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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?
9/11/2017
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
9/11/2017
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
9/11/2017
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.
Homeless dude in room 3
• 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.
9/11/2017
5
Homeless dude in room 3
• 02 sat 90%on 2l nasal canulla.
• ECGnon-diagnostic
• Labs
– BUN =110
– Creat = 11.2
– K+5.9
– hsTnT = 32
Homeless dude in room 3
• 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
Homeless dude in room 3
• 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
9/11/2017
6
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
7
• 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”
9/11/2017
8
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?
9/11/2017
9
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
9/11/2017
10
Homeless dude in room 3
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.
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• 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
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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.
9/11/2017
12
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.
9/11/2017
13
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
9/11/2017
15
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
Cullen L. JACC, 2013. 10.1016/j.jacc.2013.02.078
9/11/2017
16
ADAPT & APACE30 day MACE
Cullen L. JACC, 2013. 10.1016/j.jacc.2013.02.078
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
9/11/2017
17
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.
9/11/2017
18
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
19
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
20
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.
9/11/2017
21
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
9/11/2017
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3-8, 2017
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