Single Troponin Measurement to Rule Out Myocardial Infarction

JACC Review Topic of the Week

Allan S. Jaffe, MD; Richard Body, MD; Nicholas L. Mills, MD; Kristin M. Aakre, PHD; Paul O. Collinson, MD; Amy Saenger, PHD; Ole Hammarsten, MD; Ryan Wereski, MD; Torbjørn Omland, MD; Yader Sandoval, MD; Jordi Ordonez-Llanos, MD, PHD; Fred S. Apple, PHD

Disclosures

J Am Coll Cardiol. 2023;82(1):60-69.

Abstract and Introduction

Abstract

The term "single-sample rule-out" refers to the ability of very low concentrations of high-sensitivity cardiac troponin (hs-cTn) on presentation to exclude acute myocardial infarction with high clinical sensitivity and negative predictive value. Observational and randomized studies have confirmed this ability. Some guidelines endorse use of a concentration of hs-cTn at the assay's limit of detection, while other studies have validated the use of higher concentrations, allowing this approach to identify a greater proportion of patients at low risk. In most studies, at least 30% of patients can be triaged with this approach. The concentration of hs-cTn varies according to the assay used and sometimes how regulations permit reporting. It is clear that patients need to be at least 2 hours from the onset of symptoms being evaluated. Caution is warranted, particularly with older patients, women, and patients with underlying cardiac comorbidities.

Introduction

A major advance associated with high-sensitivity cardiac troponin (hs-cTn) assays is the ability to exclude acute myocardial infarction (MI) safely and rapidly.^[1,2] This ability has the potential to rapidly identify patients in which the likelihood of MI is low and short-term outcomes should be good. If the approach has adequate sensitivity, it will allow patients to be safely discharged from emergency departments (ED) earlier.^[1,2] This ability will alleviate ED overcrowding. The data are persuasive that when there are too many ED patients and wait times are long, all patients, regardless of their diagnoses, are at increased risk for adverse events, including mortality.^[3,4] ED overcrowding also has a negative impact on patient satisfaction.^[5]

hs-cTn assays detect low concentrations of cardiac troponin (cTn) with improved analytical precision.^[6] This allows thresholds below the 99th-percentile upper reference limit to be probed. By setting the cutoff below the limit of detection (LoD) of the assay (ie, the lowest concentration measured that is different from zero), it is possible to exclude myocardial injury and thus MI with a single blood test on arrival to the ED.^[2] This approach is used in patients who are clinically at low risk. This is a key component of its success.

The initial studies in this area were observational. Many did not include consecutive patients, and in some studies the time from symptom onset to sample acquisition was delayed for informed consent.^[7] The metrics for ruling out MI differ when one has complete ascertainment rather than a selected cohort because the frequency of MI and thus the pretest probability of disease are less in the unselected cohort.^[8] In addition, the low values obtained may or may not result in patient discharge. Thus, observational studies cannot evaluate the real-world impact of implementing these early rule-out strategies. This can be done in randomized implementation trials, which we strongly endorse.^[9]

The present review is part of an educational series from the International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Applications of Cardiac Bio-Markers concerning the use of cardiac biomarkers. The report focuses on the single-sample rule-out and its potential benefits and limitations. Although we review available data, the report is not a guideline or a meta-analysis. Instead it provides readers with an understanding of the approach and recommendations to facilitate its optimal use.

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Next Section

Abstract and Introduction
Safety Metrics Required for the Single-sample Rule-out
The Single-sample Rule-out
Clinical Studies
Conclusions
References
Sidebar

Table 1. Imprecision and Rounding Associated With Various Cardiac Troponin Cutoff Concentrations
Threshold, ng/L	Retain, ng/L	CVa, %	Discharge, ng/L	CVa, %
1	1.5	25.5	0.4	30.6
2	2.5	12.8	1.4	15.3
3	3.5	8.5	2.4	10.2
4	4.5	6.4	3.4	7.7
5	5.5	5.1	4.4	6.1
6	6.5	4.3	5.4	5.1
7	7.5	3.6	6.4	4.4
8	8.5	3.2	7.4	3.8
9	9.5	2.8	8.4	3.4
10	10.5	2.6	9.4	3.1
11	11.5	2.3	10.4	2.8
12	12.5	2.1	11.4	2.6

At a concentration of 3 ng/L, patients will be admitted with a cardiac troponin concentration of 3.5 ng/L or greater (upper threshold 0.5 ng/L), thus CVa = (0.5/3) × 100 (16.7%); discharge will be at 2.4 ng/L (minimum lower threshold 0.6 ng/L), thus CVa = (0.6/3) × 100 (20.0%).
CVa = coefficient of analytical variation.

