Bertil Lindahl Akademiska sjukhuset Uppsala

Bertil Lindahl Akademiska sjukhuset Uppsala

Kriterier för akut hjärtinfarkt Bevis på myokardskada/nekros: Konstaterad höjning och/eller sänkning av biomarkörer (företrädesvis troponin) med minst ett värde över den 99e percentilen hos en frisk referenspopulation Samt minst ett av följande kliniska fynd överrensstämmande med ischemi: 1. Symtom på ischemi, främst bröstsmärta 2. EKG-förändringar tydande på ischemi (nya ST-T-förändringar eller nytillkommet vänstersidigt skänkelblock) 3. Utveckling av patologisk q-våg i EKG 4. Bildbevis på nytillkommen hjärtmuskelskada 5. Konstaterad trombos i något av hjärtats kranskärl Thygesen et al. Third Universal definition of Myocardial Infarction, 2012

Acute Chest Pain (6-8 million/year in the US) Clinical history ctn ECG ACS (working diagnosis) Coronary angiography & other imaging techniques No ACS serious condition nonserious condition AMI (final diagnosis) UA (final diagnosis)

2015 ESC Guidelines for the management of ACS

hs-ctn assays 1 Criterion 2 Criterion Apple FS. Clin Chem, 2009

hs-ctn assays Validerade kommersiellt tillgängliga assays som marknadsförs som hs-ctn assays: 1. hs-ctnt (Elecsys, Roche) 2. hs-ctni (ARCHITECT STAT, Abbot) 3. hs-ctni (VIDAS, biomérieux) 4. hs-ctni (ADVIA Centaur, Siemens)

2015 ESC Guidelines for the management of ACS

UA AMI Wilson SR et al., Am Heart J. 2009

Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry. Eggers KM, Lindahl B, Melki D, Jernberg T. Eur Heart J. 2016 Aug 7;37(30) Retrospective register-based study (37 710 coronary care unit admissions; SWEDEHEART registry) We compared the case mix, the use of diagnostic procedures, treatments, and 1- year all-cause mortality 1 year before the implementation of a ctn assay with improved sensitivity (study period 1) and 1 year thereafter (study period 2). CONCLUSIONS: The implementation of a ctn assay with improved sensitivity was associated with an increase in the number of patients who due to their ctn-status were identified as suitable for beneficial therapies. There was no inappropriate increase in hospital resource utilization. As such, ctn assays with improved sensitivity provide an opportunity to improve the clinical management of patients with suspected ACS.

RAPID RULE-OUT Biomarkerbased strategies 3h: ESC 2011 algorithm 2h:2h-Advanced diagnostic protocol and 2h-algorithm 1h: 1h-algorithm 0h: dual-marker Strategy (ctn+ copeptin) 0h: undetectable Hs ctn

Diagnostic strategies (AMI!) 1. Only positive criteria for rule in patients not ruled in after a certain time period are by definition ruled out.

AMI nonami Time from admission

Roffi M et al. Eur Heart J 2016

Keller et al. N Engl J Med 361;9 august 27, 2009

Diagnostic strategies (AMI!) 1. Only positive criteria for rule in patients not ruled in after a certain time period are by definition ruled out 2. Positive criteria for both rule in and rule out

Lindahl B, Venge P and Wallentin L. Early diagnosis and exclusion of acute myocardial infarction by biochemical monitoring. Coronary Artery Disease 1995 AMI nonami Time from admission

Diagnostic strategies (AMI!) 1. Only positive criteria for rule in patients not ruled in after a certain time period are by definition ruled out 2. Positive criteria for both rule in and rule out Single hs-ctn value (below LOD) 1 or 2 h protocol hs-ctn with no increase combination with another biomarker combination with risk score

ESC 1 h-algorithm (hs-ctnt) 0h <12 and 0-1h <3 0h 52 or 0-1h 5 Reichlin 2012 (APACE; n=436) NPV 100% Reichlin 2015 (APACE; n=1320) NPV 99.9% Mueller 2015 (TRAPID; n=1282) NPV 99.1% Mokhtari 2016 (Lund; n=1038) NPV 97.8%

ESC 1 h-algorithm (hs-ctnt) 0h <12 and 0-1h <3 0h 52 or 0-1h 5 Reichlin 2012 (APACE; n=436) NPV 100% PPV 84% Reichlin 2015 (APACE; n=1320) NPV 99.9% PPV 78.2% Mueller 2015 (TRAPID; n=1282) NPV 99.1% PPV 77.2% Mokhtari 2016 (Lund; n=1038) NPV 97.8% PPV 67.3%

0h <5 and 0-1h <2 0h 52 or 0-1h 6 Rubini- Gimenez 2015 (APACE; n=905) NPV 99.6%

Proportion of chest pain patients in whom AMI has been ruled out (APACE) Below LoD 0/1 hours-alghoritm n (total) % NPV n (total) % NPV Roche 2072 26.5% 98.4% 1320 59.5% 99.9% Abbott Architect 1567 12.6% 100% 905 50.5% 99.6% Rubini Gimenez M, et al. Int J Cardiol 2013; Reichlin T, et al. CMAJ 2015; Rubini Gimenez M, et al. Am J Med 2015.

Hs-cTnT below LOD at admission Rubini Giménez et al. Rapid rule out of acute myocardial infarction using undetectable levels of highsensitivity cardiac troponin. Int J Cardiol. 2013.

