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Clinical applications of high-sensitivity troponin testing: from diagnosis to prognosis

Evan J. Wiens, MD MSc FRCPC, Megan Deviaene, MD, Ashish H. Shah, MD MD-
Res(UK) FRCP(UK)

PII: S0828-282X(22)00316-6
DOI: https://doi.org/10.1016/j.cjca.2022.05.008
Reference: CJCA 4346

To appear in: Canadian Journal of Cardiology

Received Date: 1 December 2021

Revised Date: 2 May 2022
Accepted Date: 4 May 2022

Please cite this article as: Wiens EJ, Deviaene M, Shah AH, Clinical applications of high-sensitivity
troponin testing: from diagnosis to prognosis, Canadian Journal of Cardiology (2022), doi: https://
doi.org/10.1016/j.cjca.2022.05.008.

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© 2022 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.

Clinical applications of high-sensitivity troponin testing: from diagnosis to prognosis

Evan J Wiens MD MSc FRCPC1,2, Megan Deviaene MD1, Ashish H Shah MD MD-Res(UK)
FRCP(UK)1,2

1. Department of Internal Medicine, University of Manitoba, Winnipeg, Canada

2. Section of Cardiology, University of Manitoba, Winnipeg, Canada

Corresponding author:

Evan J. Wiens MD, MSc, FRCPC

Clinical Fellow
Section of Cardiology
Department of Internal Medicine
Max Rady College of Medicine, University of Manitoba
Room Y3500-11, St. Boniface Hospital
409 Tache Ave
Winnipeg, Manitoba, Canada, R2H 2A6
C: 204-470-3855 F: 204-233-2157
ewiens4@manitoba-physicians.ca

Short title: Applications of high-sensitivity troponin testing

Disclosures/funding sources: None

Brief Summary

High-sensitivity cardiac troponin (hs-cTn) is critical in the diagnosis of acute coronary

syndrome. However, it can also inform risk of cardiovascular events and mortality. Patients with
unstable angina and normal-range hs-cTn have a very favorable short-term prognosis and do not
appear to suffer increased risk of cardiovascular events and mortality. Such patients can often be
treated in the outpatient setting
Introduction

High-sensitivity cardiac troponin (hs-cTn) testing is critical in the evaluation of

patients with chest pain. Interestingly, the value of hs-cTn extends beyond the acute setting

and can provide prognostic information. Patients with ischemic cardiac chest pain without

elevation of hs-cTn have been shown to be at exceptionally low risk of suffering an adverse

event, including acute myocardial infarction (AMI) or mortality, in the short-term.

Current evidence suggests that unstable angina with negative troponin is a benign entity

acutely and may be managed safely in the outpatient setting, which can be beneficial for

patients and the healthcare system.

Acute coronary syndrome (ACS), encompassing ST-elevation myocardial infarction

(STEMI), non-STEMI (NSTEMI), and unstable angina (UA) is a high-risk condition requiring

prompt attention and management. STEMI is an electrocardiographic diagnosis, whereas

biomarkers play an important role in diagnosing NSTEMI given the varying and sometimes

atypical symptomatology and low sensitivity of the electrocardiogram (EKG). Historically used

biomarkers, such as aspartate aminotransferase beginning in the 1960s, followed by lactate

dehydrogenase, creatine kinase, and myoglobin were limited by lack of sensitivity and

specificity. Cardiac troponin, a protein comprising part of the myofibrillar apparatus involved in

cardiomyocyte contraction, emerged as a cardiac biomarker in the late 1990s. High-sensitivity

assays detecting troponin isoforms T and I are clinically equivalent and are both remarkably

specific for cardiac injury, although not necessarily defining injury caused by ischemia only.1

hs-cTn elevation (>99th percentile of a reference population) with an acute rise or fall is a

requirement for diagnosis of NSTEMI in the Fourth Universal Definition of Myocardial

