Cardiology/original research
Performance of Novel High-Sensitivity Cardiac Troponin I Assays for 0/1-Hour and 0/2- to 3-Hour Evaluations for Acute Myocardial Infarction: Results From the HIGH-US Study

Presented at the American Association for Clinical Chemistry annual scientific meeting, August 2018, Chicago, IL; the American College of Cardiology scientific meeting, March 2019, New Orleans, LA; and the Society for Academic Emergency Medicine meeting, May 2019, Las Vegas, NV.
https://doi.org/10.1016/j.annemergmed.2019.12.008Get rights and content

Study objective

We determine the accuracy of high-sensitivity cardiac troponin I (hs-cTnI), European-derived, rapid, acute myocardial infarction, rule-out/rule-in algorithms applied to a US emergency department (ED) population.

Methods

Adults presenting to the ED with suspected acute myocardial infarction were included. Plasma samples collected at baseline and between 40 and 90 minutes and 2 and 3 hours later were analyzed in core laboratories using the Siemens Healthineers hs-cTnI assays. Acute myocardial infarction diagnosis was independently adjudicated. The sensitivity, specificity, and negative and positive predictive values for rapid acute myocardial infarction rule-out/rule-in using European algorithms and 30-day outcomes are reported.

Results

From 29 US medical centers, 2,113 subjects had complete data for the 0/1-hour algorithm analyses. With the Siemens Atellica Immunoassay hs-cTnI values, 1,065 patients (50.4%) were ruled out, with a negative predictive value of 99.7% and sensitivity of 98.7% (95% confidence interval 99.2% to 99.9% and 96.3% to 99.6%, respectively), whereas 265 patients (12.6%) were ruled in, having a positive predictive value of 69.4% and specificity of 95.7% (95% confidence interval 63.6% to 74.7% and 94.7% to 96.5%, respectively). The remaining 783 patients (37.1%) were classified as having continued evaluations, with an acute myocardial infarction incidence of 5.6% (95% confidence interval 4.2% to 7.5%). The overall 30-day risk of death or postdischarge acute myocardial infarction was very low in the ruled-out patients but was incrementally increased in the other groups (rule-out 0.2%; continued evaluations 2.1%; rule-in 4.8%). Equivalent results were observed in the 0/2- to 3-hour analyses and when both algorithms were applied to the hs-cTnI ADVIA Centaur measurements.

Conclusion

The European rapid rule-out/rule-in acute myocardial infarction algorithm hs-cTnI cut points can be harmonized with a demographically and risk-factor diverse US ED population.

Introduction

Accelerated diagnostic protocols with testing intervals as short as 1 hour and integrating high-sensitivity cardiac troponin (hs-cTn) assays to aid in the diagnosis of acute myocardial infarction have been incorporated into European guidelines and validated in cohorts from European countries and elsewhere.1, 2, 3, 4, 5 hs-cTn Assays have been recently approved for use in the United States.6 The differences between acute myocardial injury and acute myocardial infarction are highlighted in the recent “Fourth Universal Definition of Myocardial Infarction” document.7 In our report, the diagnosis of myocardial injury was not considered by the adjudication committee; only the diagnosis of acute myocardial infarction was considered. In the United States, many clinicians view the introduction of hs-cTn assays for acute myocardial infarction diagnosis with trepidation. Lower acute myocardial infarction rates are reported in patients undergoing evaluation in US emergency departments (EDs) compared with other regions of the world.8, 9, 10 This observation is also supported by recent publications from single-center urban academic medical centers.11, 12, 13

Editor’s Capsule Summary

What is already known on this topic

Accelerated diagnostic protocols for acute myocardial infarction using high-sensitivity cardiac troponin (hs-cTn) assays have been developed and validated in European and Australasian populations.

What question this study addressed

What is the diagnostic accuracy of hs-cTn accelerated protocols for acute myocardial infarction in a US emergency department population?

What this study adds to our knowledge

In a US population, hs-cTn accelerated protocols have high sensitivity at the rule-out threshold and high specificity at the rule-in threshold used in European studies.

How this is relevant to clinical practice

hs-cTn Accelerated protocols are validated in the US population and can be used to guide practice if the reported sensitivity and specificity are considered acceptable.

It is unknown whether the high sensitivity and negative predictive value of hs-cTn assays with acceptable positive predictive value and specificity that were observed in European cohorts will be maintained in more diverse US populations.

The goal of the present study was to evaluate the performance of new high-sensitivity cardiac troponin I (hs-cTnI) assays from Siemens Healthineers on the Atellica Immunoassay Analyzer (Siemens Healthineers, Walpole, MA)14 and the ADVIA Centaur XP (Siemens Healthineers) system15 in the High-Sensitivity Cardiac Troponin I in the United States (HIGH-US) study. To evaluate harmonizing algorithms globally, we used the specific cut points from a rapid 0/1-hour and 0/2- to 3-hour rule-out/rule-in algorithm validated in a western European population1 and assessed the negative and positive predictive value in a multicenter US population. We hypothesized that these hs-cTnI assays would demonstrate very high negative predictive values and acceptable positive predictive values, with baseline and interval testing in as little as 1 hour in US ED patients, despite anticipated demographic and risk-factor diversity compared with European and other cohorts outside the United States.