Table 2. Single-Sample Rule-Out Threshold Values for Commercially Available High-Sensitivity Cardiac Troponin Assays
Assay	Threshold, ng/L	n	Proportion Ruled Out, %	Outcome Prevalence, %	Rule-Out Performance						Outcome	First Author
Assay	Threshold, ng/L	n	Proportion Ruled Out, %	Outcome Prevalence, %	NPV (95% CI)	Sensitivity (95% CI)	TN	FN	TP	FP	Outcome	First Author
Abbott ARCHITECT STAT (hs-cTnI)	<5	3,799	61^a	3.8^a	99.6 (99.3–99.8)	^a	2,302	9	136	1,352	Type 1 MI or cardiovascular death at 30 d	Shah et al¹³
	<5	32,837	71^a	1.6^a	99.8 (99.7–99.8)	^a	23,205	55	462	9,115	Type 1 MI or cardiovascular death at 30 d	Bularga et al⁵³
	<5	1,326	50	19.9	98.9 (98.2–99.6)	94.7 (91.4–98.1)	803	9	162	352	Type 1 MI or cardiovascular death at 30 d	Sandoval et al⁵⁴
	<5	18,601	49	12.5	99.5 (99.3–99.7)	98.0 (96.4–98.9)	9,081	49	2,268	7,203	Type 1 MI or cardiovascular death at 30 d	Chapman et al⁵⁵
	<2	1,631	27	10.5	99.6 (98.9–100)	98.8 (97.2–100)	442	2	169	1,018	Type 1 MI or cardiovascular death at 30 d	Sandoval et al⁵⁴
	<2	971	23	13.1	99.3 (97.4–99.8)	98.4 (94.4–99.8)	219	3	124	625	NSTEMI during index hospitalization	Tjora et al⁵⁶
Siemens ADVIA, Centaur (hs-cTnI)	<5	2,212	46	12.5	99.6 (99.2–100)	98.6 (97.2–100)	1,040	4	273	895	Acute MI or cardiovascular death at 30 d	Sandoval et al⁴³
Siemens ADVIA, Centaur (hs-cTnI)	<2	2,212	21	12.5	99.8 (99.3–100)	99.6 (98.9–100)	455	1	276	1,480	Acute MI or cardiovascular death at 30 d	Sandoval et al⁴³
Siemens Atellica IM (hs-cTnI)	<5	2,212	47	12.5	99.6 (99.2–100)	98.6 (97.2–100)	1,015	4	273	920	Acute MI or cardiovascular death at 30 d	Sandoval et al⁴³
Siemens Atellica IM (hs-cTnI)	<2	2,212	23	12.5	99.6 (99.1–100)	99.3 (98.3–100)	505	2	275	1,430	Acute MI or cardiovascular death at 30 d	Sandoval et al⁴³
Beckman Coulter Access (hs-cTnI)	<2	1,871	34	5.2	99.8 (99.1–100)	99.0 (94.4–100)	637	1	97	1,136	Type 1 MI or cardiac mortality during index hospitalization	Greenslade et al⁴⁴
Beckman Coulter Access (hs-cTnI)	<4	686	30	15.0	100 (98.2–100)	100 (96.5–100)	206	0	106	374	NSTEMI during index hospitalization	Boeddinghaus et al⁵⁷
Roche Elecsys Gen 5 (hs-cTnT)	<5	971	31	12.1	99.3 (97.4–99.8	98.4 (94.4–99.8)	296	2	125	625	NSTEMI during index hospitalization	Tjora et al⁵⁶
	<5	9,241	31	15.4	99.3 (97.3–99.8)	98.7 (96.6–99.5)	2,811	14	1,409	5,007	Index MI	Pickering et al³³
	<3	7,651	20	17.0	99.0 (93.7–99.8)	99.1 (97.4–99.7)	1,495	7	1,293	4,856	Index MI	Pickering et al³³
Roche Elecsys Gen 5 (hs-cTnT) (U.S. only)	<6	1,979	32	7.0	99.8 (99.1–100)	99.3 (96.1–100)	623	1	140	1,215	Adjudicated index MI	Sandoval et al³²

^aAnalysis population restricted to patients with a presentation concentration of high-sensitivity cardiac troponin below the sex-specific 99th-percentile threshold.
FN = false negative; FP = false positive; MI = myocardial infarction; NPV = negative predictive value; NSTEMI = non–ST-segment elevation myocardial infarction; TN = true negative; TP = true positive.