Infarction and in current guidelines.2 Furthermore, the presence or absence of biomarker

elevation has long been used to divide NSTEMI and unstable angina (UA) in patients with

cardiac-sounding chest pain (Figure 1). However, contemporary data suggests the value of hs-

cTn extends beyond just ruling-in NSTEMI, and can actually rule-out adverse cardiac events

including mortality in the short- to mid-term with excellent reliability. This article focuses on

how hs-cTn testing can assist with prognostication and risk-stratification in patients with

suspected ACS and, importantly, challenge the longstanding dichotomous division of UA and

NSTEMI.

hs-cTn for Risk Stratification in Patients with Suspected ACS

It is important to accurately diagnose NSTEMI in patients presenting with chest pain,

since NSTEMI is associated with a high risk of mortality in the short-term.3 However, in

healthcare systems with limited capacity in the emergency department (ED) and hospital, it is

beneficial to be able to rapidly rule-out NSTEMI to facilitate safe, expeditious discharge.

In the last decade, multiple retrospective and prospective studies have attempted to define

situations in which a very low or unchanging hs-cTn level rules out any subsequent hs-cTn rise,

thereby ruling out NSTEMI, which requires an acute rise or fall in hs-cTn for diagnosis.2 hs-cTn

rises rapidly in NSTEMI, typically within 1 hour of symptoms, and various strategies have been

found to rule-out NSTEMI with very high sensitivity and negative predictive value; such

strategies have been adopted in European Society of Cardiology (ESC) guidelines (Figure 1).2

Such strategies rely on hs-cTn values at presentation to the ED either in isolation, or with

subsequent hs-cTn values 1- or 2-hours after. Reference values are assay-specific and are

validated for both hs-cTnT and hs-cTnI (Figure 1). These values were derived from clinical

outcome studies and are significantly lower than the assay upper limit of normal as determined

by the 99th percentile of a reference population; taking Roche Elecsys hs-cTnT as an example,
the “very-low’ rule-out value is <5 ng/L, the 1-hour rule-out is <12 ng/L, and the 99th percentile

upper limit of normal is <14 ng/L. When properly applied, patients who meet such rule-out

criteria will not have a subsequent significant rise in hs-cTn or be diagnosed with NSTEMI, and

can likely be managed as outpatients provided life-threatening non-cardiac causes of chest pain

have been ruled out.2

Although rapidly ruling-out NSTEMI is important, when discharging a patient from the

ED one wants to be confident that they will not suffer an adverse event in the future, such as

ACS or mortality, that could have been prevented by hospital admission and expedited invasive

management. Because of this, patients with UA are often admitted to hospital and treated with

interventions such as anticoagulation and coronary angiography3 that may be unnecessary and

are associated with risk.2

Fortunately hs-cTn assays, along with clinical judgment,4 can be useful to inform short-

term risk, reassure the healthcare provider and the patient, and often obviate the need for

inpatient evaluation. As an example, a prospective study evaluating 1167 patients incorporated

clinical evaluation by the ED physicians into the 1-hour hs-cTnT algorithm (Roche Elecsys).

When applied in patients judged by ED physicians to be at “low-risk” for ACS with a “low-risk”

EKG, the 1-hour rule-out hs-cTn algorithm excluded AMI and mortality at 30 days with 100%

negative predictive value (NPV).4 These findings were confirmed by Chew et al. subsequently in

the RAPID-TnT randomized clinical trial, which showed that the 1-hour hs-cTnT protocol was

non-inferior to standard of care for ruling-out AMI and mortality at 30 days, but was associated

with reduced length-of-stay in the ED. Similarly, various studies have demonstrated that a single

very low hs-cTn (below the level of detection) can rule out adverse events at 30-days as well as

at 1 year,2,3 although the usefulness of this strategy is limited in jurisdictions such as the United
States where the lower limit at which hs-cTn is permitted to be reported is higher than the

concentrations required for rapid rule-out algorithms.

