Troponin T High-sensitive Assay for Diagnosis of Acute MI
Troponin T High-sensitive Assay for Diagnosis of Acute MI
Objective To obtain summary estimates of the accuracy of a single baseline measurement of the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) for the diagnosis of acute myocardial infarction in patients presenting to the emergency department.
Design Systematic review and meta-analysis of diagnostic test accuracy studies.
Data sources Medline, Embase, and other relevant electronic databases were searched for papers published between January 2006 and December 2013.
Study selection Studies were included if they evaluated the diagnostic accuracy of a single baseline measurement of Elecsys Troponin T high-sensitive assay for the diagnosis of acute myocardial infarction in patients presenting to the emergency department with suspected acute coronary syndrome.
Study appraisal and data synthesis The first author screened all titles and abstracts identified through the searches and selected all potentially relevant papers. The screening of the full texts, the data extraction, and the methodological quality assessment, using the adapted QUADAS-2 tool, were conducted independently by two reviewers with disagreements being resolved through discussion or arbitration. If appropriate, meta-analysis was conducted using the hierarchical bivariate model.
Results Twenty three studies reported the performance of the evaluated assay at presentation. The results for 14 ng/L and 3-5 ng/L cut-off values were pooled separately. At 14 ng/L (20 papers), the summary sensitivity was 89.5% (95% confidence interval 86.3% to 92.1%) and the summary specificity was 77.1% (68.7% to 83.7%). At 3-5 ng/L (six papers), the summary sensitivity was 97.4% (94.9% to 98.7%) and the summary specificity was 42.4% (31.2% to 54.5%). This means that if 21 of 100 consecutive patients have the target condition (21%, the median prevalence across the studies), 2 (95% confidence interval 2 to 3) of 21 patients with acute myocardial infarction will be missed (false negatives) if 14 ng/L is used as a cut-off value and 18 (13 to 25) of 79 patients without acute myocardial infarction will test positive (false positives). If the 3-5 ng/L cut-off value is used, <1 (0 to 1) patient with acute myocardial infarction will be missed and 46 (36 to 54) patients without acute myocardial infarction will test positive.
Conclusions The results indicate that a single baseline measurement of the Elecsys Troponin T high-sensitive assay could be used to rule out acute myocardial infarction if lower cut-off values such as 3 ng/L or 5 ng/L are used. However, this method should be part of a comprehensive triage strategy and may not be appropriate for patients who present less than three hours after symptom onset. Care must also be exercised because of the higher imprecision of the evaluated assay and the greater effect of lot-to-lot reagent variation at low troponin concentrations.
Systematic review registration PROSPERO registration number CRD42013003926.
Emergency physicians commonly encounter chest pain and other symptoms suggestive of acute coronary syndrome, which account for approximately 5% to 10% of all visits to the emergency department. Timely diagnosis of such patients, especially ruling in or out of acute myocardial infarction, is of paramount importance. Delays in confirming the diagnosis may increase the risk of complications, and missing it may have fatal consequences for the patient. Until recently, the triage tools used by emergency physicians—clinical symptoms, history, 12 lead electrocardiogram, and standard troponin assays—did not allow early exclusion of evolving acute myocardial infarction. To avoid inadvertent discharge home, approximately 80% of all patients with chest pain were admitted to hospital for clinical observation and further testing, despite the fact that only a small proportion of them (approximately 25%) were eventually diagnosed as having myocardial infarction.
The need to triage patients with chest pain more effectively and efficiently—to avoid unnecessary hospital admissions and to speed up the diagnostic process—has driven the development of the so called high sensitivity cardiac troponin assays. To be classified as high sensitivity, a cardiac troponin assay should meet two criteria: firstly, its total imprecision (coefficient of variation) at the 99th centile of the healthy reference population should be 10% or less; secondly, measureable concentrations above the limit of detection and below the 99th centile should be attainable for at least 50% of the reference population. Over the past few years in the United Kingdom, standard troponin assays have gradually been replaced with high sensitivity ones. Although authoritative data on how and to what extent they are used in different National Health Service trusts are unavailable, anecdotal evidence strongly suggests both that standard troponin assay use remains common and that where used high sensitivity assays are being used in the same manner as standard troponin assays, not capitalising on their greater sensitivity.
