What can we learn from EQAs and audits for cardiac marker testing?

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1 What can we learn from EQAs and audits for cardiac marker testing? Dr P. O. Collinson MA MB BChir FRCPath MD FACB Consultant Chemical Pathologist and Director of Clinical Blood Sciences, Head of Vascular Risk Management, Departments of Chemical Pathology and Cardiology, St George s Hospital

2 Conflicts of interest Member NICE Diagnostics Advisory Committee National Clinical Lead National Laboratory Medicine Catalogue

3 Acknowledgements The CARMAGUE group Pulkki,K.; Suvisaari,J.; Collinson,P.; Ravkilde,J.; Stavljenic- Rukavina,A.; Hammerer-Lercher,A.; Baum,H.; Dieijen- Visser,M.P.; Laitinen,P. Everyone who participated in the CARMAGUE survey Dr Alan Reid UK NEQAS

4 What can we learn from EQAs and audits for cardiac marker testing? Biomarkers of myocardial necrosis Biomarkers of cardiac failure What is the audit standard Audit and reality how do we use cardiac biomarkers in Europe? How does this compare with the evidence Assay performance Conclusions

5 Biomarkers of myocardial necrosis What is the audit standard

6 Circulation 2007; 116:

7 Criteria for acute myocardial infarction Detection of the rise and/or fall cardiac biomarkers (preferably troponin) with at least one value above the 99 th centile of the upper reference limit together with evidence of ischaemia with at least one of the following: Symptoms of ischaemia ECG changes of new ischaemia (new ST.-T changes or new LBBB) Development pathological Q-wave s in the ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Acceptable imprecision (coefficient of variation) at the 99th percentile for each assay should be defined as 10%.

8 Biomarkers of myocardial necrosis Audit and reality how do we use cardiac biomarkers in Europe?

9 What markers are measured? 18% 3% 51% 18% ctn CKMB mass CKMB act Myo

10 What markers are measured? ctni ctnt CKMB mass CKMB act Myo ctni ctnt CKMB mass CKMB act Myo

11 What markers are used for the diagnosis of AMI? 14% ctn CKMB mass 11% CKMB act Myo 15% 60%

12 Where do laboratories get their information decision limits % CV 99th percentile ROC curve Other 10% CV 99th percentile ROC curve Other

13 Where do laboratories get their information decision limits for AMI Data sheet IFCC//NACB ESC / ACC 2000 Universal definition Peer-reviewed literature Reference limits Locally derived Data sheet IFCC//NACB ESC / ACC 2000 Universal definition Peer-reviewed literature Reference limits Locally derived

14 Where do laboratories get their information reference intervals Volunteers (screened Volunteers (unscreeneed) Blood donors Data sheet Published literature

15 Biomarkers of myocardial necrosis How does this compare with the evidence

16 Biomarkers of myocardial necrosis - how does this compare with the evidence Test selection

17 Diagnostic value of serial measurement of cardiac markers in patients with chest pain: Limited value of adding myoglobin to troponin I for exclusion of myocardial infarction Eggers et al Am Heart J 2004;148:574 81

18 Diagnostic sensitivity of cardiac markers at the time of admission classified according to time of onset of chest pain Eggers et al Am Heart J 2004;148:574 81

19 n = 773 Ann Clin Biochem 2006; 43:273-80

20 Keller, T. et al. N.Engl.J.Med. 2009; 361,

21 The RATPAC Trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers): A randomised controlled trial of point-of-care cardiac markers in the emergency department The point-of-care cardiac marker panel comprised creatine kinase MB mass (CK-MB), myoglobin and troponin I (ctni), measured at presentation and 90 minutes later, using the Siemens Stratus CS analyser participants were recruited across 6 hospitals between 30th January 2007 and 2nd June 2008.(1125 POCT, 1118 to standard care). Heart 2010

22 True positive rate (Sensitivity) ctni to 0.98 CK-MB to 0.90 n =1125 No discrimination ctni 1 CK-MB Myoglobin to 0.81 Myoglobin False positive rate (1 - Specificity)

