State of the Art Lecture: Chest Pain in the Emergency Department - PowerPoint PPT Presentation

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 Funding: High-STEACS clinical trial (PI) NCT01852123 British Heart Foundation Special Project Grant (SP/12/10/29922 ) Abbott Diagnostics (reagent only) Sponsors : University of Edinburgh NHS Lothian Interests: Consultancy and speaker fees (Roche, Abbott Diagnostics, Beckman & Coulter, Singulex, GlaxoSmithKline, Sanofi-Aventis); Research grants (Abbott Diagnostics) NICE Diagnostics Advisory Committee, Scottish Inter-Collegiate Guideline Network ACCA Masterclass 2017

Universal definition of myocardial infarction “A rise and/or fall of cardiac troponin with at least one value above the 99 th percentile upper reference limit (URL ) from a healthy reference population” JACC 2012;60(16):1581-98

Universal definition of myocardial infarction 23 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North America 400; Europe 402; South America 400; Asia Pacific 400; Middle east 239; Africa 161 Anand et al. 2016 (unpublished)

10 20 30 40 50 60 0 High-sensitivity Global Global Contemporary POC N America High-sensitivity N. America Contemporary POC Anand et al. 2016 (unpublished) High-sensitivity Europe Europe Contemporary POC High-sensitivity L America Latin America Contemporary POC High-sensitivity Asia Pacific Asia pacific Contemporary POC High-sensitivity ME / Africa ME / Africa Contemporary POC

High-sensitivity cardiac troponin assays 99 th percentile Diagnostic Threshold Limit of Detection Limit of Detection Frequency Troponin 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 pathways Korley & Jaffe J Am Coll Cardiol. 2013;61(17):1753-8

Cardiac troponin concentrations within the reference range Odds ratio of death/recurrent MI 0 10 20 30 40 50 Cardiac troponin I concentration, n = 2,092 ng/L Cardiac troponin concentrations in normal reference range associated with risk Mills NL et al BMJ 2012;344:bmj.e1533;

Chest pain attendances in the Emergency Department 300000 Hospital admissions in UK 250000 200000 Myocardial infarction Chest pain 150000 100000 50000 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Goodacre et al. HTA 2013: 17 (1) 1-188

Can we rule out myocardial infarction safely in the Emergency Department? Royal Botanical Gardens, Edinburgh, Scotland

Rapid rule out in the Emergency Department Troponin concentration, ng/L Peak concentration Onset of chest pain Contemporary assay High-sensitivity assay (99 th centi +12 hrs Presentatio 1 3 6 n

Rapid rule out pathways for myocardial infarction Conventional Contemporary High-sensitivity High-sensitivity + cTn +/- cTn +/- hs-cTn +/- hs-cTn continuous 0 h 0 h 0 h 0 h 0 h 0 h 1 h 2 h 3 h 3 h ADP + risk scores 6-12 h ADP = accelerated diagnostic pathway; cTn = cardiac troponin; hs = high-sensitivity

Accelerated Diagnostic protocol to Assess Patients with chest Pain symptoms using contemporary Troponins (ADAPT) Patients with negative findings for each component of ADAPT 0 h who had MACE during up to 30- TIMI Score = 0 days AND 2 h No ischemia on ECG AND 38 Troponin <99 th centile at 0 and 2 hrs 33 1 1 20% identified as low risk with 227 9 5 MACE rate of 1:400 at 30 days n=1,975 (NPV 99.7%) Cullen et al. J Am Coll Cardiol 2012;59:2091- 2098

Risk scores in the era of contemporary troponin testing JAMA. 2015 Nov 10;314(18):1955-65.

High-sensitivity cardiac troponin at 0 and 3 hours (European Society of Cardiology) 0 h 3 h Upper limit of normal (ULN) = 99 th centile Eur Heart J. 2016;37(3):267-315.

Retrospective validation of the ESC 0 and 3 hour pathway Abbott ARCHITECT high-sensitivity troponin I assay >99 th centile at presentation and 3 hours Sensitivity Specificity AMI Not AMI NPV (%) PPV (%) (%) (%) Test positive 10 5 Brisbane 66.7 97.9 97.9 66.7 ADAPT (38.3 to 88.2) (95.1 to 99.3) (95.1 to 99.3) (38.4 to 88.2) Test negative 5 231 Test positive 47 7 Christchurch 60.3 97.9 91.3 87.0 ADAPT (48.5 to 71.2) (95.7 to 99.1) (87.8 to 93.9) (75.1 to 94.6) Test negative 31 324 Test positive 21 1 Christchurch 75.0 99.5 96.7 95.5 ADAPT-ADP (55.1 to 89.3) (97.4 to 100) (93.4 to 98.7) (77.2 to 99.9) Test negative 7 208 Test positive 6 1 Christchurch 75.0 98.9 97.8 85.7 EDACS (34.9 to 96.8) (94.1 to 100) (92.4 to 99.7) (42.1 to 99.6) Test negative 2 91 Parsonage et al. Heart 2016; Pickering et al. Heart 2016

