State Of The Art Lecture: Chest Pain In The Emergency Department
State of the Art Lecture:Chest Pain in the EmergencyDepartmentACCA Masterclass 2017Professor Nicholas L MillsConsultant CardiologistButler BHF Senior Clinical Research FellowRoyal Infirmary of Edinburgh@highSTEACS @troponinpapers
DisclosuresFunding:High-STEACS clinical trial (PI) NCT01852123British Heart Foundation Special Project Grant (SP/12/10/29922 )Abbott Diagnostics (reagent only)Sponsors:University of EdinburghNHS LothianInterests:Consultancy and speaker fees (Roche, Abbott Diagnostics, Beckman& Coulter, Singulex, GlaxoSmithKline, Sanofi-Aventis); Researchgrants (Abbott Diagnostics)NICE Diagnostics Advisory Committee,Scottish Inter-Collegiate Guideline NetworkACCA Masterclass 2017
Universal definition of myocardial infarction“A rise and/or fall of cardiac troponin with at least one value above the99th percentile upper reference limit (URL) from a healthy reference population”JACC 2012;60(16):1581-98
Universal definition of myocardial infarction23 countries across high and low to middle income countries (1,902 hospitals)North America 400; Europe 402; South America 400; Asia Pacific 400; Middle east 239;Africa 161Anand et al. 2016 (unpublished)
GlobalN. AmericaEuropeLatin AmericaAnand et al. 2016 (unpublished)Asia pacificME / AfricaPOCAsia L ensitivityPOCN ity60ME / Africa50403020100
High-sensitivity cardiac troponin assaysDiagnostic ThresholdLimit of DetectionFrequency99th percentileTroponin Concentration (ng/L) Greater analytical precision at very low concentrations (10-100 fold) Quantification of cardiac troponin concentrations in the majority of healthy persons Permit development of accelerated diagnostic pathwaysKorley & Jaffe J Am Coll Cardiol. 2013;61(17):1753-8
Odds ratio of death/recurrent MICardiac troponin concentrations within the reference range01020304050Cardiac troponin I concentration,ng/LCardiac troponin concentrations in normal reference range associatedwith riskMills NL et al BMJ 2012;344:bmj.e1533;n 2,092
Chest pain attendances in the Emergency DepartmentHospital admissions in UK300000250000200000Myocardial infarctionChest pain1500001000005000001998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009Goodacre et al. HTA 2013: 17 (1) 1-188
Can we rule out myocardial infarction safely in the Emergency Department?Royal Botanical Gardens, Edinburgh, Scotland
Peak concentrationOnset of chest painTroponin concentration, ng/LRapid rule out in the Emergency DepartmentContemporary assayHigh-sensitivity assay (99th centPresentation136 12hrs
Rapid rule out pathways for myocardial High-sensitivity cTn /-cTn /-hs-cTn /-hs-cTn continuous0h0h2h0h0h0h0h1h3hADP riskscores6-12 hADP accelerated diagnostic pathway;cTn cardiac troponin; hs high-sensitivity3h
Accelerated Diagnostic protocol to Assess Patients withchest Pain symptoms using contemporary Troponins (ADAPT)0hTIMI Score 0Patients with negative findingsfor each component of ADAPTwho had MACE during up to 30daysAND2hNo ischemia on ECGAND38Troponin 99thcentile at 0 and 2 hrs331120% identified as low risk withMACE rate of 1:400 at 30 days(NPV 99.7%)95Cullen et al. J Am Coll Cardiol 2012;59:2091-227n 1,975
Risk scores in the era of contemporary troponin testingJAMA. 2015 Nov 10;314(18):1955-65.
High-sensitivity cardiac troponin at 0 and 3 hours(European Society of Cardiology)0h3hUpper limit of normal(ULN) 99th centileEur Heart J. 2016;37(3):267-315.