23 True positive rate (Sensitivity) ( ) 0.86 ( ) 0.78 ( ) 0.83 ( ) 0.58 ( ) n = 1090 No discrimination ctni 2 CK-MB 2 Myoglobin 2 Delta CK-MB Delta Myoglobin False positive rate (1 - Specificity)

24 Serial troponin is the test of choice and CK-MB and myoglobin measurement should be abandoned

25 Biomarkers of myocardial necrosis - how does this compare with the evidence Reference populations

26 Impact of population selection on distribution % CI Notched Outlier Boxplot % CI Mean Diamond 80 Outliers > 1.5 and < 3 IQR Troponiningroups Outliers > 3 IQR ctni S all ctnt all ctni B all ctni S Sc ctnt Sc ctni B Sc ctni S N ctnt N ctni B N Troponin in groups

27 Appropriate patient selection is required for reference range derivation

28 Biomarkers of myocardial necrosis Assay performance

29 EQA participation 9% % 2010 No external quality assessment National quality assessment European quality assessment International quality assessment No external quality assessment National quality assessment European quality assessment International quality assessment

30 Overview of Performance of Cardiac Markers in UK NEQAS Schemes Alan Reid Scheme Organiser, UK NEQAS Cardiac Markers Glasgow, Scotland, UK September 2010 UK NEQAS for Cardiac Markers (Glasgow)

31 Current Participant Distribution - Troponin I Methods Method N Method N Abbott Architect (ABI2) 62 Tosoh AIA Systems 600/360 (ETTI) 4 Abbott AxSYM (ABI3) 3 SMSD Immulite 2000 (IMTI) 6 Beckman Coulter Access/Dxi/Lxi (AccuTnI) (BEA) 41 SMSD Immulite 2500 (IMTI5) 10 SMSD Advia Centaur (CCU) 65 OCD (J&J) Vitros(ORI) 10 SMSD (Dade) Stratus CS (DAI) 10 Randox Evidence (REV) 1 SMSD (Dade) Dimension/Xpand/RXL (DDI) 7 Roche Cobas 6000 (ctni) 1 SMSD (Dade) Dimension Vista (DDVI) 3 UK NEQAS for Cardiac Markers (Glasgow)

32 UK NEQAS for Cardiac Markers (Glasgow) Troponin I System Method Means

33 ctni Batch 7608V < MDL < MDL < MDL UK NEQAS for Cardiac Markers (Glasgow)

34 UK NEQAS for Cardiac Markers (Glasgow) ctni Batch 6207V

35 UK NEQAS for Cardiac Markers (Glasgow) ctni Batch 6007V

36 Between Lab Precision Profile Cardiac Troponin I (Abbott Architect) %CV [ctni] , , , , µg/l CV= 14.0% (2010) µg/l CV= 11.6% (2009) µg/l CV= 14.2% (2008) µg/l CV= 12.1% (2007) MDL: 0.01 ug/l UK NEQAS for Cardiac Markers (Glasgow)

37 Between Lab Precision Profile Cardiac Troponin I - Beckman Coulter Access/Dxi/Lxi (AccuTnI) %CV [ctni] , , , , , UK NEQAS for Cardiac Markers (Glasgow) µg/l CV=11.3% (2010) 0.044µg/L CV=14.3% (2009) µg/l CV=16.0% (2008) µg/l CV=14.5% (2007) MDL: 0.01 µg/l

38 Between Lab Precision Profile Cardiac Troponin I (SHDL Centaur (Ultra)) %CV [ctni] UK NEQAS for Cardiac Markers (Glasgow) , , µg/l CV= 9.8% (2010) 0.052µg/L CV=13.3% (2009) µg/l CV=12.6% (2008) µg/l CV= 8.0% (2007) MDL: µg/l

39 Current Participant Distribution - Troponin T Systems Method Method Code Number of Participants All Roche ctnt Systems RELT 91 All Roche hs ctnt Systems RTHSU 38 UK NEQAS for Cardiac Markers (Glasgow)

40 UK NEQAS for Cardiac Markers (Glasgow) [ctnt] Batch 7608V

41 UK NEQAS for Cardiac Markers (Glasgow) [ctnt] Batch 6207V

42 [ctnt] Batch 6007V CV: 6.5% CV: 2.7% UK NEQAS for Cardiac Markers (Glasgow)