Recent prospective studies have evaluated the real-world implementation of rule-out

algorithms.2,5 Among 1588 patients who satisfied the hs-cTnT rule-out algorithm (Roche Cobas

E 411), 76.1% were discharged directly from the ED, reducing the average length of stay in the

ED by >2 hours. Importantly, these rapid discharges were safe; among the 1309 patients

discharged directly from the ED, only 1 suffered mortality at 30 days (due to lung cancer). The

performance of the hs-cTnI algorithms has also been assessed, including by Nowak et al. in the

HIGH-US study (Siemens Healthineers Atellica Immunoassay Analyzer and ADVIA Centaur

XP), in which the suggested algorithms successfully ruled-out AMI and mortality at 30-days

with >99% NPV in a diverse real-world population in the United States.

It is clear that the algorithms reflected in the current guidelines2 can identify patients at

exceptionally low risk of suffering an adverse event in the short term, particularly when used in

conjunction with clinical assessment and EKG. Such low-risk patients warrant appropriate

workup and follow-up; however, in the absence of significantly limiting angina, healthcare

providers can confidently manage these patients in an outpatient setting.

It is important to note that although upper reference limits for hs-cTn differ between

males and females, current guidelines do not incorporate sex-specific hs-cTn reference values

and are applied without reference to sex.2 Ongoing study is required to determine how to

optimally incorporate sex differences into these diagnostic algorithms.

Beyond its value in patients with chest pain, hs-cTn level is correlated with increased risk

of hypertension, coronary artery disease, heart failure, and death in the general population.1 hs-

cTn elevation >99th percentile is associated with a greater than twofold increase in risk of cardiac
events among patients with chronic kidney disease.2 In addition, such elevations are associated

with increased morbidity and mortality in patients with chronic heart failure; stable coronary

disease; and hypercholesterolemia, in which statin therapy has been associated with reduction in

hs-cTn levels and better clinical outcomes.1

Unstable Angina in the Era of hs-cTn

Non-ST elevation ACS (NSTE-ACS) has traditionally been divided into NSTEMI and

UA (Figure 1), with UA being defined as chest pain, felt to be cardiac in nature, that is new in

onset or of increased frequency or intensity but not associated with a rise or fall in cardiac

biomarkers. As the use of hs-cTn assays has become more widespread, the incidence of NSTEMI

has increased and UA concordantly decreased; hs-cTn assays are now detecting small NSTEMIs

which would have been diagnosed as UA with previous biomarkers.2 Therefore, the traditional

dichotomy differentiating NSTEMI and UA may no longer be relevant. This is exemplified by

the almost perfect NPV of hs-cTn in excluding short-term morbidity and mortality as discussed

above, in direct contrast to the frequent adverse outcomes observed in patients with NSTEMI.2,3

This suggests that unstable angina with hs-cTn concentrations below the 99th percentile is benign

in the short term and a distinct clinical entity from hs-cTn-positive UA or NSTEMI, as opposed

to existing within the spectrum of NSTE-ACS as it traditionally has.

This was demonstrated in a substudy of RAPID-CPU.3,5 Patients meeting diagnostic

criteria for NSTEMI had a high risk of mortality exceeding 10% at 12 months. Patients who had

UA and a stably elevated (>99th percentile) hs-cTn that was non-diagnostic for NSTEMI (did not

rise or fall) had a mortality rate exceeding 5% at 12 months. By contrast, patients diagnosed with

UA and normal-range hs-cTn (<99th percentile but higher than level of detection) had mortality

rates of only 1.9% at 12 months, and patients with UA and hs-cTnT below level-of-detection had
mortality rates of 0% at 12 months (Figure 2). Patients with UA and hs-cTn <99th percentile had

lower rates of mortality than patients diagnosed with non-ACS chest pain. However, even in the

very-low risk group the prevalence of significant coronary artery disease requiring

revascularization was >30%,3 underscoring the need for appropriate investigation and follow-up.

