2-Hour cTnIStratus CS: 2-Hour cTnI

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Stratus CS: Delta cTnIStratus CS: Delta cTnI

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What is the best marker of What is the best marker of AMI?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

Proud Card Member Since 1981Proud Card Member Since 1981

Breakfast of Champions !!Breakfast of Champions !!

No Excuses!No Excuses!

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

Myocardial InfarctionMyocardial Infarction

Francis M. Fesmire, MD, FACEPDirector Heart-Stroke Center, Erlanger Medical CenterAssociate Professor, UT College of Medicine

Just Do It!!!Just Do It!!!