Validity of a Novel Point-of-Care Troponin Assay for Single-Test Rule-Out of Acute Myocardial Infarction

Key Points

Question

Could a single troponin measurement with a novel point-of-care assay (TnI-Nx) be used to safely and effectively rule out acute myocardial infarction?

Findings

In a preliminary cohort study of 354 patients presenting to an emergency department with symptoms of myocardial infarction, a TnI-Nx assay had an area under curve similar to that of a laboratory-based high-sensitivity cardiac troponin I assay. An assessment of risk with an TnI-Nx assay stratified more than half of the patients to a low-risk category, with 100% sensitivity.

Meaning

A novel point-of-care assay that can give results within 15 minutes could facilitate rapid risk stratification, resulting in earlier discharge of low-risk patients.

This cohort study compares the efficacy of a novel point-of-care troponin assay with an established assay in patients with possible acute myocardial infarction.

Abstract

Importance

Emergency department (ED) investigations of patients with suspected acute myocardial infarction (AMI) are time consuming, partly because of the turnaround time of laboratory tests. Current point-of-care troponin assays shorten test turnaround times but lack precision at lower concentrations. Development of point-of-care troponin assays with greater analytical precision could reduce the decision-making time in EDs for ruling out AMI.

Objective

To determine the clinical accuracy for AMI of a single troponin concentration measured on arrival to ED with a new-generation, higher precision point-of-care assay with a 15-minute turnaround time.

Design, Setting, and Participants

This observational study occurred at a single urban regional ED. Adults presenting acutely from the community to the ED with symptoms suggestive of AMI were included. Troponin concentrations were measured on ED arrival with both a novel point-of-care assay (i-STAT TnI-Nx; Abbott Point of Care) and a high-sensitivity troponin I assay (Architect hs-cTnI; Abbott Diagnostics).

Main Outcomes and Measures

The primary outcome was type 1 AMI during index presentation. We compared the discrimination ability of the TnI-Nx assay with the hs-cTnI assay using the area under receiver operator characteristic curve (AUC) and sensitivity, negative predictive value, and the proportion of negative test results at thresholds with 100% sensitivity.

Results

Of 354 patients (255 [72.0%] men; mean [SD] age, 62 [12] years), 57 (16.1%) experienced an AMI. Eighty-five patients (24.0%) presented to the ED less than 3 hours after symptom onset. No difference was found between the AUC of the TnI-Nx assay (0.975 [95% CI, 0.958-0.993]) and the hs-cTnI assay (0.970 [95% CI, 0.949 to 0.990]; P = .46). A TnI-Nx assay result of less than 11 ng/L identified 201 patients (56.7%) as low risk, with a sensitivity of 100% (95% CI, 93.7%-100%) and a negative predictive value of 100% (95% CI, 98.2%-100%). In comparison, an hs-cTnI assay result of less than 3 ng/L identified 154 patients (43.5%) as low risk, with a sensitivity of 100% (95% CI, 93.7%-100%) and a negative predictive value of 100% (95% CI, 97.6%-100%).

Conclusions and Relevance

A novel point-of-care troponin assay that can produce a result 15 minutes after blood sampling had comparable discrimination ability to an hs-cTnI assay for ruling out AMI after a single blood test. Use in the ED may facilitate earlier decision making and could expedite the safe discharge of a large proportion of low-risk patients.

Introduction

Investigation of patients with possible acute myocardial infarction (AMI) is a common clinical scenario associated with significant health care resource burden. Strategies that reduce the time taken to rule out AMI may rationalize the use of resources and accelerate safe discharge of low-risk patients. High-sensitivity cardiac troponin (hs-cTn) assays have been shown to have sufficient accuracy at low concentrations to enable AMI to be ruled out in a large proportion of patients after analysis of just 1 blood sample taken on presentation to the emergency department (ED).^1,2 The turnaround time between a blood draw and the reporting of assay results is an important limiting factor to rapid decision making. In this process, the time taken for transporting the blood to a central laboratory and the subsequent centrifugation to prepare a plasma sample is a significant component of the turnaround time. Point-of-care cardiac troponin assays that use whole blood and have short analysis times (of approximately 15 minutes) may expedite decision making. To date, such assays have lacked the precision required at very low concentrations (as demonstrated by hs-cTn assays) that is necessary to accurately enable early rule-out after a single baseline blood sample.³

The aim of this study was to assess the diagnostic performance of a single test with a novel high precision point-of-care troponin I (TnI-Nx) assay capable of accurate measurement of very low concentrations of troponin I with a 15-minute turnaround time. This brief report describes the initial analysis of the preliminary cohort.

Methods

This preliminary cohort analyzed was part of an observational study (Australia New Zealand Clinical Trials Registry identifier: ACTRN12611001076965) in patients with symptoms of possible acute coronary syndrome who attended a single, regional, general and tertiary metropolitan emergency department (ED) in Christchurch, New Zealand. Patients were recruited between July 5, 2016, and January 5, 2018, as part of ongoing ED recruitment. We assessed the diagnostic performance for AMI of a novel point-of-care cardiac troponin assay (I-Stat TnI-Nx; Abbott Point of Care).