Pickering JW, et al. Submitted. NPV for hs-ctnt <5 ng/l (n=7842)

Shah et al, Lancet 2015

Proportion of chest pain patients in whom AMI has been ruled out (APACE) Below LoD 0/1 hours-alghoritm n (total) % NPV n (total) % NPV Roche 2072 26.5% 98.4% 1320 59.5% 99.9% Abbott Architect 1567 12.6% 100% 905 50.5% 99.6% Rubini Gimenez M, et al. Int J Cardiol 2013; Reichlin T, et al. CMAJ 2015; Rubini Gimenez M, et al. Am J Med 2015.

Proportion of chest pain patients in whom AMI has been ruled out (APACE) Below LoD 0/1 hours-alghoritm Own unpublished n (total) data: % 62 % NPV were n (total) rule-out, % of these NPV 38 % had HEARTscore 4 (8 % had highly suspicious Roche 2072 26.5% 98.4% 1320 59.5% 99.9% Abbott Architect symptoms of ACS ) 1567 12.6% 100% 905 50.5% 99.6%

0/1 hour alghoritm - prognosis Mueller 2015 (TRAPID; n=1282)

Mueller C et al. TRAPID-AMI

Stable hs-ctnt Levels and Outcomes in Patients With Chest Pain There was a strong and graded association between all detectable levels of hs-ctnt and risk for MI, heart failure, and cardiovascular and noncardiovascular mortality.

Cardiac Troponin and Risk Score 410 consecutive chest pain patients 4 th generation ctnt (Roche) or ctni (Stratus) HEART score 3 months event rate including index diagnosis (CV death, AMI, unplanned PCI or CABG. Melki D, Jernberg T. HEART Score: A Simple and Useful Tool That May Lowerthe Proportion of Chest Pain Patients Who Are Admitted. Crit Pathways in Cardiol. In press.

Melki D, Jernberg T. HEART Score: A Simple and Useful Tool That May Lowerthe Proportion of Chest Pain Patients Who Are Admitted. Crit Pathways in Cardiol. In press. Event rate all patients (n=410) 1 pat. - PCI Event rate patients with neg admission ctn (n=380)

The combination provides incremental diagnostic value only when using conventional ctn assays (NPV 98-99%) Major limitation: the complexity to add an additional analyzer into the laboratory work-flow

Caveats in conjunction with all available clinical information not all patients in whom AMI are ruled-out are necessarily candidates for rapid discharge very early (<2 hours) presenters after the onset of symptoms late-risers in high-sensitivity ctn (about 1% of patients) percentage of patients of eligible for rule-out, NPV and PPV depends on population characteristics such as the local prevalence of AMI challenging patients such as patients on chronic hemodialysis and patients presenting >12h after chest pain onset structured and validated clinical pathways for the significant proportion of patients in the no rule-out, no rule-in zone are needed

Conclusions rule-out hs-ctn assays are critical for establishing positive rule-out criteria With positive rule-out criteria it seems to be possible to rule out AMI in 10-60% of chest pain patients within 0-1 hour from admission to the ED It is still unclear which strategy (very low cut-off, 1-2 h protocol, combination with other markers or Score) is the best option Large multi-center studies validating the different strategies are much needed The study population and the Gold Standard for AMI diagnosis are critical to consider when comparing different studies

RULE-IN STRATEGIES Arbetsdiagnos! The ESC 2011 Guideline hs-ctn time 0 and after 3h (at least 1 value> 99th + rising/fall) ABSOLUTE DELTA CHANGES (optimal cut-off?) PPV= 84% RELATIVE AND DIFFERENT DELTA PPV= 95.8%

One-Hour Rule-out and Rule-in of Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin T Reichlin T et al. Arch Intern Med. 2012

0h/1h-algorithm 0h/2h-algorithm Setting ED ED Specificity for AMI 95-97% 97-99%% PPV for AMI 70-81% 77-85% % ruled-in* 12-16% 8-14% Characteristics if using:** hs-ctnt 1,2,6 (Elecsys) hs-ctni 3,7 (Architect) hs-ctni 4 (Dimension Vista) s-ctni ultra 5 (Centaur) Hs-cTnT 52 OR 1h delta 5 Hs-cTnI 52 OR 1h delta 6 Hs-cTnI 107 OR 1h delta 19 s-ctni 166 OR 1h delta 30 Validation +++ +++ Additional advantages Also provides guidance for rule-out Hs-cTnT 53 OR 1h delta 10 Hs-cTnI 64 OR 1h delta 15 s-ctni 166 OR 1h delta 36 Also provides guidance for rule-out

Conclusions For very early rule-in with a high PPV, both a higher decision limit than the 99 th percentile and a delta higher than the +logrcv are required However, then only a relative small proportion of the AMIs will rule-in The optimal early rule-in criteria are still unclear Large multi-center studies validating the different strategies are much needed The study population and the Gold Standard for AMI diagnosis are critical to consider when comparing different studies

Further reading Thygesen K et al; the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. How to use highsensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012 Jun 21. Mueller C et al. Rapid Rule-out of Acute Myocardial Infarction - Novel Biomarker-based Strategies. Eur Heart J Acute Cardiovasc Care. 2016 Jul 1. pii: 2048872616653229. [Epub ahead of print] Möckel M et al. Rule-in of Acute Myocardial Infarction - Focus on Troponin. Eur Heart J Acute Cardiovasc Care. 2016 Jun 2. pii: 2048872616653228. [Epub ahead of print]