hit the road jack -...

9/11/2017

1

Hit the road Jack!

A review ofADPs(Accelerated Diagnostic Protocols)

30 minutes

W. FRANK PEACOCK, MD, FACEP, FACC

2017 COI Disclosures:W. Frank Peacock, MD, FACEP,FACC

• Research Grants:Abbott, Janssen, Roche, ZS Pharma

• Consultant:Bayer, Beckman, Boehrhinger-Ingelheim, Instrument Labs Janssen, Relypsa, Roche, ZS Pharma

• Expert Testimony:Johnson and Johnson

• Ownership Interests:Comprehensive Research Associates LLC Emergencies in Medicine LLC, Ischemia DX, LLC.

Survey

▪ Know your troponin platform?

▪ Know your troponin cutpoint?

▪ Not the number, but how defined?

▪ Have 2 troponin cutpoints?

▪ How often do you perform a troponin?

▪ 1, 2, 3, 4 times

▪ How many hours apart?

▪ 1, 2, 3, 4, 6hours

▪ Any other markers?

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2

Chest Pain Protocol VS. ADP

A CHEST PAIN PROTOCOL

A series of activities to identify a patient as:

1) Having an event

2) Being at risk for having an event

AN ACCELERATED DIAGNOSTIC PROTOCOL

A series of activities to identify the patient as:

1) NOT having an event

2) Being at low risk for having an event

47 year old dude, 45 minutes of left chest pressure while golfing and drinking beer, now resolved………………. What’s next?

ECGACC/AHA guidelines; ECG within 10 mins of arrival

What is an event?

▪ Myocardial Infarction

▪ Fatal Arrhythmia

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3

How often is the EKG diagnostic?

2%

N=10,869

Pope JH, et al. Missed Diagnosis of Acute Cardiac Ischemia in the ED, NEJM 2000;342:1163-70

10.4 million annual ER CP

STEMI = 208,000

3500 ER’s = 59 STEMI/ER/yr

No ECG ∆ = 10,192,000/yr

= 2,912/ER/yr

= to find 59

What’s next?

Tn I/TCKMB

Myoglobin

How often is the Tn diagnostic?

8%

N=10,869

Pope JH, et al. Missed Diagnosis of Acute Cardiac Ischemia in the ED NEJM 2000;342:1163-70

10.4 million annual ER CP

Total NSTEMI = 822,000

3500 USA ER’s = 238/ER/yr

9,568,000 –Tn/yr

2733 -Tn/ER

to find 238

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4

Hs Tn (CLINICAL) Definition

Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin Chem 2009;55:1303–6.

Do you have a high sensitive troponin?

Homeless dude in room 3

• 47 year old homeless alcoholic gentlemen

• Presents with epigastric abdominal pain, dyspnea, and pedal edema x 3 days.

• He has been a diabetic for 18 years, generally poorly controlled, with increasing renal dysfunction that required the start of hemodialysis 2 years ago, for which he has been largely non-compliant.


• Temp 37.2,HR 110, RR 24, BP 184/97

• Physical exam

– JVD to the angle of the mandible

– Lungs with basilar rales

– Heart has regular rate without gallop

– Abdomen is non-tender

– Extremities have 2+ pitting edema.

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• 02 sat 90%on 2l nasal canulla.

• ECGnon-diagnostic

• Labs

– BUN =110

– Creat = 11.2

– K+5.9

– hsTnT = 32


• He is seen by the ER Dr.

• Dx= renal failure & volume overload, requires emergency dialysis.

• Repeated hsTnT = 31

• The ER Dr. calls the nephrologist who refuses the case without a cardiology consult


• Cardiologist is called

– Says he doesn’t needto see this patient

– It is a “troponin leak”

• another FP hsTN

– Says the assay is“too sensitive”.

• Nephrologist agrees to accept transfer to dialysis suite.

