Cardiac Biomarkers
W. Frank Peacock, M.D., FACEP
Professor, Emergency Medicine
Cleveland Clinic
Biomarker?
• What is a biomarker?
– An expensive lab test
– Commonly Protein with levels that correspond to
• Diagnosis
• Prognosis
– Most common method of measurement
• ELISA
Lab-test-ology
Sensitivity
TP/(TP+FN)
Specificity
TN/(TN+FP)
Lab-test-ology
•
•
•
•
LOB
LOD
CV
99th %ile
CV vs LOD
Assay w LOD 5 pg/mL
99th %ile
LOD
CV and
th
99 %ile
The box of
undetectableness
Where is the 99th%ile?
10% CV
CV and
30% CV
20% CV
10% CV
th
99 %ile
Historical timing of
cardiac necrosis markers
80
70
60
50
40
30
20
10
0
TnI
CKMB
Myo
0
2
4
6
8
12 18 24 32 48 72
Hours After Onset of MI
Mortality at 42 Days (% of Patients)
TIMI IIIB: Troponin I Levels
Predict Mortality In UA/NSTEMI
7.5
8
6.0
6
3.7
3.4
4
1.7
2
1.0
831
174
0 to <0.4
0.4 to <1.0
148
134
50
67
0
Risk
Ratio
1.0 to <2.0 2.0 to <5.0
5.0 to <9.0
>9.0
6.2
7.8
Cardiac Troponin I (ng/ml)
1.0
1.8
3.5
3.9
Antman EA, et al. N Engl J Med. 1996;335:1342-1349
• Emergency docs
2000
– This crap is useless in almost all patients
– Only helpful if positive
• Rarely positive, <5% of chest pain
– The rest of chest pain requires other testing
• Cardiologists own troponin
– Tactics-TIMI 18
– IF it is detectable, it is an MI, otherwise forget it
– If positive, don’t even bother thinking, just call
the cath lab
C Statistic
Area Under the Receiver Operator
Characteristic (ROC) Curve
C Stat = 1.0
A PERFECT Test
C Stat = 0.69
OK test
C Stat = 75
AUC = C Statistic
C Stat = 50%
REALLY BAD TEST
718 consecutive
ED suspect AMI
MI/USA 238 (33.1%)
Reichlin T. N Engl J Med 2009;361:858-67.
ACEP Marker Recommendations
• Level A recommendations
Can you
trust them?
Don’t use markers to exclude non-AMI ACS
(ie, unstable angina)
• Level B recommendations
Use any of the following to exclude NSTEMI
• 8-12 hours after symptom onset
– A single (-) CK-MB mass, TnI, or TnT
• Serial measures if < 8 hours after symptom onset
– Baseline and 90 mins
» A (-) myoglobin with a (-) CKMB, or (-) Tn
– (-) 2-hour delta
» CK-MB and Tn
Historical timing of
cardiac necrosis markers
80
70
60
50
40
30
20
10
0
hsTnI
TnI
CKMB
Myo
0
2
4
6
8
12 18 24 32 48 72
Hours After Onset of MI
If It Moves, It Is Bad
Marker
Comparator
ing Tn
ing Tn
vs. stable
Troponin
ing CKMB
ing CKMB
vs. stable
CKMB
OR for 30 day
MACE
95% CI
2.25
1.42-3.55
3.04
1.94-4.75
0.67
0.48-0.95
0.96
0.57-1.60
Logistic regression models showing the odds ratios for predicting ACS
MACE: MI, revascularization (PCI or CABG), or positive testing (>70% stenosis at
catheterization, [+] MPI or non-invasive stress testing) within 30 days of index visit.
McMullin N. AJEM 2009.
Cumulative proportion free of events
Event Free vs cTnT Values
Normal
<0.01 g/L
Marginal
<0.01-0.09 g/L
Frank
elevation
>0.01 g/L
P=0.004
Days after admission to the hospital
AJC 93:278, 2004
You can’t have it both ways…
®
STRIVE
Tn, its not just for AMI anymore
Tn Elevation w/o Overt Cardiac Ischemia
• Trauma
• contusion, ablation, pacing, ICD firings,
cardioversion, endomyocardial biopsy,
cardiac surgery, interventional closure of
ASDs
• CHF
• Aortic valve disease and HOCM with significant
•
•
•
•
•
•
•
•
•
LVH
HTN
Hypotension, often with arrhythmias
Postoperative noncardiac surgery patients who
seem to do well
Renal failure
Critically ill patients, esp with diabetes,
respiratory failure, gi bleeding, sepsis
Drug toxicity, eg adriamycin, 5 FU, herceptin,
snake venoms, carbon monoxide poisoning
Hypothyroidism
Abnormalities in coronary vasomotion, including
coronary vasospasm
Apical ballooning syndrome
• Inflammatory diseases
– myocarditis, eg. Parvovirus B19, Kawasaki
•
•
•
•
•
•
•
•
•
disease, sarcoid, smallpox vaccination, or
myocardial extension of BE
Post PCI patients who appear to be
uncomplicated
Pulmonary embolism, severe pulmonary
hypertension
Sepsis
Burns, esp if TBSA > 30%
Infiltrative diseases including amyloidosis,
hemachromatosis, sarcoidosis and scleroderma
Acute neurological disease
– CVA, subarchnoid bleeds
Rhabdomyolysis with cardiac injury
Transplant vasculopathy
Vital Exhaustion