The Southern Health and Disability Ethics Committee approved the study, and all patients provided written consent prior to samples being taken. This study conforms to the Declaration of Helsinki.

The recruitment methods have been reported elsewhere⁴; briefly, eligible patients were 18 years or older who presented from the community to the ED with symptoms, first manifested within the previous 24 hours, that were suggestive of AMI⁵ and who attending physicians planned to investigate with serial cardiac troponin assays. The principal exclusion criteria were ST-elevation AMI or a clear noncardiac cause for symptoms. Patients were managed as per local guidelines, which use the Emergency Department Assessment of Chest Pain Score–Accelerated Diagnostic Pathway⁶ with serial troponin I measurements in all patients, with the Abbott Architect high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott Diagnostics). This pathway risk-stratifies patients based on electrocardiogram results, serial hs-cTnI assays, and the Emergency Department Assessment of Chest Pain Score, which takes into account the age, history, and presenting symptoms of the patient.

Blood was drawn into 9-mL lithium-heparin tubes on presentation and immediately centrifuged, with the plasma aliquoted and stored at −80°C. Troponin concentrations were subsequently measured by the hs-cTnI assay on an Architect platform and I-Stat TnI-Nx assay (Abbott Point of Care) on an I-Stat blood analyzer (Abbott Point of Care) on the same samples at the same time. The hs-cTnI assay has a limit of detection of 1.1 to 1.9 ng/L and a 99th percentile of 26.2 ng/L. The TnI-Nx assay reports results in the range from 1 to 1500 ng/L (with all concentrations measured as greater than 1500 ng/L reported as >1500 ng/L). The TnI-Nx is a new enzyme-linked immunosorbent assay that improves detection of troponin I by leveraging paramagnetic beads and electrochemical detection of the resulting enzyme signal. This assay has a turnaround time of approximately 15 minutes and can be used with plasma or whole blood. Further manufacturer-provided details of the TnI-Nx technology are given in eMethods in Supplement 1. All samples were measured twice on both analyzers from the same thawed aliquot, and the mean concentrations were used in the analysis (eFigure 1 in Supplement 1). Laboratory staff from Abbott Point of Care measured cTnI concentrations with the I-Stat TnI-Nx assay in Christchurch, New Zealand, over a 2-week period in February 2018. Abbott Point of Care and all laboratory staff were blinded to the clinical details, including diagnostic and outcome details of the patients. The TnI-Nx results were provided to the research group’s data analysis team, led by 1 researcher (J.W.P.).

The primary outcome was index presentation type-1 AMI adjudicated by a senior cardiologist blinded to the TnI-Nx results. Classification of AMI was based on the global taskforce universal definition for AMI, requiring evidence of a rise or fall in troponin, with at least 1 concentration above the sex-specific 99th percentile together with evidence of myocardial ischemia (ie, ischemic symptoms, electrocardiogram changes, or imaging evidence).⁷ The serial reference troponin results used for the adjudication of an AMI diagnosis were measured with the hs-cTnI assay as part of usual care.

We assessed discrimination for type 1 AMI by the area under the receiver operator characteristic curve (AUC). We assessed the rule-out potential by calculating the sensitivity, negative predictive value, and the proportion below each TnI-Nx concentration threshold. Statistical calculations were made in R version 3.4.3 (R Foundation for Statistical Computing).

Results

Of 354 patients enrolled, 57 (16.1%) experienced an index AMI. Patients were predominantly men (255 [72.2%]) with a mean (SD) age of 62 (12) years (Table). The first blood sample was taken a median (interquartile range [IQR]) of 4.5 (3-8.1) hours after symptom onset.

Table. Demographics and Presenting Features.

Variable	Entire Cohort (N = 354), No. (%)
Male	255 (72.0)
Age, mean (SD), y	62 (12)
Smoking	46 (13.2)
Blood pressure, mean (SD), mm Hg
Systolic	148 (27)
Diastolic	83 (14)
Comorbidities
Diabetes	46 (13.0)
Dyslipidemia	234 (66.0)
Hypertension	189 (53.3)
Heart failure	19 (5.4)
Myocardial infarction	100 (28.2)
Peripheral vascular disease	21 (5.9)
Angina	159 (44.9)
Coronary artery bypass graft	21 (5.9)
Percutaneous transluminal coronary angiography	106 (29.9)
Transient ischemic attack	12 (3.4)
Time from symptom onset, median (interquartile range), h	4.5 (3-8.1)
Time categories from symptom onset, h
<2	28 (7.9)
2-2.99	57 (16.1)
3-24	269 (76.0)

The TnI-Nx concentrations in samples taken at presentation ranged from 1 to 1500 ng/L, with a median (IQR) of 9 (5-26) ng/L. Among patients with AMI, the range was 11 to 1500 ng/L, and the median (IQR) value was 169 (77-1007) ng/L. The TnI-Nx concentrations at presentation corresponded with the hs-cTnI concentrations at presentation with higher reported concentrations (Figure 1).

Figure 1. A High-Sensitivity Troponin I Assay (hs-cTnI) vs a Novel Point-of-Care Troponin Assay (TnI-Nx) at Patient Presentation.