• Care is delayed by 3 hours

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Hs Tn (STATISTICAL) DefinitionYou can’t have it both ways

Sensitivity

TP/(TP+FN)

Specificity

TN/(TN+FP)

Hs Tn (STATISTICAL) DefinitionYou can’t have it both ways

TnI cutpoint0.1 ng/L

TnI cutpoint0.04 ng/L

Sensitivity Specificity

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9/11/2017

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• Prospective observational cohort study

• hsTn pre-eat, then 2 and 4hours

• 2 weeks apart:

– Mild butter chicken

– Seriously hot lamb vindaloo

• No participant had any Tn > URL at any point Tankel AS. EM Australasia (2016) 28, 654–657

• Pre & post Vindaloo phaserelative Tn change

– 8/22 (36%) >20%

– 5/22 (23%) >50% at 4 h

• No difference vs Butter chickenphase (p>0.05)

• Large biological variability alone

• Relative change of pre-eat Tn

– 15/22 (68%) >20%

– 11/22 (50%) >50% between the 2 sessions

Tankel AS. EM Australasia (2016) 28, 654–657

“Its just a troponin leak”

• From the Interventional Cardiologists“We can’t have little elevations”

– We don’t know what to do

– We might get consulted

– I don’t want to get up at 4am

– Patients who don’t needit might get cathed

“Its TOO sensitive”

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Mortality According to Time in Hospital andTroponin Status at Presentation

Troponin-positive

Troponin-negativeCum

ula

tive

Mort

ality

(%)

25

20

15

10

5

00 1 2 3 4 5 6 7 8 9 10 11 12 13 1415

P<0.001*

Days in Hospital

*Dashed lines show 95% CI

Peacock WF et al. N Engl J Med. 2008;358:2117-26.

N=67,928

“Its just a little brick leak”Just go home and don’t worry about it

Troponinin the Gray Zone?

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Is there a grey zone?Dr’s want a cutpoint, but is it right?

• 28 studies of hsTn and 1st ever CV outcomes

• N=154,052, followed x 1 yr

• Tn detectable in 80.0%

– hs-cTnI: 82.6%

– hs-cTnT: 69.7%

Comparing lower 1/3 to upper 1/3

Outcome HR (95% CI) Events

CVD 1.43 (1.31 to 1.56) 11,763

Fatal CVD 1.67 (1.50 to 1.86) 7,775

CHD 1.59 (1.38 to 1.83) 7,061

CVA 1.35 (1.23 to 1.48) 2,526Willeit P. JACC. 70(5) 2017:558-68

Tn 99th %ile as the decision level for AMI Dx (What some stupid places have done)

• NHLBI International Study

• 276 hospital labs, 31 countries

• 21 Tn assays,from 9 manufacturers

• Local MI Cutpoint vs. Manufacturer 99th %ile URL

Bagai A. Am Heart J 2017;190:135-9

7%

32%35%

12%15%

• Rise and/or fall of cTnwith at least one value>99th%ile and one of:

– Symptoms of ischemia.

– Not known tobe

• old ST-T wave changes

• LBBB

Type IIIYou’re dead

Type IV, VCath and CABG

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N=438

Scaled TnT

(divided by

URL)

Vasudevan A. Am J Nephrol 2017;45:304–309. DOI: 10.1159/000458451

This is

Skinny

Jackson

This is

An MI

E l e v a t i o n s o f C a r d i a c T r o p o n i n V a l u e s b e c a u s e o f M y o c a r d i a l I n j u r y

• Plaque rupture.

• Intraluminal coronary artery th rombus formation.

• Tachy-lbrady- arrhythmias.

• Aortic diss ection or severe aortic valve disease.

• Hyp ertrophic cardiomyopathy.

or septic shock.• Card iogen ic hypovolaemic

• Severe respiratory failure.

• Severe anaemia.

• Hypertension with or without LVH.

• Coronary spasm.

• Coro nary embol ism or v ascu lit is.