Cardiologists are in a tizzy


All these “false positives”
What
now?
Emergency docs think this is great

There is no such thing as a false positive
when your talking about being
DEAD
Do we really gotta be
doing serial troponin’s
anymore???
Reichlin T. N Engl J Med 2009;361:858-67.
• The decade of 2000-10
2012
– Will be remembered as when the cardiologists
owned troponin
• Used to be an MI marker
– Those days are gone
• Emergency Medicine
– Taking troponin back from the cardiologists!
– IT IS NOT AN AMI MARKER ANYMORE
• Now it’s a 14 day death marker
– I don’t care about 30 days or 180 days from now
– I REALLY don’t care about a year from now
Myocardial Infarction
It’s a changing world
• An MI used to be
– >40 and sweating with chest pain
– Positive markers in 8-12 hours
• Now
– It aint >40
– It aint sweating
– It aint even chest pain
It would be really great if they had
it written on their forehead!!
If you think this is the way they look…
In 2011,
you will miss 423,600
Acute Myocardial Infarction’s
1/3 have no chest pain
Canto JG et al. JAMA. 2000;283:3223-3229
% With Chest Pain During AMI
Stratified by Age
SOB
W&D
N/V
Syncope
Confused
®
STRIVE
This one is
having an
AMI
When your laying naked around the ER, they all look the same……
®
STRIVE
28
Closing Time

You don’t have
to go home,
but you can’t
stay here….
– Semisonic
®
STRIVE
The ER docs
challenge
Admit them all:
and let the insurance
company sort
them out…
Discharge them all
and let God sort
them out…
®
STRIVE
Emergency Medicine Roulette
What % are discharged from the ED??
®
STRIVE
• 14 Asia-Pacific region EDs
• >18yo with >5 mins CP
• Risk stratification (blinded to care team)
– TIMI<1, ECG non-dx,
– Negative 0 & 2hr POC Tn, CKMB, myo
• Endpoint: 30 day MACE
Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3
TIMI Risk Score
Risk factors:
Age 65 years
–
3 risk factors for CAD
–
Prior coronary stenosis
50%
–
–
–
–
ST-segment deviation on
ECG
2 anginal events in last 24
hours
45
40
35
(Days 1-14), %
–
Rate of Composite Endpoint

30
25
20
15
10
5
0
40.9
26.2
19.9
13.2
8.3
4.7
0/1
2
3
4
5
6/7
Use of ASA in last 7 days
Elevated serum cardiac
markers CK-MB or troponin
Number of Risk Factors1
Each risk factor is assigned 1 point, and the total represents a given patient’s TIMI Risk Score1
Event rates (all-cause mortality, MI, or urgent revascularization) increase with each 1-point
increase in score (P<0.001 by chi square test for trend)1
®
STRIVE
33
1. Antman EM et al. JAMA. 2000;284:835-842.
• N=3582
– 30 day MACE in 421 (11·8%)
– Most often NSTEMI
• ADP identified 9·8% (352/3582) as low risk
– 3 (0·9%) had 30 day MACE
Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3
• Potential costs savings in low risk negative
ADP patients
• Hospital LOS
– Median
– Mean
26·0 h (IQR 9·9–37·0)
43·2 h (95% CI 36·2–51·2)
Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3
He is a 67 year old, hypertensive, obese man. He took an aspirin
this morning, he still smokes and has high cholesterol. Many of his
family have CAD. He has been a diabetic for 15 years, and 4 years
ago he had an MI.
George is sitting in his bar
at his restaurant across the street
Age > 65, 3 risk factors, H/O MI, took asa: TIMI Risk score = 4
from
the ofEmergency
Department
19.9% chance
death, MI, or UTVR in the next
14 days
STRIVE
®
He is a 67 year old, hypertensive, obese man. He took an aspirin this
morning, he still smokes and has high cholesterol. Many of his family
have CAD. He has been a diabetic for 15 years, and 4 years ago he
had an MI.
TIMI Risk score = 4
19.9% chance of death, MI, or UTVR in the next 14 days
STRIVE
George is laying in the ED,
diaphoretic, with crushing CP,
nauseated, BP = 100/70
®
Can we discharge you??
Derivation by blinded sampling (N= 703)
• 130 (18.5%) AMI
– None w initially undetectable hs-cTnT
– Sn 100.0%, NPV 100.0%
• 27.7% would have ‘ruled out’ for AMI
– 2 (1.0%) died or had AMI w/in 6 months
» (1 peri-procedural AMI, 1 non-cardiac death)
Validation by standard practice (N= 915)
– 1 patient (0.6%) with initially undetectable hscTnT
developed subsequent elevation (to 17ng/L)
• Sn 99.8% (99.1-100.0)
• NPV 99.4% (96.6-100.0).
Body, et al. JACC, 2011
European Society of Cardiology
• A Tn @ presentation cannot R/O NSTEMI
– Repeated Tn 3 hours after admit or more CP.
– LOE 1B
• Tn is preferred over CKMB
• Myoglobin is not specific or sensitive enough
– Is not recommended.
ESC Guidelines