43 Precision Profiles 2010 Cardiac Troponin T (All Systems) %CV [ctnt] ctnt ,hs ctnt MDL: 0.01 ug/l UK NEQAS for Cardiac Markers (Glasgow) 0.040ug/L CV= 3.5% (hs ctnt assay) 0.019ug/L CV= 21.6% (ctnt assay)

44 Evidence Biomarkers of myocardial necrosis - assay performance

45 Assay performance to achieve a true 99 th centile High Diagnostic certainty Low n 10% CV ng/l

46 Candidate assays the scorecard

47 Scorecard designations of ctn assays. Acceptance designation Total imprecision at the 99th percentile, CV% Guideline acceptable <10 Clinically usable > 10 to < 20 Not acceptable >20 Assay designation Measurable normal values below the 99th percentile, % Level 4 (third generation, hs) > 95 Level 3 (second generation, hs) 75 to < 95 Level 2 (first generation, hs) 50 to < 75 Level 1 (contemporary) <50 Adapted from Apple Clin Chem 2009

48 Company/platform/assay 1 99th percentile, µg/l 10% CV, µg/l Acceptance designation Assay designation Abbott Architect Clinically usable Level 1 Beckman Access Accu Clinically usable Level 2 biomerieux Vidas Ultra Not acceptable Level 1 Ortho-Clinical Diagnostics Vitros ECi ES Guideline acceptable Level 1 Radiometer AQT Clinically usable Level 1 Roche Elecsys 2010 < Clinically usable Level 1 Siemens Centaur Ultra Guideline acceptable Level 1 Siemens Dimension RxL Clinically usable Level 1 Siemens Immulite 2500 STAT Not acceptable Level 1 Siemens Stratus CS Guideline acceptable Level 1 Siemens VISTA Guideline acceptable Level 1 Tosoh AIA II < Clinically usable Level 1 Roche Elecsys hs-ctnt Guideline acceptable Level 4 Research hs assays Beckman Access hs-ctni Guideline acceptable Level 4 Nanosphere hs-ctni Guideline acceptable Level 3 Singulex hs-ctni Guideline acceptable Level 4 Adapted from Apple Clin Chem 2009

49 Is it really what it says on the tin?

50 Depends how you calculate it

51 Assay 1 Assay 2 Assay 3 99 th centile claim % CV claim % CV claim th centile % CV wr % CV wr % CV wd % CV wd % CV bd % CV bd % CV tip % CV tip

52 Assay 1 Assay 2 Assay 3 99 th centile claim % CV claim % CV claim th centile % CV wr % CV wr % CV wd 23.8 (79.3%) 10 (77%) 27 (45%) 20% CV wd

53 Ability to detect normals

54 Positive samples in a reference population % positive ctnt hs ctni ultra ctni AccuI

55 Biomarkers of myocardial necrosis - conclusions There does not seem to be a total shift to the troponin only standard Assay agreement is limited for ctni Assay performance differs in real life from performance claims There is a need for independent verification of supplier claims, prefererably by multicentre collaborations and data pooling studies. Some assays have significant limitations

56 Afterthoughts Is the 10% CV at the 99 th centile essential?

57 Biomarkers of cardiac failure What is the audit standard Audit and reality how do we use cardiac biomarkers in Europe? How does this compare with the evidence Assay performance Conclusions

58 Biomarkers of cardiac failure What is the audit standard

59 Eur Heart J Oct;29(19): Epub 2008 Sep 17. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM).

Eur Heart J 2008;29:2388-2442 The European Society of Cardiology

60 Flow chart for the diagnosis of HF with natriuretic peptides in untreated patients with symptoms suggestive of HF. Eur Heart J 2008;29: The European Society of Cardiology All rights reserved. For permissions please journals.permissions@oxfordjournals.org

61 CHRONIC HEART FAILURE National clinical guideline for diagnosis and management in primary and secondary care August 2010 NICE Clinical Guideline No Measure serum natriuretic peptides (B-type natriuretic peptide [BNP] or N-terminal pro-b-type natriuretic peptide [NTproBNP]) in patients with suspected heart failure without previous MI. [new 2010] 3. Because very high levels of serum natriuretic peptides carry a poor prognosis, refer patients with suspected heart failure and a BNP level above 400 pg/ml (116 pmol/litre) or an NTproBNP level above 2000 pg/ml (236 pmol/litre) urgently, to have transthoracic Doppler 2D echocardiography and specialist assessment within 2 weeks. [new 2010]