Retrospective validation of the ESC 0 and 3 hour pathwayAbbott ARCHITECT high-sensitivity troponin I assay 99th centile at presentation and APT-ADPChristchurchEDACSAMINot AMITest positive105Test negative5231Test positive477Test negative31324Test positive211Test negative7208Test positive61Test negative291Sensitivity(%)Specificity(%)NPV (%)PPV (%)66.797.997.966.7(38.3 to 88.2) (95.1 to 99.3) (95.1 to 99.3) (38.4 to 88.2)60.397.991.387.0(48.5 to 71.2) (95.7 to 99.1) (87.8 to 93.9) (75.1 to 94.6)75.0(55.1 to 89.3)99.5(97.4 to 100)96.795.5(93.4 to 98.7) (77.2 to 99.9)75.0(34.9 to 96.8)98.9(94.1 to 100)97.885.7(92.4 to 99.7) (42.1 to 99.6)Parsonage et al. Heart 2016; Pickering et al. Heart2016
Case 3860h3h63 year old women with left sided chest pain 2 hours prior to arrival in the Emergency Department.Cigarette smoker with a family history of premature coronary artery disease. Examination normal.Initial 12-lead electrocardiogram was unremarkablehs-cTnI concentrations were 10, 16 and 187 ng/Lat presentation, and at 3 and 12 hours
Limitations of the 99th centile in 0 and 3 hour pathways0h3hAgeSex0 hrs3 hrsPeakPainonsetAgeSex0 hrs3 hrsPeakPainonset82F111526150 mins58M263346180 mins63F1016167150 mins66M1231202270 mins74M5857180 mins60M262932120 mins62M273243150 mins56M814307-87M516691150 mins77M212656270 mins73M262941-66M222536-61M123051180 mins84M171653-75M232539150 mins60M1414170270 minshs-cTnI at presentation and at 3 hours missed 16/330 ofpatients with myocardial infarction identified at 12 hoursn 330
SHOULD WE USE DIFFERENT THRESHOLDS TO RULE IN AND RULE OUT MI?Botanical Building, Balboa Park, San Diego, California
Ruling out with high-sensitivity cardiac troponin Tusing the limit of detection (LOD) at presentation0hHigh-sensitivity cardiac troponin T LOD (5 ng/L) at 0 h rules outmyocardial infarction in 20-44% of patients with an NPV 98.6%CohortYearnFNTNNPVProportionManchester (1)20117030130100.0%27%APACE (2)20132,072854298.6%26%Manchester (3)201546319599.0%20%France (4)2016413117699.5%43%TRAPID-AMI (5)20161,283455699.3%44%(1) Body et al JACC. 2011;54:1332; (2) Rubini Gimenez et al. Int J Cardiol. 2013;168:3896-901; (3) Body et al. ClinChem. 2015;61:983-9. (4) Chenevier-Gobeaux et al. Clin Biochem. 2016;49:1113-1117. (5) Body et al. Acad EmergMed. 2016;23:1004-13.
Enhanced precision with high-sensitivity cardiac troponin IAbbott ARCHITECT high-sensitivity cardiac troponin I (hscTnI) assayCoefficient of variation (%)30 20% CV 20% CV 10% CV252015105012345High-sensitivity cardiac troponin I concentration, ng/LCoefficient of variation 20% 2 ng/LShah AS et al Lancet 2015;386:2481-8
Optimal threshold to rule out at presentation with hs-cTnI0hAim: to define a threshold that identifies patients with suspected acute coronarysyndrome at presentation as low risk of myocardial infarction for immediatedischargeDerivation: n 4,870 consecutive patientsacross hospitals in Scotland, UKValidation: n 1,434 consecutivepatients in Minneapolis, USAIndex myocardial infarction, subsequent myocardial infarction or cardiac death at 30 daysShah AS et al Lancet 2015;386:2481-8
Optimal threshold to rule out at presentation with hs-cTnI0hwomenmenn 4,870NPV is 99.6% (95% CI 99.3 to 99.8) at troponin concentrations 5 ng/LShah AS et al Lancet 2015;386:2481-8