Due to improved analytical sensitivity,
low troponin levels can be detected in
stable angina and in healthy patients.

The mechanisms of this troponin
release are not yet explained, but ANY
measurable troponin is associated with
an unfavourable prognosis.
®
STRIVE
Low Level Troponins
One Cut-off or Two?
AMI
Sp=85%
16
Myocardial
necrosis
Frequency
14
12
AMI
Sp=99%
10
Wait and see,
do more tests
8
6
4
2
0
1
3
5
7
9
11
13
15
17
pg/ml cTNI
19
21
23
25
27
29 More
The Now and Then of High
Sensitivity Troponins
Last decade
Next decade
• Detectable Tn
• Good bye specificity
– 99th %ile cutpoint
• Great specificity
• Better sensitivity
– No real clinical disposition
impact for the ER
• Serial testing of less
necessary
• 2 cutpoints?
• Second marker
– copeptin, ST-2, MPO,
IMA, etc
• Hello sensitivity
• Exclude ischemia?
• Challenges
– The role of cardiology
consults
– EDUCATION…………
So next time
you want to
get a
troponin….
• Risk stratify (after decide it might be ACS)
• You want to send that patient home?
– Put on your thinking cap!
– AMI? Something else?
• Can always repeat
Results
25 participating hospitals
N=1,360 patients
Overall
Mean DTBT 115.770.1 minutes
Median 100; IQR=73,138
Central lab
Mean DTBT 119.2  70.5 minutes
Median 103; IQR=76,141
Point of Care
Mean DTBT 68.2  40.8 minutes
Median 62.5, IQR=43,83.5
Peacock WF et al. Acad Emerg Med. 2004;11:569–570.
Saves about
1 hour
Delay = Death
N= 13,934,542
• Adverse events increase with the mean LOS in similar patients in
the same ED shift
•
OR for Death if LOS ≥6 v <1 hr cohorts
– Hi Acuity 1.79
Low Acuity 1.71
BMJ 2011; 342:d2983
Overcrowding = Long waits
Long waits = Death
• N= 62,495
• Risk ratio for DEATH
– Per hour of ED stay = 1.1 (p < 0.001)
– Per hour of ED wait = 1.2 (p=0.01)
MJA 2006; 184: 208–212
Delay = Bad Care
• N=42,780
• Long ED stays less often received guideline-recommended
NSTEMI therapies
Ann Emerg Med. 2007; 50; 489-96
Delay = Bad Care
• N=694 patients
Delayed/No antibiotics
– OR 1.05 for each additional WR patient
– OR 1.14 for each additional WR hour
Ann Emerg Med. 2007;50:510-516
Delay = Bad Care
• N=13,758
• Nontreatment of pain associated with
waiting room number
OR = 1.03 for each additional waiting patient
Ann Emerg Med. 2008;51:1-5.]
Delay = Bad Care
• N=162 “boarded” patients (waiting for room)
• Undesirable event
• Missed meds, lab results, arrhythmias, or other adverse
events
• 27.8% had an undesirable event
Ann Emerg Med. 2009;54:381-385.]
14,054,431
patients:
waiting = bad
outcomes or
death
What business
intentionally kills
its customers?
If you had a way of
getting data quickly,
wouldn’t you?
The era of POC needing
to justify itself is over.
We are now in the era
where the central lab must
prove it is not killing our patients.
POC vs Lab Singulex
• 295 MIDAS patients
155 (52.5%) NCCP
67 (22.7%) USA
61 (20.7%) NSTEMI
12 (4.1%) STEMI
Sensitivity Specificity Negative
Point of Care
Positive
Area Underneath
Predictive
Predictive
ROC curve
Value
Value
(C-Statistic)
86
94
95
82
94
90
86
96
68
94
Alere
Central Lab
Singulex
Sn
Sp
NPV
PPV
AUC
POC
86
94
95
82
94
Lab
90
86
96
68
94