Case 386 0 h 3 h 63 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 unremarkable hs-cTnI concentrations were 10, 16 and 187 ng/L at presentation, and at 3 and 12 hours

Limitations of the 99 th centile in 0 and 3 hour pathways Ag Sex 0 hrs 3 hrs Peak Pain Ag Sex 0 hrs 3 hrs Peak Pain e onset e onset 0 h 82 F 11 15 26 150 mins 58 M 26 33 46 180 mins 63 F 10 16 167 150 mins 66 M 12 31 202 270 mins 3 h 74 M 5 8 57 180 mins 60 M 2 6 2932 120 mins 62 M 27 32 43 150 mins 56 M 8 14 307 - 87 M 5 16 691 150 mins 77 M 21 26 56 270 mins 73 M 26 29 41 - 66 M 22 25 36 - 61 M 12 30 51 180 mins 84 M 17 16 53 - n=330 75 M 23 25 39 150 mins 60 M 14 14 170 270 mins hs-cTnI at presentation and at 3 hours missed 16/330 of patients with myocardial infarction identified at 12 hours

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 T using the limit of detection (LOD) at presentation High-sensitivity cardiac troponin T<LOD (5 ng/L) at 0 h rules out 0 h myocardial infarction in 20-44% of patients with an NPV >98.6% Cohort Year n FN TN NPV Proportio n Manchester (1) 2011 703 0 130 100.0% 27% APACE (2) 2013 2,072 8 542 98.6% 26% Manchester (3) 2015 463 1 95 99.0% 20% France (4) 2016 413 1 176 99.5% 43% TRAPID-AMI (5) 2016 1,283 4 556 99.3% 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. Clin Chem. 2015;61:983-9. (4) Chenevier-Gobeaux et al. Clin Biochem. 2016;49:1113-1117. (5) Body et al. Acad Emerg Med. 2016;23:1004-13.

Enhanced precision with high-sensitivity cardiac troponin I Abbott ARCHITECT high-sensitivity cardiac troponin I (hs- cTnI) assay 30 >20% CV ) tion (% 25 <20% CV <10% CV ria 20 Coef fi cient of va 15 10 5 0 1 2 3 4 5 Hig h-sensitivity ca rdia c troponin I concentration, ng /L Coefficient of variation 20% ~ 2 ng/L Shah AS et al Lancet 2015;386:2481-8

Optimal threshold to rule out at presentation with hs-cTnI Aim: to define a threshold that identifies patients with suspected acute coronary 0 h syndrome at presentation as low risk of myocardial infarction for immediate discharge Derivation : n=4,870 consecutive patients Validation : n=1,434 consecutive patients in Minneapolis, USA across hospitals in Scotland, UK Index myocardial infarction, subsequent myocardial infarction or cardiac death at 30 days Shah AS et al Lancet 2015;386:2481-8 Shah AS et al Lancet 2015;386:2481-8

Optimal threshold to rule out at presentation with hs-cTnI 0 h women men n=4,870 NPV is 99.6% (95% CI 99.3 to 99.8) at troponin concentrations <5 ng/L Shah AS et al Lancet 2015;386:2481-8 Shah AS et al Lancet 2015;386:2481-8

Optimal threshold to rule out at presentation with hs-cTnI 0 h women men n=4,870 Derivation cohort : 68% of women and 59% of men <5 ng/L on presentation Shah AS et al Lancet 2015;386:2481-8 Shah AS et al Lancet 2015;386:2481-8

Performance of <5 ng/L threshold in key subgroups 0 h n=4,870 Negative predictive value

One year outcomes in patients without myocardial infarction 0 h n=4,870 Risk stratification of patients without myocardial infarction Shah AS et al Lancet 2015;386:2481-8

HOW CAN WE INTEGRATE RISK STRATIFICATION THRESHOLDS OUR HOW TO INTEGRATE RISK STRATIFICATION THRESHOLDS INTO THE PATHWAYS? PATHWAY Scottish wildflowers, Edinburgh Botanical Building, Balboa Park, San Diego, California

High-STEACS pathway Obtain presentation hs-TnI sample ≥ 0 h ≥ 5 ng/L AND >16 ng/L (women) ≤ 16 ng/L (women) <5 ng/L* >34 ng/L (men) ≤ ≤ ≤ 34 ng/L (men) ≤ ≤ ADMIT WITH MYOCARDIAL INFARCTION / INJURY RULE OUT MYOCARDIAL INFARCTION / INJURY *patients <2 hours from symptom onset require serial testing 3 h Repeat hs-cTnI 3 hours from presentation ≤ CHANGE ≥ 3 ng/L CHANGE <3 ng/L ≤ AND AND >16 ng/L (women) ≤ 16 ng/L (women) ≤ 16 ng/L (women) >34 ng/L (men) ≤ ≤ 34 ng/L (men) ≤ 34 ng/L (men) Admit and hs-cTnI 6 hours from presentation Shah et al. Lancet 2016;387:2289-91 ≤ 16 ng/L (women) >16 ng/L (women) ≤ 34 ng/L (men) >34 ng/L (men)