Authors and Disclosures

Allan S. Jaffe, MD^a,b, Richard Body, MD^c,d,e, Nicholas L. Mills, MD^f,g, Kristin M. Aakre, PHD^h,i,j, Paul O. Collinson, MD^k,l,m, Amy Saenger, PHD^n,o, Ole Hammarsten, MD^p, Ryan Wereski, MD^f, Torbjørn Omland, MD^q,r, Yader Sandoval, MD^s, Jordi Ordonez-Llanos, MD, PHD^t,u and Fred S. Apple, PHD^n,o, on behalf of the IFCC Committee on Cardiac Bio-Markers

^aDepartment of Cardiology, Mayo Clinic, Rochester, Minnesota, USA; ^bDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; ^cEmergency Department, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; ^dDivision of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; ^eHealthcare Sciences Department, Manchester Metropolitan University, Manchester, United Kingdom; ^fUsher Institute, University of Edinburgh, Edinburgh, United Kingdom; ^gBritish Heart Foundation/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; ^hDepartment of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; ⁱDepartment of Heart Disease, Haukeland University Hospital, Bergen, Norway; ^jDepartment of Clinical Science, University of Bergen, Bergen, Norway; ^kDepartment of Clinical Blood Sciences, St George's University Hospitals NHS Foundation Trust, London, United Kingdom; ^lDepartment of Cardiology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom; ^mSt George's University of London, London, United Kingdom; ⁿDepartment of Laboratory Medicine and Pathology, Hennepin Healthcare/Hennepin County Medical Center, Minneapolis, Minnesota, USA; ^oDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA; ^pDepartment of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden; ^qDepartment of Cardiology, Akershus University Hospital, Lørenskog, Norway; ^rInstitute of Clinical Medicine, University of Oslo, Oslo, Norway; ^sMinneapolis Heart Institute, Abbott Northwestern Hospital, and Minneapolis Heart Institute Foundation, Minneapolis, Minnesota, USA; ^tClinical Biochemistry Department, Hospital de Sant Pau, Barcelona, Spain; and the ^uFoundation for Biochemistry and Molecular Pathology, Barcelona, Spain.

Address For Correspondence
Dr Allan S. Jaffe, Department of Cardiovascular Diseases, Mayo Clinic, Gonda Vascular Center, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: jaffe.allan@mayo.edu.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Funding Support and Author Disclosures
Dr Mills is supported by the British Heart Foundation through a Chair Award (CH/F/21/90010), a Programme Grant (RG/20/10/34966), and a Research Excellent Award (RE/18/5/34216). Dr Jaffe has consulted for Abbott, Beckman Coulter, Siemens, Roche, Ortho Diagnostics, ET Healthcare, SphingoTec, Radiometer, SpinChip, LumiraDX, Astellas, Amgen, Novartis, and RCE Technologies; and holds patent 20210401347 along with others. Dr Body has received consulting fees from Roche, Aptamer Group, Abbott, Psyros Diagnostics, Siemens Healthineers, Beckman Coulter, and Radiometer; and has participated on advisory boards for the FORCE Trial (funded by the National Institute for Health and Care Research), the REWIRE trial (Queen Mary University), the PRONTO trial (funded by the National Institute for Health and Care Research), and LumiraDx. Dr Mills has received research grants from Abbott Diagnostics and Siemens Healthineers; and has received personal fees for participation on advisory boards or speaking from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, LumiraDx, and Psyros Diagnostics. Dr Aakre is an associate editor of Clinical Biochemistry; is chair of the International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Applications of Cardiac Bio-Markers; has served on advisory boards for Roche Diagnostics and SpinChip; has received consulting honoraria from CardiNor; has received lecture honorarium from Siemens Healthineers and Snibe Diagnostics; and has received research grants from Siemens Healthineers and Roche Diagnostics. Dr Collinson is an associate editor of the Journal of Applied Laboratory Medicine; is an advisory board member for Psyros Diagnostics; and has previously advised LumiraDX, Radiometer, and Siemens. Dr Saenger has received consulting fees from Radiometer. Dr Hammarsten has stock options with Aligned Bio. Dr Omland has received consulting fees from Roche, Bayer, and CardiNor; has received honoraria from Roche; has a patent pending with Roche; has participated on advisory boards for Bayer and Roche; has a fiduciary role with CardiNor; holds stock in CardiNor; and has received equipment and material from Novartis and Abbott. Dr Sandoval has been on advisory boards and has served as a speaker for Abbott Diagnostics and Roche Diagnostics; and holds patent 20210401347 along with others. Dr Ordonez-Llanos has received consulting fees from AWE Medical and Hemcheck. Dr Apple has received consulting fees from HyTest and AWE Medical; has received advisory fees from Werfen, Siemens Healthineers, and Qorvo Biotechnology; has received nonsalaried grant support through the Hennepin Healthcare Research Institute from Abbott Diagnostics, Abbott POC, Roche Diagnostics, Siemens Healthineers, Quidel/Ortho, Becton Dickinson, and Beckman Coulter; and has received fees for serving as associate editor for Clinical Chemistry. Dr Wereski has reported that he has no relationships relevant to the contents of this paper to disclose.