• Coro nary endothelial dysfunction withou t

significant CAD.

lnJ }nQJ e1 J; I\9:mv,q_c_ _- . Tii f-,_ f--. -

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"'

: 7 1 ;

ry-·--_<. - . , _

• Cardiac contusion, surgery, ablation, pacing, or

defibrillator shocks.

• Rhabdomyolysis with cardiac involvement.

• Myocarditis.

• Cardiotoxic agents, e.g. anthracyc lines, herceptin.

• Heart failure.

• Stress (Takotsubo) cardiomyopathy.

Severe pu lmonary embol ism or pu lmonary

hypertension.

Sepsis and crit ically ill patients.

• Renal failure.

• Severe acute neurological diseases e.g. stroke

subarachnoid haemorrhage.

Infiltrative diseases e.g. amyloidos is s arcoido sis.

• Strenuous exercise.

H e a r t Jou maJ ( 2012 ) 33 : 2 5 5 1 - 2 5 6 7

.1093 /eu rh ea r t j /eh s 1 8 4

Educational Deficit

House of Medicine

• Troponin is now like hemoglobin

– You don’t consult a hematologistfor every low hemoglobin

• Figure out why it is elevated, just like you figure out why the hemoglobin is low.

Cardiologists

• Troponin is not a cath test, don’t actlike it is.

• Quit calling elevations FP

– There is no such thing as FP for death

• No more “troponin leak”

– Structural proteins don’t leak.

• No more “troponosis”

– This does a disservice to our patients

9/11/2017

11

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

718 consecutive

ED suspect AMI

MI/USA 238 (33.1%)

Why an ADP?Accelerated Diagnostic Protocol

• Reason for an ADP

• ER docs vs risk scores

–Docs are risk adverse

–Docs always admit more than scores

Why do we admit sooo many?

LAWYER

ER Dr.

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What is an acceptable miss rate?• Survey, 84% response rate

• N= 1029 emergency physicians

Than M. Int J Cardiol (2013 )166(3):752-4

83.2%95.9% 79.2%

Hospitalization: NO CHANGE IN LOW RISK PE OUTCOMES,

MARKEDLY increases Hospital Acquired Condtions

Premier Database

▪ Definitions

▪ Short LOS < 2 days

▪ Adverse PE events(aPE) Recurrent DVT,major bleed, or death

▪ Net clinical benefit (NCB) 1 - APE + hospital a acquired conditions (HAC)

▪ 6,746 PE

▪ 1,918 Low risk by sPESI

▪ 688 (35.9%) LRPE had a short LOS

▪ After PSM: 784 LRPE patients

14

12

10

8

6

4

2

0

HACH

1.5

13.3No Difference in

aPE btwn. Short11.7 12.5 vs Long LOS

(p>0.05)

9.1

5.9 5.1 7.6 6.5

2.1

Long LOS

APIpt cost

ShortLOS

x1k Opt cost

x1k NCB x 10

887%

increase

in HAC

Early Risk Stratification of NSTE ACS

I IIa IIb III

CS

12-lead ECG (within 10 minutes)

Troponin or CK-MB assay

• Immediate

• Repeated within 8-12 hrs of sx, if negative

Repeat ECG if negative and clinical suspicion is high for A

TIMI or GRACE Risk Scoring

BNP, CRP for risk assessment

Search for non-coronary causes of

symptoms

Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-74.

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ADP is for discharging!

Maybe that is a good idea?

ADP1) Non-Dx ECG

2) (-) Tn x2

3) Low Risk Score

Risk Scores

▪TIMI

▪HEART

▪EDACS

▪CRUSADE

▪GRACE

Risk Factors in the ED? DO NOT work alone

I*trACS analysis of 10,806 ED visits

Evaluated conventional risk factor

burden as a predictor of 30 d ACS dx

Age No Risk Factors

Neg LR

≥ 4 Risk Factors

Pos LR

<40 0.17 7.39

40-65 0.53 2.13

>65 0.96 1.09 AnnHan G, et al.