Section snippets

Study Design and Setting

In the HIGH-US study, adults aged 22 years and older who presented to the ED with any suspected acute myocardial infarction prompting the clinical ordering of a cardiac troponin level test and who signed consent were prospectively enrolled in a Food and Drug Administration (FDA) 510(k) study. The EDs were located in 29 centers across the United States in both tertiary urban settings and community hospitals (Figure E1, available online at http://www.annemergmed.com). In accordance with

Results

Our reported results are specifically those of the hs-cTnI assay using plasma on the Atellica Immunoassay Analyzer. No significant differences were found for the 0/1- and 0/2- to 3-hour algorithms when the Atellica Immunoassay Analyzer and the ADVIA Centaur XP system values and the plasma and serum measurements were compared (Figures E2 and E3 and Tables E1 and E2, available online at http://www.annemergmed.com).

Limitations

First, although the HIGH-US study was designed to be inclusive of a broad demographic, we cannot say with confidence that these results apply to nonblack or nonwhite races because relatively few of these patients were enrolled. Second, if hs-cTnI and not a variety of contemporary troponin assays had been used to adjudicate for acute myocardial infarction diagnosis, the positive predictive value and number of ruled-in acute myocardial infarctions of the algorithms may have been higher. The

Discussion

Several hs-cTn assays are now approved by the FDA for use in the United States to aid in the diagnosis of acute myocardial infarction, and more are expected in the near term. To our knowledge, this is the first US-based multicenter prospective study to report the efficacy of rapid hs-cTn algorithms in a US ED population representative of the diversity and heterogeneity of the intended use population. However, the percentage of blacks enrolled (40%) was higher than the 17% to 19% black

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    Please see page 2 for the Editor’s Capsule Summary of this article.

    Supervising editor: Steve Goodacre, PhD. Specific detailed information about possible conflict of interest for individual editors is available at https://www.annemergmed.com/editors.

    Author contributions: All authors made substantial contributions to the study, were involved in drafting the article and critically revising it for intellectual content and accuracy, and approved the final version of the article submitted for publication. RMN, RHC, FSA, AJS, AL, and CRd conceived and designed the study and acquired results. RMN, RHC, FSA, AJS, AL, WFP, and CRd analyzed the results and wrote the article. GD was responsible for the statistical analyses. RMN takes responsibility for the paper as a whole.

    All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    Funding and support:By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The HIGH-US study was funded by Siemens Healthcare Diagnostics Inc. Dr. Nowak has received fees from Siemens Healthineers as a consultant for the design and conduct of this trial. He has been or is a consultant for Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Ortho Clinical Diagnostics, and Abbott. Dr. Christenson has received fees from Siemens Healthineers for consultancy work on design and conduct of high-sensitivity cardiac troponin I clinical trials and is a consultant for Siemens Healthineers, Roche Diagnostics, Quidel Diagnostics, and Beckman Coulter. Dr. McCord has received research support from Roche, Siemens Healthineers, Abbott, and Beckman Coulter and has served as a consultant for Roche and Siemens Healthineers. Dr. Apple reports serving on the board of directors for HyTest Ltd and the advisory board for Siemens Healthcare and Instrumentation Laboratory. He reports serving as a consultant for LumiraDx; he has served as a nonsalaried principle investigator through Hennepin Healthcare Research Institute for Abbott Diagnostics, Abbott Point of Care, Roche Diagnostics, Siemens Healthcare, Quidel/Alere, Ortho Clinical Diagnostics, and Beckman Coulter. He reports serving as an associate editor for Clinical Chemistry. Dr. Singer reports serving as a consultant for Jansen, Pfizer, BNS, and AstraZeneca. Dr. Limkakeng reports receiving grant funding from Roche Diagnostics, Abbott Laboratories, Bristol-Myers Squibb, Ischemia Care, LTD, and GE AstraZeneca; and serving as a consultant for BioMérieux and ZS Pharma. Dr. Peacock reports receiving research grants from Abbott, BrainCheck, ImmunArray, Janssen, Ortho Clinical Diagnostics, Relypsa, and Roche; serving as a consultant for Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Ischemia Care, Dx, ImmunArray, Instrument Labs, Janssen, Nabriva Therapeutics, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens Healthineers; and providing expert testimony for Johnson & Johnson. He also reports stock/ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Association LLC, Emergencies in Medicine LLC, and Ischemia DC LLC. Dr. deFilippi reports receiving research support from Inova; serving as a consultant for Abbott Diagnostics, Fujirebio, Metabolomics, Ortho Diagnostics, Roche Diagnostics, and Siemens Healthineers; receiving honoraria from WebMD; and receiving royalties from UpToDate.

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