Cardiac Biomarkers

W. Frank Peacock, M.D., FACEPProfessor, 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 LODAssay w LOD 5 pg/mL

LOD

99th %ile

CV and 99th%ile

10% CV

The box of undetectableness

Where is the 99th%ile?

CV and 99th%ile

10% CV20% CV

30% CV

01020

30405060

7080

0 2 4 6 8 12 18 24 32 48 72

Hours After Onset of MI

CKMB

Myo

TnI

Historical timing of cardiac necrosis markers

TIMI IIIB: Troponin I Levels Predict Mortality In UA/NSTEMI

1.0

1.7

3.4

3.7

6.0

7.5

0

2

4

6

8

0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 >9.0

831 174 148 134 6750

Risk Cardiac Troponin I (ng/ml)Ratio 1.0 1.8 3.5 3.9 6.2 7.8

Mo

rtal

ity

at 4

2 D

ays

(% o

f P

atie

nts

)

Antman EA, et al. N Engl J Med. 1996;335:1342-1349

2000• Emergency docs– 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 StatisticC Statistic

AUC = C StatisticC Stat = 50%REALLY BAD TEST

C Stat = 1.0A PERFECT Test

C Stat = 75

C Stat = 0.69OK test

Area Under the Receiver Operator Characteristic (ROC) Curve

Reichlin T. N Engl J Med 2009;361:858-67.

718 consecutiveED suspect AMI

MI/USA 238 (33.1%)

ACEP Marker Recommendations

• Level A recommendations 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

Can you trust them?

01020

30405060

7080

0 2 4 6 8 12 18 24 32 48 72

Hours After Onset of MI

CKMB

Myo

TnI

Historical timing of cardiac necrosis markers

hsTnI

If It Moves, It Is Bad

Marker Comparator OR for 30 day MACE

95% CI

ing Tn

vs. stable Troponin

2.25 1.42-3.55

ing Tn 3.04 1.94-4.75

ing CKMB

vs. stable CKMB

0.67 0.48-0.95

ing CKMB 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.

Event Free vs cTnT ValuesEvent Free vs cTnT Values

Days after admission to the hospital

AJC 93:278, 2004

Normal<0.01 g/L

Marginal<0.01-0.09 g/L

Frank elevation>0.01 g/LP=0.004

STRIVE®

You can’t have it both ways…

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

What now?Cardiologists are in a tizzyCardiologists are in a tizzy

All these All these ““false positivesfalse positives””

Emergency docs think this is greatEmergency docs think this is great

There is no such thing as a false positive There is no such thing as a false positive when your talking about being when your talking about being

DEADDEAD

Reichlin T. N Engl J Med 2009;361:858-67.

Do we really gotta be doing serial troponin’sanymore???

2012• The decade of 2000-10 – 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 InfarctionIt’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!!

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

If you think this is the way they look…

STRIVE®

% With Chest Pain During AMIStratified by Age

SOBW&DN/VSyncopeConfused

STRIVE®

28

When your laying naked around the ER, they all look the same……

This one is having an AMI

STRIVE®

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??

• 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

STRIVE®

33

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

– Use of ASA in last 7 days

– Elevated serum cardiac markers CK-MB or troponin

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

4.78.3

13.2

19.9

26.2

40.9

0

5

10

15

20

25

30

35

40

45

0/1 2 3 4 5 6/7

Number of Risk Factors1R

ate

of

Co

mp

os

ite

En

dp

oin

t

(Da

ys

1-1

4),

%

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 26·0 h (IQR 9·9–37·0) – Mean 43·2 h (95% CI 36·2–51·2)

Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3

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.

Age > 65, 3 risk factors, H/O MI, took asa: TIMI Risk score = 419.9% chance of death, MI, or UTVR in the next 14 days

George is sitting in his barat his restaurant across the streetfrom the Emergency Department

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 = 419.9% chance of death, MI, or UTVR in the next 14 days

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.

STRIVE®

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.

Low Level TroponinsOne Cut-off or Two?

0

2

4

6

8

10

12

14

16

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 More

pg/ml cTNI

Fre

qu

ency

Myocardial necrosis AMI

Sp=99%Wait and see, do more tests

AMISp=85%

The Now and Then of High Sensitivity Troponins

Last decade

• Detectable Tn– 99th %ile cutpoint

• Great specificity• Better sensitivity

– No real clinical disposition impact for the ER

• Serial testing of less necessary

Next decade

• Good bye specificity• 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 115.770.1 minutesMedian 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 minutesMedian 62.5, IQR=43,83.5

Peacock WF et al. Acad Emerg Med. 2004;11:569–570.

Saves about1 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 therapiesAnn 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?

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.

If you had a way of getting data quickly, wouldn’t you?

POC vs Lab Singulex

• 295 MIDAS patients155 (52.5%) NCCP

67 (22.7%) USA

61 (20.7%) NSTEMI

12 (4.1%) STEMI

Sensitivit

y

Specificit

y

Negative

Predictive

Value

Positive

Predictive

Value

Area Underneath

ROC curve

(C-Statistic)

Point of Care

Alere

86 94 95 82 94

Central Lab

Singulex

90 86 96 68 94

Sn Sp NPV PPV AUC

POC 86 94 95 82 94

Lab 90 86 96 68 94