EM, 2006

TIMI Risk Score: 2 week MACE

4.78.3

13.2

19.9

26.2

40.945

40

35

30

25

20

15

10

5

0

0/1 2 3 4 5 6/7

▪ Risk factors:▪ Age 65 years

▪ 3 risk factors for CAD

▪ Prior coronary stenosis50%

▪ 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

Number of Risk Factors1

Each risk factor is = 1 point, and total represents TIMI Risk Score

Event rates (all-cause mortality, MI, or UTVR) increase with each 1-point increase in score

Rate

of

Co

mp

osit

e

En

dp

oin

t

(Day

s1-1

4),

%

Antman EM et al. JAMA. 2000;284:835-842.

9/11/2017

14

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

▪ 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

▪ 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

ASPECT

How good are the parts?Than M. Lancet, 2011. DOI:10.1016/S0140-6736(11)60310-3

Sensitivity NPV

ECG 35.2 89.3

POC markers 82.9 96.1

TIMI 96.7 97.5

POC + ECG 88.8 96.7

TIMI + ECG 98.1 98.3

ADP 99.3 99.1

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Impact of a troponin with higher low level sensitivity

ADAPT (N=1975)

TIMI Low risk 30 d MACE

0 25.3% (392) 0.25% (1)

Than M. JACC 2012;59:2091–8)

ASPECT (N=3582)

TIMI Low risk 30 d MACE

0 9.8% (352) 0.9% (3)

ADAPT & APACE

▪ ED suspected ACS

▪ N= 2544; ECG, TIMI, 0- and 2-h hsTnI

▪ Primary endpoint: 30 d MACE

ADAPT (Aus) APACE (Basel)

Median (IQR) time to symptom

onset (hrs)

4.6 (1.7, 14.9) 4 (2,11)

Overall MACE 247 (15.1%) 156 (17.2%)

MACE: death, cardiac arrest, AMI, an emergency revascularization,

cardiogenic shock, ventricular arrhythmia or AV block needing intervention

Cullen L. JACC, 2013. 10.1016/j.jacc.2013.02.078

ADAPT & APACE

ADAPT (N=1635) APACE (N= 909)

TIMI Low risk 30 d MACE Low risk 30 d MACE

0 19.6% (320) 0% (0) 25.3% (230) 0% (0)

≤1 41.5% (678) 0.8% (2) 38.6% (351) 0.8% (1)

Low Risk:

Non-ischemic ECG, hs-TnI ≤26.2ng/L,

and TIMI=0 or TIMI ≤1


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ADAPT & APACE30 day MACE


ADAPT (N=1635) APACE (N= 909)

TIMI Sn NPV Sn NPV

0 100%

(98.5-100)

100%

(98.8-100)

≤1 99.2%

(97.1-99.8)

99.7%

(98.9-99.9)

99.4%

(96.5-100)

99.7% (98.4-

100)

Prospective RCT:

2-hour ADP vs Standard of care (SOC)

▪ ADP: TIMI = 0, Tn at 0 and 2 hrs SOC: Tn at 0 and 6-12 hrs

▪ D/C by 6 hours with no MACE ADP = 19.3%(52/270) (30/SOC = 11% 272)

(OR, 1.92; 95% CI, 1.18-3.13; P = .008).

▪ SOC needed 20 hours to discharge the same proportion of patients as in ADP by 6 hours.

Than M. JAMA Intern Med. 2014 Jan;174(1):51-8.