To improve this situation, the National Institute for Health and Care Excellence (NICE) has recently published guidance on the clinical application of high sensitivity troponin assays in the early rule-out of acute myocardial infarction. The guidance recommends the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) and the ARCHITECTSTAT high sensitive troponin I (Abbott Laboratories) for use with early rule-out protocols that include blood samples taken at the patient’s presentation to the emergency department and a second sample three hours later. A third assay, the AccuTnI+3 (Beckman Coulter) has also been evaluated, but owing to insufficient evidence it is recommended only for use in clinical research. The guidance recommends the use of the 99th centile as a cut-off value when deciding whether to rule out acute myocardial infarction or to refer the patient for further investigations. Given the high negative predictive value of high sensitivity troponin assays and the fact that patients who present with very low cardiac troponin concentrations also have a very low risk of myocardial infarction, a rule-out strategy based on a single sample at presentation and lower decision thresholds, such as the assay’s limit of detection or limit of blank, has also been proposed. The limit of blank is the highest apparent analyte concentration (analytical noise) expected to be found when replicates of a blank sample containing no analyte are tested. The limit of detection, on the other hand, is the lowest analyte concentration likely to be reliably distinguished from the limit of blank and at which detection is feasible. Using these cut-off values may provide the means to identify patients at very low risk in whom acute myocardial infarction could be excluded without a second troponin measurement. The effectiveness and feasibility of such a strategy, however, will depend on a range of factors, including the diagnostic sensitivity and the precision of the assay at such low threshold values.
We did a systematic review and meta-analyses of studies evaluating the diagnostic accuracy of the Elecsys Troponin T high-sensitive assay (hereinafter referred to as the high sensitivity troponin T assay) for early diagnosis of acute myocardial infarction in patients presenting to the emergency department with chest pain and other symptoms suggestive of acute coronary syndrome. The review protocol was registered on the PROSPERO database (registration number CRD42013003926). Here we report the results pertaining to the hypothesis that a single use of the high sensitivity troponin T assay at presentation is sensitive enough to allow the safe exclusion of acute myocardial infarction. The accuracy estimates obtained for serial measurements and change in troponin concentration (the other objective stated in our review protocol) will be reported in a separate publication.
The high sensitivity troponin T assay is a modification of Roche’s fourth generation standard troponin T assay. The specifications provided by the manufacturer are as follows. The assay’s limit of blank is 3 ng/L, the limit of detection is 5 ng/L, and the limit of quantification (the lowest analyte concentration that can be reproducibly measured with coefficient of variation of 10% or less) is 13 ng/L. The 99th centile of a healthy reference population recommended as a positivity threshold for the diagnosis of acute myocardial infarction is 14 ng/L, and the estimated turnaround time is 18 minutes. The assay is also available as a short turnaround time version with an estimated turnaround time of nine minutes. It is commercially available and in clinical use worldwide with the exception of the United States, where it is used for research but has not yet obtained clearance from the US Food and Drug Administration.
Abstract and Introduction
Abstract
Objective To obtain summary estimates of the accuracy of a single baseline measurement of the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) for the diagnosis of acute myocardial infarction in patients presenting to the emergency department.
Design Systematic review and meta-analysis of diagnostic test accuracy studies.
Data sources Medline, Embase, and other relevant electronic databases were searched for papers published between January 2006 and December 2013.
Study selection Studies were included if they evaluated the diagnostic accuracy of a single baseline measurement of Elecsys Troponin T high-sensitive assay for the diagnosis of acute myocardial infarction in patients presenting to the emergency department with suspected acute coronary syndrome.
Study appraisal and data synthesis The first author screened all titles and abstracts identified through the searches and selected all potentially relevant papers. The screening of the full texts, the data extraction, and the methodological quality assessment, using the adapted QUADAS-2 tool, were conducted independently by two reviewers with disagreements being resolved through discussion or arbitration. If appropriate, meta-analysis was conducted using the hierarchical bivariate model.
Results Twenty three studies reported the performance of the evaluated assay at presentation. The results for 14 ng/L and 3-5 ng/L cut-off values were pooled separately. At 14 ng/L (20 papers), the summary sensitivity was 89.5% (95% confidence interval 86.3% to 92.1%) and the summary specificity was 77.1% (68.7% to 83.7%). At 3-5 ng/L (six papers), the summary sensitivity was 97.4% (94.9% to 98.7%) and the summary specificity was 42.4% (31.2% to 54.5%). This means that if 21 of 100 consecutive patients have the target condition (21%, the median prevalence across the studies), 2 (95% confidence interval 2 to 3) of 21 patients with acute myocardial infarction will be missed (false negatives) if 14 ng/L is used as a cut-off value and 18 (13 to 25) of 79 patients without acute myocardial infarction will test positive (false positives). If the 3-5 ng/L cut-off value is used, <1 (0 to 1) patient with acute myocardial infarction will be missed and 46 (36 to 54) patients without acute myocardial infarction will test positive.
Conclusions The results indicate that a single baseline measurement of the Elecsys Troponin T high-sensitive assay could be used to rule out acute myocardial infarction if lower cut-off values such as 3 ng/L or 5 ng/L are used. However, this method should be part of a comprehensive triage strategy and may not be appropriate for patients who present less than three hours after symptom onset. Care must also be exercised because of the higher imprecision of the evaluated assay and the greater effect of lot-to-lot reagent variation at low troponin concentrations.
