point of care troponin tests - the international federation · pdf file ·...

Point of care troponin tests

Professor Paul Collinson

MA MB BChir FRCPath MD FACB FESC

Consultant Chemical Pathologist and Professor of

Cardiovascular Biomarkers,

Departments of Chemical Pathology and Cardiology, St

George’s Hospital and Medical School, London

POCT testing

• Mentioned by Hippocrates and Galen

• Described in the 7th century by the Byzantine Theophilus

Protospatharios

POCT

• Codified in the UK

– Anon. Seynge of Urynes. London: R. Kele, 1552

• Techniques included tasting the urine

– no wonder the English make such awful wine

• Soon to be re-introduced as a cost saving alternative.

Rapid diagnostic protocols in the ED

• Increasing demand on ED facilities

• Chest pain is the largest single medical presenting

complaint

Overview

• The clinical problem

• The troponin paradighm

• The evolution of POCT

• The clinical and laboratory shift

• The state of the art

• The future state

The clinical problem

The healthcare burden of chest pain – the patient paradox

• Chest pain and related complaints accounted for 6% of

adult emergency department attendances

• Two thirds were admitted, creating a substantial health

care burden

• A minority had diagnostic ECG changes. Approximately

one third of attendances and half of the admissions had a

clinical diagnosis of ACS without clear ECG changes.

• The majority have a final diagnosis that excludes an

acute coronary syndrome (ACS)Goodacre S et al. Heart 2005;91:229-30.

Collinson P et al. Heart 2014;100:140-145.

Rule out AMI

- role of troponin testing

• Studies have shown that rapid rule out of AMI within 2

hours in the ED is feasible.

– Than M et al Lancet 2011;377:1077-1084

– Than M et al J Am Coll Cardiol 2012;59:2091-2098.

– Cullen L et al Int J Cardiol 2013;168:2602-2608.

– Than M et al JAMA Intern Med 2014;174:51-58.

The troponin paradighm

Advantages of cTn over other markers

• Cardiospecific

• Sensitive - diagnosis using CK or CK-MB is flawed.

Elevation of cTn in patients “without AMI”

– occurs in 33% of patients

– indicates myocardial damage

– predicts major adverse cardiac events (MACE)• death

• MI

• readmission with UAP

• need for urgent revascularisation

Evidence base

• Multiple publications showed that troponin could be used

as the single definitive test for acute myocardial

infarction for diagnosis and risk stratification

• Specific treatments could be related to troponin elevation

– Low molecular weight heparin

– Revascularisation

– GlycoproteinIIb/IIIa antagonists

• Sufficient publications to allow a meta-analysis and

subsequent HTA

The evolution of POCT

• Two tracks

– Hand held qualitative strip tests

– Instruments suitable for stat near to patient testing

Hand held qualitative strip tests

• Immunochromatography (GLORIA)– Spectral Cardiac Status

– CardiacT

Application

Zone

Reaction

Zone

Detection

Zone

TnT

wholeblood

gold gold

reagent fleeceGlass fibre fleece

plasma plasma

signalcontrol

membrane

synth.

peptide

Strept

avidin

Application Reaction Detection

MAB 2 MAB 1

biotin biotin

Hand held qualitative strip tests

• Quantitative immunochromatography– Cardiac reader

– Triage

Instruments suitable for stat near to

patient testing• Dry chemistry analysers

– Seralyser (Serum)

– Kodak Ektachem DT-60 (Serum)

– Reflotron

Instruments suitable for stat near to

patient testing• Whole blood systems (Stat lab/POCT)

• Stratus CS

• First Medical AlphaDx

• AIO

• ISTAT

• RAMP

• Pathfast

• AQT90

The clinical and laboratory shift

- then• Diagnostic protocols were based on single measurements

at 10-12 hours from admission

• Laboratory assays were relatively insensitive

• POCT diagnostic performance was excellent

Diagnostic performance

• Troponin T

– CardiacT

• Diagnostic equivalence to CLT

– Hirschl MM et al Resuscitation 1996;32:193-98.

– (REACTT) Investigators Study Group. Acad Emerg Med

1997;4:1018-24.

• Prognostic risk stratification

– Antman EM et al. J Am Coll Cardiol 1998;31:326-30.

– Ohman EM et al. Am J Cardiol 1999;84:1281-86.

– Hamm CW et al, NEJM 1997;337:1648-53.

Survival without cardiac events (death/MI) during 30 days of follow-

up according to cTnT and cTnI status

Hamm et al. NEJM 1997;337:1648-53

Diagnostic performance

• Troponin I

– Cardiac STATus

• Prognostic risk stratification

Hamm CW et al.N.Engl.J.Med. 1997;337:1648-53.

• CK-MB/Myoglobin

– Cardiac STATus


Schwartz JG et al. Am.J.Emerg.Med. 1997;15:303-7.

Schouten Y et al. Clin.Chem.Lab Med. 1998;36:469-73.