62 Biomarkers of cardiac failure Audit and reality how do we use cardiac biomarkers in Europe?

63 BNP utilisation BNP NTproBNP None BNP NTproBNP None Slice 4

64 BNP utilisation BNP NTproBNP outpatients emergency department coronary unit other, please specify outpatients emergency department coronary unit other, please specify

65 BNP decision limits BNP NTproBNP Assay package insert information Peer-reviewed literature Age and gender related reference limits Locally derived decision/reference limits Published literature Assay package insert information Peer-reviewed literature Age and gender related reference limits Locally derived decision/reference limits Published literature

66 Biomarkers of cardiac failure How does this compare with the evidence

67 BNP/NTproBNP

68 Chronic heart failure patients with suspected CHF Rosenberg, J. et al. Eur Heart J :66-73

69 Rosenberg, J. et al. Eur Heart J :66-73

71 Biomarkers of cardiac failure Assay performance

72 BNP EQA BNP NTproBNP No external quality assessment National quality assessment European quality assessment International quality assessment No external quality assessment National quality assessment European quality assessment International quality assessment

73 Performance Criteria Plot BNP (Abbott Systems) Between System Precision Profile 2007, %CV : ng/l CV= 9.9% ng/l CV = 15.3% ng/l CV = 10.1% 2010: ng/l CV= 17.8% ng/l CV = 20.0% ng/l CV = 11.5% [BNP] (ng/l) 2007: ng/l CV= 9.9% ng/l CV = 9.0% ng/l CV = 6.9% 2008: ng/l CV= 9.2% ng/l CV = 12.2% ng/l CV = 9.6% UK NEQAS for Cardiac Markers (Glasgow) , , ,

74 Performance Criteria Plots BNP (SHDL Centaur) Between System Precision Profile 2007, %CV ng/L CV= 24.6% ng/l CV = 12.8% 333.0ng/L CV = 22.2% ng/l CV= 18.8% ng/l CV = 16.0% ng/l CV = 16.6% ng/l CV= 8.1% ng/l CV = 9.0% ng/l CV = 5.9% UK NEQAS for Cardiac Markers (Glasgow) [BNP] (ng/l) , , ,

75 NT-proBNP (ng/l) - Roche Systems Between Laboratory Precision Profile [NT-proBNP] (ng/l) , , , UK NEQAS for Cardiac Markers (Glasgow)

76 NT-proBNp (ng/l) SMSD Dimension/Immulite Systems Between Laboratory Precision Profile %CV [NT-proBNP] (ng/l) , , , UK NEQAS for Cardiac Markers (Glasgow)

77 Biomarkers of cardiac failure - conclusion Uptake of BNP measurement is inadequate More use of BNP measurement should be made primary care More work on decision limits is required

78 Conclusions Despite the evidence based and clear guidelines for cardiac troponin utilisation, the majority of laboratories do not have an evidence based testing policy Laboratories appear to lag behind the evidence for test utilisation. A lack of universal EQA participation remains a significant concern

79 References Collinson P, Pulkki K, Suvisaari J, Ravkilde J, Stavljenic- Rukavina A, Hammerer-Lercher A et al. How well do laboratories follow guidelines on cardiac markers? The cardiac marker guideline uptake in Europe study. Clin Chem 2008;54: Pulkki K, Suvisaari J, Collinson P, Ravkilde J, Stavljenic- Rukavina A, Hammerer-Lercher A et al. A pilot survey of the use and implementation of cardiac markers in acute coronary syndrome and heart failure across Europe The CARdiac MArker Guideline Uptake in Europe (CARMAGUE) study. Clin Chem Lab Med 2009;47:

Troponin when is an assay high sensitive?

Troponin when is an assay high sensitive? Professor P. O. Collinson MA MB BChir FRCPath FRCP edin MD FACB EurClin Chem Consultant Chemical Pathologist and Professor of Cardiovascular Biomarkers, Departments