Systematic review registration PROSPERO registration number CRD42013003926.
Introduction
Emergency physicians commonly encounter chest pain and other symptoms suggestive of acute coronary syndrome, which account for approximately 5% to 10% of all visits to the emergency department. Timely diagnosis of such patients, especially ruling in or out of acute myocardial infarction, is of paramount importance. Delays in confirming the diagnosis may increase the risk of complications, and missing it may have fatal consequences for the patient. Until recently, the triage tools used by emergency physicians—clinical symptoms, history, 12 lead electrocardiogram, and standard troponin assays—did not allow early exclusion of evolving acute myocardial infarction. To avoid inadvertent discharge home, approximately 80% of all patients with chest pain were admitted to hospital for clinical observation and further testing, despite the fact that only a small proportion of them (approximately 25%) were eventually diagnosed as having myocardial infarction.
The need to triage patients with chest pain more effectively and efficiently—to avoid unnecessary hospital admissions and to speed up the diagnostic process—has driven the development of the so called high sensitivity cardiac troponin assays. To be classified as high sensitivity, a cardiac troponin assay should meet two criteria: firstly, its total imprecision (coefficient of variation) at the 99th centile of the healthy reference population should be 10% or less; secondly, measureable concentrations above the limit of detection and below the 99th centile should be attainable for at least 50% of the reference population. Over the past few years in the United Kingdom, standard troponin assays have gradually been replaced with high sensitivity ones. Although authoritative data on how and to what extent they are used in different National Health Service trusts are unavailable, anecdotal evidence strongly suggests both that standard troponin assay use remains common and that where used high sensitivity assays are being used in the same manner as standard troponin assays, not capitalising on their greater sensitivity.
To improve this situation, the National Institute for Health and Care Excellence (NICE) has recently published guidance on the clinical application of high sensitivity troponin assays in the early rule-out of acute myocardial infarction. The guidance recommends the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) and the ARCHITECTSTAT high sensitive troponin I (Abbott Laboratories) for use with early rule-out protocols that include blood samples taken at the patient’s presentation to the emergency department and a second sample three hours later. A third assay, the AccuTnI+3 (Beckman Coulter) has also been evaluated, but owing to insufficient evidence it is recommended only for use in clinical research. The guidance recommends the use of the 99th centile as a cut-off value when deciding whether to rule out acute myocardial infarction or to refer the patient for further investigations. Given the high negative predictive value of high sensitivity troponin assays and the fact that patients who present with very low cardiac troponin concentrations also have a very low risk of myocardial infarction, a rule-out strategy based on a single sample at presentation and lower decision thresholds, such as the assay’s limit of detection or limit of blank, has also been proposed. The limit of blank is the highest apparent analyte concentration (analytical noise) expected to be found when replicates of a blank sample containing no analyte are tested. The limit of detection, on the other hand, is the lowest analyte concentration likely to be reliably distinguished from the limit of blank and at which detection is feasible. Using these cut-off values may provide the means to identify patients at very low risk in whom acute myocardial infarction could be excluded without a second troponin measurement. The effectiveness and feasibility of such a strategy, however, will depend on a range of factors, including the diagnostic sensitivity and the precision of the assay at such low threshold values.
We did a systematic review and meta-analyses of studies evaluating the diagnostic accuracy of the Elecsys Troponin T high-sensitive assay (hereinafter referred to as the high sensitivity troponin T assay) for early diagnosis of acute myocardial infarction in patients presenting to the emergency department with chest pain and other symptoms suggestive of acute coronary syndrome. The review protocol was registered on the PROSPERO database (registration number CRD42013003926). Here we report the results pertaining to the hypothesis that a single use of the high sensitivity troponin T assay at presentation is sensitive enough to allow the safe exclusion of acute myocardial infarction. The accuracy estimates obtained for serial measurements and change in troponin concentration (the other objective stated in our review protocol) will be reported in a separate publication.
The high sensitivity troponin T assay is a modification of Roche’s fourth generation standard troponin T assay. The specifications provided by the manufacturer are as follows. The assay’s limit of blank is 3 ng/L, the limit of detection is 5 ng/L, and the limit of quantification (the lowest analyte concentration that can be reproducibly measured with coefficient of variation of 10% or less) is 13 ng/L. The 99th centile of a healthy reference population recommended as a positivity threshold for the diagnosis of acute myocardial infarction is 14 ng/L, and the estimated turnaround time is 18 minutes. The assay is also available as a short turnaround time version with an estimated turnaround time of nine minutes. It is commercially available and in clinical use worldwide with the exception of the United States, where it is used for research but has not yet obtained clearance from the US Food and Drug Administration.
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