The minimum reported hs-cTnI concentration is less than 1.9 ng/L, and the maximum reported TnI-Nx concentration is greater than 1500 ng/L. Jittering has been used to avoid overlapping points.

No difference was observed in the AUC between the TnI-Nx assay (0.975 [95% CI, 0.958-0.993]) and the hs-cTnI assay (0.970 [95% CI, 0.949-0.990]; P = .46; eFigures 2 and 3 in Supplement 1). The lowest TnI-Nx concentration on presentation in any patient with an AMI was 11 ng/L, meaning 201 patients (56.7%) had TnI-Nx concentrations less than 11 ng/L, and the sensitivity and negative predictive value for this threshold were both 100%, with 95% CIs of 93.7% to 100% for sensitivity and 98.2% to 100% for negative predictive value (Figure 2). Similarly, the lowest hs-cTnI concentration of any patient with AMI was 3 ng/L, which meant that 154 patients (43.5%) had hs-cTnI concentrations less than 3 ng/L. The sensitivity for this threshold were 100% (95% CI, 93.7%-100%) and the negative predictive value was 100% (95% CI, 97.6%-100%).

Figure 2. Diagnostic Performance of the Thresholds of a Novel Point-of-Care Troponin Assay (TnI-Nx) and a High-Sensitivity Troponin I Assay (hsTnI) to Rule Out Acute Myocardial Infarction.

Sensitivity (white circles), negative predictive value (blue circles), and the percentage below each threshold (shaded area) as a function of the troponin I assay threshold for TnI-Nx (A) and hsc-TnI (B). Values have been offset by ± 0.1 ng/mL for clarity. The dotted line is the threshold below which the sensitivity and negative predictive value are 100%.

Discussion

In this Brief Report, we present the early results of the first assessment of the clinical accuracy of a novel point-of-care troponin I assay (TnI-Nx) to rule out type 1 AMI in the ED. The results suggest that the new TnI-Nx assay has similar clinical sensitivity to hs-cTn assays to accurately enable early rule out after a single baseline blood sample. This is important because it means that it may be possible to safely rule out AMI within 15 minutes of blood draw in the ED for a substantial proportion of patients.

Additional usefulness of this assay is likely to be found outside of the ED, such as in rural hospitals and general practices where there is limited rapid access to laboratory-based troponin assays. A point-of-care assay able to accurately rule out AMI may prevent long and unnecessary transfers to secondary hospitals. Application of the assay within ambulances may also be possible.

We do not describe the TnI-Nx assay as high sensitivity, because that is yet to be established. High-sensitivity designation requires that the assay coefficient of variation at the 99th percentile of a healthy population to be less than 10% and that the assay measure troponin concentrations between the level of detection and the 99th percentile in at least 50% of healthy individuals.⁸ Recently, 1 study has produced evidence that the cardiac troponin I assay Pathfast cTnI-II (LSI Medience Corp) meets these criteria.⁹ The US Food and Drug Administration previously approved this assay to be used as a point-of-care device. To our knowledge, this assay has not been evaluated for the use we describe, with thresholds below the 99th percentile.

Limitations

Because the cohort in this study was small and adjudication was by a single adjudicator, this study should be regarded as preliminary. The positive predictive value has not been presented because this report focused on very early rule-out of AMI and the reference range and 99th percentile of this assay are yet to be established. Also, we did not include in our primary outcome type 2 AMI, although these patients were not excluded. We note that, among patients with a TnI-Nx concentration less than the 11-ng/L threshold, none had hs-cTnI concentrations greater than the hs-cTnI 99th-percentile threshold. This means that, if we had used as our primary outcome type 1 AMI or type 2 AMI rather than only type 1 AMI, the sensitivity and negative predictive value of the assay would not have changed. While the performance to date is good, it should be noted that this study tested plasma rather than whole blood and that we did not directly compare the turnaround time of this assay within the ED with that of the central laboratory assay. Additional studies are needed to assess whole-blood and bedside performance, cost-effectiveness, performance as a function of time from symptom onset, and performance in conjunction with clinical risk scores and electrocardiogram as well as create validated decision-making thresholds. The decision-making threshold of 11 ng/L was used in this study only for illustrative purposes and for comparison with a similarly derived hs-cTnI threshold. To establish a validated diagnostic threshold for TnI-Nx will require data sets with more patients with AMI and a threshold determination and validation method that accounts for random sampling.¹⁰

Conclusions

The I-Stat TnI-Nx assay represents an advance in point-of-care troponin technology. This preliminary study suggests its performance could enable it to be used to rapidly and safely to rule out myocardial infarction in a large proportion of patients with symptoms suggestive of acute coronary syndrome.

Supplement 1.

eMethods. The manufacturer’s description if the I-Stat TnI-Nx point of care assay.

eFigure 1. Analytical performance of assays on presentation to the ED.

eFigure 2. Diagnostic performance of assays on presentation to the ED.

eFigure 3. Receiver Operator Characteristic curves for diagnosis of AMI on presentation to the ED.

Supplement 2.

Data Sharing Statement.