Diagnosis

• Multiple markers

– Cardiac STATUS/CardiacT


Luscher MS et al. Cardiology 1998;89:222-8.

Sylven C et al.Am.Heart J. 1998;135:677-83.

– Biosite Triage


Ng SM et al. Am. J. Cardiol. 2001; 611-7

McCord J et al. Circulation 2001; 104; 1483-8

– Stratus CS

• Risk stratification

Newby LK et al. Circulation 2001;103:1832-7.

The clinical and laboratory shift

- now• Improved sensitivity of laboratory based assays

culminating in high sensitivity troponin assays

• Rapid diagnostic protocols based on very short time

intervals

Troponin measurement in 2015

• High sensitivity troponins

Company/platform/ assay LOD 99th percentile ng/L 10% CV ng/L

Siemens Stratus CS 30 70 60

Abbott iStat 20 80 100

Alere Triage 50 NA NA

Alere Triage Cadio 3 10 22 37

AQT90 Flex 9.5 23 39

Respose RAMP 30 100 210

Roche cardiac reader 50 NA NA

Radiometer AQT90 cTnT 8 17 26

Radiometer AQT90 cTnI 9.5 23 39

Assay performance vs evidence base

Rule out AMI - assays used

• Studies have shown that rapid rule out of AMI within 2

hours in the ED is feasible.

– Than M et al Lancet 2011;377:1077-1084 (Triage)

– Than M et al J Am Coll Cardiol 2012;59:2091-2098 (Architect

99th 28 ng/L 10% CV 32 ng/L Beckman 99th centile 40ng/L

10% CV 60 ng/l).

– Cullen L et al Int J Cardiol 2013;168:2602-2608 (Beckman 99th

centile 40ng/L 10% CV 60 ng/l).

– Than M et al JAMA Intern Med 2014;174:51-58 (Architect 99th

28 ng/L 10% CV 32 ng/L).

The evidence base for POCT

Randomised Assessment of Treatment using

Panel Assays of Cardiac markers (RATPAC)

To measure the effect of PoC triple test on:

1. Proportion of patients successfully discharged home

after ED assessment

2. LoS and hospital bed use

3. Use of CCU and cardiac treatments

4. Major adverse events

5. Health and social care costs

Goodacre SW et al. Heart 2011;97:190-196.

Goodacre S et al. Health Technol Assess 2011;15:iii-102.

Study design

• Pragmatic randomised controlled trial comparing

diagnostic assessment with the PoC triple test to

conventional diagnostic assessment without the triple test

• Multi-centre (six hospitals)

Participants

• Patients presenting to the ED with chest pain due to

suspected but not proven AMI in whom a negative point-

of-care marker test could potentially rule out AMI and

allow discharge home

Intervention

• PoC triple test at baseline and 90 minutes

• Admission recommended if:

Troponin I greater than or equal to 0.03 ng/ml on either sample (changed to 0.07 ng/ml)

Sustained elevation in CK-MB

25% rise in myoglobin from baseline

• Discharge recommended if none of these and patient remains well

• Clinician is ultimately responsible for decision to admit or discharge

Control

• No PoC testing

• Normal access to laboratory testing

• Management at discretion of clinician, according to local

protocols

• Clinician is ultimately responsible for decision to admit

or discharge

Primary outcome

• The proportion of patients successfully discharged home

after ED assessment, defined as discharge with no

adverse event during the following three months

• Discharge defined as either having left hospital or in

hospital with a decision to discharge by 4 hours after

attendance

Secondary outcomes• LoS and use of hospital beds

• Proportion managed on CCU and receiving cardiac treatments

• Re-attendance or admissions over 3 months

• Adverse events (death, non-fatal AMI, life-threatening arrhythmia, emergency

revascularisation or hospitalisation for myocardial ischaemia)

• Proportion of admitted patients shown to have MI

• Health and social care resource use over 3 months

• Health utility (EQ-5D) at 1 and 3 months

Primary outcome

Successful discharge home:

• Either left hospital or a decision made to discharge by 4

hours

• No MAE during follow-up

Primary outcome

• Odds ratio for successful discharge with point-of-care

• Adjusted for age, gender and known CHD

• Odds ratio = 3.59

• 95% CI 2.86 to 4.52

• p<0.001

• Point-of-care testing increases successful discharge

0.00

0.25

0.50

0.75

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port

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ospi

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0 6 12 18 24 30 36 42 48Time to discharge (hours)

Point of Care Standard Care

Duration from arrival to discharge from hospital

Length of initial stay

• Median: 8.8 h (PoC) v 14.2 h (SC)

• P<0.001 (Mann-Whitney)

Inpatient days

Number of days in hospital

706050403020100

Fre

qu

en

cy

700

600

500

400

300

200

100

0

Point-of-care

Number of days in hospital

706050403020100

Fre

qu

en

cy

700

600

500

400

300

200

100

0

Standard care

Major adverse events

Point of

care

Standard

Care

OR (95% CI) P-value

Death 6 (1%) 2 (<1%) 3.4

(0.7 to 17.3)