Optimal threshold to rule out at presentation with hs-cTnI0hwomenmenn 4,870Derivation cohort : 68% of women and 59% of men 5 ng/L on presentationShahShah ASAS etet alal LancetLancet 2015;386:2481-82015;386:2481-8
Performance of 5 ng/L threshold in key subgroups0hn 4,870Negative predictive value
One year outcomes in patients without myocardial infarction0hn 4,870Risk stratification of patients without myocardial infarctionShah AS et al Lancet 2015;386:2481-8
HOWWE INTEGRATESTRATIFICATIONTHRESHOLDSHOWCANTO burghBotanicalBalboaPark, San Diego, California
wayB. Novel pathwayHigh-STEACS pathwayTnI sample60h 16 ng/L (women) 34 ng/L (men) 5 ng/L AND 16 ng/L (women) 34 ng/L (men) 16 ng/L (women) 34 ng/L (men)Repeat hs-cTnI 3 hours from presentationCHANGE 3 ng/LAND 16 ng/L (women) 34 ng/L (men)CHANGE 3 ng/LAND 16 ng/L (women) 34 ng/L (men) 16 ng/L (women) 34 ng/L (men)Admit and hs-cTnI 6 hours from presentation 16 ng/L (women) 34 ng/L (men) 16 ng/L (women) 34 ng/L (men)ADMIT WITH MYOCARDIAL INFARCTION / INJURY 16 ng/L (women) 34 ng/L (men)AND CHANGE 50% 99th centileRULE OUT MYOCARDIAL INFARCTION / INJURY3hm presentation 5 ng/L*ADMIT WITH MYOCARDIAL INFARCTION / INJURYen)n)Obtain presentation hs-TnI sample*patients 2 hours from symptomonset require serial testingShah et al. Lancet 2016;387:2289-91
Validation of risk stratification thresholds 5 ng/L at presentationNPV [95%CI]Carlton et al (3,155 patients)JAMA Cardiology 201699.2% [98.8 - 99.5%]Boeddinghaus et al (2,828 patients) 99.1% [98.5 - 99.5%]Eur. Heart. J. 2016 3 ng/L at three hoursNPV [95%CI]Internal Validation (310 patients)Circulation 201798.8% [97.4-99.9%]External Validation (2,533 patients) 99.9% [99.7-100%]Circulation 2017Carlton et al JAMA Cardiology 2016; Chapmen et al.
How do the High-STEACS and ESC pathways compare?0hHigh-STEACS pathwayESC 3 hour pathwayNPV 99.5% [99.0-99.9%]NPV 97.9% [96.9-98.7%]Rules out 74% at 3 hrsRules out 79% at 3 hrs3hChapman et al. Circulation 2017n 1,218
99.5%Negative predictive value (95%CI)All0hOnset 3 hrs 6 hrs 6 hrs3hAge 65 yrs 65 yrsSexmenwomenIHDHigh-STEACSESC PathwayyesnoChapman et al. Circulation 2017
Implementation of HighSTEACS pathway* Retest at 3h if 2h fromonsetEMERGENCY DEPARTMENTHOSPITAL ADMISSIONShah et al. Lancet 2016;387:2289-91
High-Sensitivity cardiac Troponin at presentation tO Rule outmyocardial InfarCtion: (HiSTORIC) a stepped wedge clusterrandomised trialStepped-wedge cluster randomised trial05 sites6Standard care3h5 sitesStandard careValidation12RANDOMISATION0h18High-STEACS pathway30 monthsFollow upEarly ImplementationStandard careHigh-STEACS pathway Follow upLate ImplementationAim: to evaluate the efficacy and safety of implementation of High-STEACS pathwayto rule out myocardial infarction in consecutive patients with suspected acute coronary syndromewww.clinicaltrials.gov number: NCT01852123
www.highsteacs.cominfo@highsteacs.com
Rapid rule out pathways for myocardial High-sensitivity cTn /-cTn /-hs-cTn /-hs-cTn continuous0h0h2h0h0h0h0h1h3hADP riskscores6-12 hADP accelerated diagnostic pathway;cTn cardiac troponin; hs high-sensitivity3h
Development of a one hour pathway for myocardial infarction0h1hRubini Gimenez et al. Am J Med. 2015; 128,861-870
High-sensitivity cardiac troponin at 0 and 1 hours(European Society of Cardiology)0h1hMueller C et al. Ann Emerg. Med. 2016;68:76-87;Eur Heart J. 2016;37:267-315.