HEART Score for 6 week MACE

Hx: Hi =2, Mod =1, Slight =0

ECG: Sig ST dep =2, NS repol =1, Nl =0

Age: ≥65 =2, 45-65 =1, ≤ 45 =0

Risks: ≥3 =2, 1-2 =1, 0=0

Tn: ≥3x ULN =2

1-3 ULN =1

≤ ULN =0Low risk = 0-3;<2% MACE risk

RISKS

Hyperchole, HTN, DM

Tobbacco

(+) FH,

Obesity

MACE = AMI, PCI, CABG, (+) cath,death

https://www-ncbi-nlm-nih-gov.ezproxyhost.library.tmc.edu/pubmed/24100783

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HEART Pathway Randomized Trial

▪ 282 ED suspected ACS patients, randomized to HEART or standard tx

▪ HEART N=141, with score < 4, negative Tn at 0 and 3 hours

▪ 75 low risk, 56 discharged

▪ Standard care N=141, per ACC/AHA guidelines

▪ X low risk, 26 discharged.

▪ Results: No MACE in either arm

▪ HEART lower objective cardiac testing; 68.8 vs 56.7% (P=0.048)

▪

▪

lower LOS; 9.9 vs 21.9 hours (P=0.013)

higher early discharges by 21.3% (39.7% versus 18.4%; P<0.001).

Mahler S. Circ Cardiovasc Qual Outcomes. 2015 March ; 8(2): 195–203

EDACS-ADPEmergency Department Assessment Chest Pain Score -Accelerated Diagnostic Procedure

Characteristic Parameter Points

History 18-50 yo with CAD,

or >2 risk factors

+4

Age 18-45 +2

46-50 +4

51-55 +6

56-60 +8

61-65 +10

66-70 +12

71-75 +14

76-80 +16

81-85 +18

>85 +20

Characteristic Parameter Points

Sex Male +6

Signs and

Symptoms

Diaphoresis +3

Arm or

shoulder

radiation

+5

Pain

occurred or

worsened

with

inspiration

-4

Pain is

reproduced

with

palpation

-6

Low Risk Criteria

▪EDACS Score <16

▪No new ECG ischemia

▪Negative 0 and 2h Tn

GRACERisk Assessment for ACS Score (0-258)

Age (years) Systolic BP (mm Hg) Killip Class

<40 0 <80 63 Class I 0

40-49 18 80-99 58 Class II 21

50-59 36 110-119 47 Class III 43

60-69 55 120-139 37 Class IV 64

70-79 73 140-159 26

80 91 160-199 11

>200 0

Heart Rate (bpm) Creatinine (mg/dL)Cardiac arrest at

admission

43

<70 0 0-0.39 2 Elevated cardiac 1570-89 7 0.4-0.79 5 markers90-109 13 0.8-1.19 8 ST-segment 30110-149 23 1.2-1.59 11 deviation150-199 36 1.6-1.99 14

>200 46 2.0-3.99 23

>4.0 31 DeAraújo Gonçalves P et al. Eur Heart J. 2005;26: 865-872.

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PEARL

Comparing Scores

▪ PEARL data set: 7 Eds N=458

▪ Patient with suspected ACS

▪ Dr documented risk of MI

before Tn results as Low, Moderate, or High

TIMI

GRACE

HEART-2

EDACS

HEART

-1

Singer A. Am JEM, 2017, Jan 5.

pii: S0735-6757(17)30003-7.

doi: 10.1016/j.ajem.2017.01.003.

[Epub ahead of print]

Scores: standard cutpoint

Low risk

definition

N % with AMI Sensitivity

Clinical Low 136 5.9 (3.0-11.2) 88.7 (78.5-94.7)

HEART 0-3 146 4.1 (1.9-8.7) 91.5 (81.9-96.5)

TIMI 0 26 0 (0-12.9) 100 (93.6-100)

GRACE <51 14 7.1 (1.3-31.5) 98.6 (91.4-99.9)

EDACS <16 195 1.0 (0.2-4.1) 97.1 (89.1-99.5)

Singer A. Am J EM. 2017 Jan 5. pii: S0735-6757(17)30003-7. doi: 10.1016/j.ajem.2017.01.003.