0.142

Non-fatal AMI 5 (<1%) 5 (<1%) 0.9

(0.3 to 3.2)

0.903

Hospitalisation for

ACS

18 (2%) 9 (1%) 1.8

(0.8 to 4.1)

0.149

Life threatening

arrhythmia

6 (1%) 2 (<1%) 3.2

(0.6 to 15.9)

0.160

Emergency

revascularisation

10 (1%) 14 (1%) 0.7

(0.3 to 1.5)

0.324

Proportion diagnosed with MI

Point of care Standard care P-value

All patients 82/1125

(7.3%)

76/1118

(6.8%)

0.650

Admitted

patients

82/763

(10.7%)

75/971

(7.7%)

0.029

Total costs


Barnsley £1058 £923 0.538

Derriford £1467 £1308 0.529

Edinburgh £1356 £710 0.025

Frenchay £1163 £1058 0.625

Leeds £785 £999 0.345

Leicester £1496 £1115 0.148

All hospitals £1217 £1006 0.047

RATPAC

summary of key findings

• POCT results in

– More rapid hospital discharge

– More accurate diagnosis (less missed AMI)

• Costs are slightly higher

• Patient satisfaction is higher

• Troponin alone is all that is required for diagnosis

– Collinson P et al. Heart 2012;98:312-8.

Other single centre trials

• ED trial – no impact on length of stay or outcome but

earlier initiation of anti-ischaemic therapy– Renaud et al Acad Emerg Med 2008; 15:216-24

Multicentre prospective RCT’s

• No impact on LOS

– Ryan et al Ann Emerg Med 2009; 53:321-8

The future state

• To deliver a rapid rule out only POCT can deliver the

appropriate TAT

Clinical assessment and

preliminary diagnosis

Test

requestBlood

takenSent to

laboratory

Sample receipt

Pre-analytical

processing

Analysis

Result

validation

Result

transmission

Result seen

by clinician

Clinical

action

taken

Patient

Turn

around

time

Clinician Therapeutic

turnaround time

Brain to

brain time

The future state - requirements

• Hs Troponin by POCT

• Connectivity

• Integration with the EPR and care pathways

• Process rengineering

– A rapid result is not useful without action

Impact of process

• Unless process re-engineering accompanies test

introduction benefit will not occur

Management according to a pre-defined

protocol

Chest Pain - clinically stable

Meets ECG criteria for thrombolysis

Immediate assessment and thrombolysis

Admit to CCU

cTnT 12 h >0.2mg/L

STEMI confirmed

Cardiac Rehab

Follow up in post MI clinic

Does not meet criteria for thrombolysis

Chest pain ?cardiac or abnormal ECG

Trop T 12 h

cTnT <0.2 mg/LNo ECG changes

No further chest pain

Stress test

PositiveAngina

Appropriate investigation

NegativeDischarge or refer for OP

investigation of non-cardiac

chest pain as appropriate

cTnT < 0.2 mg/LECG changes

or further chest pain

UAP

Investigate

Trop T >=0.2 mg/L

NSTEMI confirmed

Investigate

Collinson et al Ann Clin Biochem 2004; 41 :397-404

Prospective RCT of POCT with CLT

CLT POCT Hospital stay 211.2 h 203.5 h ns

CCU stay rule out group 39.4 h 51.6 h ns

CCU stay rule out

group ITT

18.7 h 15.2 h 0.0269

Hospital stay rule out

group

209.3 h 149.9 h 0.0465

Cost per patient 1818.98 1532.93 286.06

Cost per annum (2825) 5182945.85 4420020.48 762925.38

Collinson et al Ann Clin Biochem 2004; 41 :397-404

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Barnsley

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Plymouth Derriford

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Edinburgh RI

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Bristol Frenchay

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Leeds General

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Leicester RI

Duration from arrival to discharge from hospital

Total costs


Barnsley £1058 £923 0.538

Derriford £1467 £1308 0.529

Edinburgh £1356 £710 0.025

Frenchay £1163 £1058 0.625

Leeds £785 £999 0.345

Leicester £1496 £1115 0.148

All hospitals £1217 £1006 0.047

Costs

• Costs were different between sites and only just achieved

statistical significance

• Economics depend on the healthcare system especially

the cost of low intensity beds

• Relief of pressure on ED beds is worth the small increase

in costs

• In subsequent economic modelling studies, rapid

troponin testing has been shown to be cost effective

Conclusions

• Cost benefit depends on a combination of decision making and TAT

• Need for POCT depends on service configuration and TAT target.

• Analytical systems capable of delivering laboratory quality contemporary sensitive cTnI measurement are available and can deliver reduced length of stay

point of care troponin tests - the international federation · pdf file ·...

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