High-sensitivity cardiac troponin at 0 and 1 hours(European Society of Cardiology)0h1hHs-cTnT algorithm2x2Algorithm did not rule-outAlgorithm ruled-outHs-cTnI algorithmAMINot AMIAMINot AMI2335642377807141931202Sensitivity (95%CI)97.1 (94.0 to 98.8)98.8 (96.4 to 99.7)NPV (95%CI)99.5 (99.0 to 99.8)99.8 (99.3 to 99.9)Proportion Rule-Out (%)64.254.2Pickering J et al. Circulation. 2016
Is there a role for ‘scores’ if hs-cTnI is used to risk stratify?
Proportion identified as low risk, %Is there a role for ‘scores’ if hs-cTnI is used to risk stratify?99NPV(95%CI)Chapman et al. 2016 (unpublished)100
High-sensitivity cardiac troponin at 0 and 3 hours(European Society of Cardiology)GRACE score
WILLIMPROVINGLOWER DIAGNOSTICTHRESHOLDSIMPROVEPATIENT SELECTIONFORCARDIACDIAGNOSIS?TROPONIN TESTINGView from Arthur’s Seat, Edinburgh, ScotlandCharles Jenks’ Cells of Life, Jupiter Artland,
Universal definition of myocardial infarctionJACC 2012;60(16):1581-98
Type 2 myocardial infarction and myocardial injury is commonn 2,929nick.mills@ed.ac.uShah AS et al Am J Med. 2015;128:493-501.
Variation in the approach to cardiac troponin testing:impact on the prevalence of type 1 myocardial infarctionnick.mills@ed.ac.uk
How does the approach to cardiac troponin testing effect performance?Prospective cohort study across two independentconsecutive patient cohorts presenting to the EmergencyDepartmentUnselected testing(n 1,054)Selected testing(n 5,815)Primary outcome: diagnosis of type 1 myocardial infarctionShah et al. 2016 (under review)
How does the approach to cardiac troponin testing effect performance?Unselected testingSelected testing 99th centileShah et al. 2016 (under review)
How does the approach to cardiac troponin testing effect performance?Unselected testingType 1 MISelected testing2%Type 2 MIType 1 MI1%14%Type 2 MIMyocardial injury 11%4%Myocardial injury 6%Positive predictive value60%14%Shah et al. 2016 (under review)
Positive predictive value, %Impact of troponin testing on diagnosisof type 1 myocardial infarctionSelected testingUnselectedtestingPrevalence, %
Positive predictive value, %Impact of troponin testing on diagnosisof type 1 myocardial infarctionSelected testingTroponin TTroponin IUnselected testingPrevalence, %
How can we improve the positive predictive value of troponin testing?Selected testingChest painYesNoECG esDiabetesNoYesIHDNoPositive predictive value, %Shah et al. 2016 (under review)
Conclusions and summary High-sensitivity cardiac troponin I assays are changing the way we risk assess anddiagnose patients with suspected myocardial infarction Patients with very low cardiac troponin concentrations are at low risk and may notrequire hospital admission or further investigation Integration of risk stratification thresholds into early rule out pathways appears toimprove safety and permits myocardial infarction to be ruled in or out by 3 hours in 95% of patients The true safety and efficacy of these pathways needs to be confirmed in trialsevaluating their implementation in clinical practice
AcknowledgmentsBritish Heart Foundation Special Project Grant(SP/12/10/29922 ) and Butler Senior Clinical Researchnick.mills@ed.ac.u
Sex-differences in the 99th centile upper reference limitDefinitive normal range (DNR) study99th centilewomen99th centilemenAbbott ARCHITECT hs-cTnI1536Beckman Access 2 hs-cTnI2352Siemens hs-cTnI4281Singulex hs-cTnI3036Roche hs-cTnT1220Reference range of high-sensitivity cardiac troponin assaysApple FS et al. Clin Chem 2012
Diagnosis of type 1 myocardial y 0MenWomen77 (69 - 83)47 (38 - 56)87 (80 - 92)68 (59 - 77)86 (80 - 91)95 (89 - 98)Shah AS et al BMJ 2015: 350:h1295.SENSITIVITY
State of the Art Lecture: Chest Pain in the Emergency Department ACCA Masterclass 2017 Professor Nicholas L Mills Consultant Cardiologist Butler BHF Senior Clinical Research Fellow Royal Infirmary of Edinburgh @highSTEACS @troponinpapers. Disclosures ACCA Masterclass 2017
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