Performance: Sensitivity set at 99%

Sensitivity set at 99%

Cutoff % Low Risk

Clinical -- --

HEART-1 0 1

HEART-2 0-2 18.9

TIMI 0 7

GRACE 49 3.2

EDACSSinger A. Am J EM. 201

127 Jan 5. pii: S0735-6757(17)3000

34.33-7. doi: 10.1016/j.ajem.2017.01.0

03.

9/11/2017

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How many will the ADP disposition (not D/C?)

10.4 million annual ER CP 3500 USA ER’s

ED D/C rate # of patients

7.0 (TIMI) 728,000

18.9 (HEART) 1,965,600

34.3 (EDACS) 3,567,200

77% (TRAPID) 8,008,000

What’s next?

In the US and

EDACS ≤ 12or HEART ≤ 2

= D/C

T rapid-AMI (hsTnT)

▪ APACE Protocol

▪ R/O <12 ng/L and 1-hr delta <3 ng/L.

▪ R/I >52 ng/L and 1-hr delta >5 ng/L

▪ Outside these ranges, OU admit

▪ N=1282

▪ R/O 813 (63.4%)

▪ NPV= 99.1%, 30d Mort 0.1%

▪ R/I 184 (PPV= 77.2%)

▪ Gray 285, to OU (of these 22.5% R/I)

▪ Overall, >75% had early dispositionMueller C. NEJM 2014

ONLY

22.8%Still stuck

in the ER

9/11/2017

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Pati

en

ts D

isch

arg

ed

Earl

y(%

)

1) Than M, Cullen L, Reid C, et al. Lancet. 2011;377:1077-84. 2) Than M, Cullen L, Aldous S, et al. J Am Coll Cardiol. 2012;59(23):2091-8.

3) Cullen L, Mueller C, Parsonage WA, et al. J am Coll Cardiol. 2013;62(14):1242-9. 4) Mueller C, Giannitsis E, Christ M, et al. Ann Emerg Med. 2016;68(1):76-87.

TRAPID-AMI4

cTnT ≤ 12 ng/L;

Δ1 hour ≤ 3 ng/L

APACE3

cTnI ≤ 26.2 ng/L

ASPECT1

cTnI ≤ 50 ng/L

ADAPT2

cTnI ≤ 30 ng/L

70

60

50

40

30

Increased Troponin Sensitivity = More ED Discharges

38.6

20.0

63.4

20

9.8

10

0

2015 ESC Guidelines

▪ The NPV for MI in patients assigned ‘rule-out’ exceeded 98% in several large validation cohorts

Eur Heart J. 2016

Jan 14;37(3):267-315.

Will the ESC guidelines work in the US?

▪ hscTnT and I at 0 and 3 h post-presentation

▪ Purpose: validate the ESC Working Group on Acute Cardiac Care rule-in algorithm

1061 hsTnI

985 hsTnT

Sn of 99th %ile

to R/O AMI HsTnI 93.2%

HsTnT 94.8%Pickering JW, et al. Heart 2016;0:1–9.

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How many patients were sent home

from the ER based on TRAPID?

“The NPV for MI in patients assigned ‘rule-out’ exceeded 98% in several large validation cohorts”

A large US ED sees 150,000 pts/y

411 pts/day

8% chest pain = 11,680 CP pts/yr

32/day

NPV =98% = 234 missed MI/yr

I will miss an MI every 1.6 days

In the USA

Peacock AlgorithmPretty much unvalidated

TIMI > 1, ≤ 4

TIMI > 4

SuspectedACS?

ECG Positive?

0 & 3 hr Tn Any (+)*

EDACS ≤ 12, or HEART ≤ 2

Cath lab

Admit BNP >400

Consider d/c and early f/u

CTA/MPI unless recently tested

Consider admit, cards consult

* Chronic stable elevations (e.g., HF, CRF, etc), high risk but not AMI

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3-8, 2017

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