Therefore, it may be more prognostically relevant to divide NSTE-ACS patients into

NSTEMI, UA with positive (but stable) hs-cTn, and UA with negative hs-cTn (normal range or

below level-of-detection), with the latter group representing a very low-risk group whose cardiac

care can be managed in an outpatient setting.2 It must be emphasized that, in all cases, STEMI

must be ruled-out and other non-cardiac causes of chest pain should be adequately investigated.

Although patients suspected to have chest pain related to coronary artery disease must be

investigated appropriately and treated with guideline-directed medical therapy, including

revascularization, the diagnosis of coronary artery disease does not necessarily need to be made

in an ED or inpatient setting. Indeed, in increasingly resource-limited health systems,

maximizing the services deliverable in the outpatient domain is of great importance, and is often

a preferable course of action for patients. In practice, this means that most patients suspected of

new or worsening angina without elevated hs-cTn, consistent with a diagnosis of UA with

negative hs-cTn, do not need admission to hospital provided their symptoms are manageable at

home. These patients, and their healthcare providers, can be reassured that they are not at

increased risk of AMI or mortality in the short term.

Conclusion

In the era of hs-cTn assays, UA is being diagnosed increasingly less frequently as the

sensitivity for detecting NSTEMI increases.2 Furthermore, there appear to exist distinct

prognostic strata within the UA population that are directly related to hs-cTn levels (Figure 2),3
and it may be more clinically relevant to classify and treat UA patients based on whether they

have elevation in hs-cTn or not. Further research is required to better define optimal treatment of

these varied patient groups, including the utility of intensified antithrombotic therapy and

coronary angiography in patients with UA with negative hs-cTn.

References

1. Park KC, Gaze DC, Collinson PO, Marber MS. Cardiac troponins: from myocardial infarction

to chronic disease. Cardiovasc Res. 2017;113:1708-18.

2. Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL et al. 2020 ESC

Guidelines for the management of acute coronary syndromes in patients presenting

without persistent ST-segment elevation: The Task Force for the management of acute

coronary syndromes in patients presenting without persistent ST-segment elevation of the

European Society of Cardiology (ESC.) Eur Heart J. 2021;42:1289-1367.

3. Giannitsis E, Biener M, Hund H, Mueller-Hennessen M, Vadaie M, Gandowitz J et al.

Management and outcomes of patients with unstable angina with undetectable, normal, or

intermediate hsTnT levels. Clin Res Cardiol. 2020;109:476-87.

4. Mokhtari A, Borna C, Gilje P, Tydén P, Lindahl B, Nilsonn H-J et al. A 1-h Combination

Algorithm Allows Fast Rule-Out and Rule-In of Major Adverse Cardiac Events. J Am

Coll Cardiol. 2016;67:1531-40.

5. Stoyanov KM, Hund H, Biener M, Gandowitz J, Riedle C, Löhr J. RAPID-CPU: a

prospective study on implementation of the ESC 0/1-hour algoritm and safety of

discharge after rule-out of myocardial infarction. Eur Heart J Acute Cardiovasc Care.

2020;9:39-51.
Figure 1. Diagnostic approach for investigation of patients with chest pain (excluding

STEMI, which is an electrocardiographic diagnosis). Various algorithms ruling-in or -out

NSTEMI are described; values are assay-specific. Alternative cardiac and non-cardiac

etiologies of elevated hs-cTn are also described as a differential diagnosis.

Adapted with permission from Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J,

Bhatt DL et al. Eur Heart J 2021;42:1289-1367.

Figure 2. Mortality up to 12 months in patients with NSTEMI and UA stratified by hsTnT

level. Patients diagnosed with UA and normal-range or undetectable hsTnT had excellent

prognosis, better than that of non-cardiac chest pain.

Reproduced with permission from Giannitsis E, Biener M, Hund H, Mueller-Hennessen M,

Vafaie M, Gandowitz J et al. Management and outcomes of patients with unstable angina and

undetectable, normal, or intermediate hsTnT levels. Clin Res Cardiol 2020;109:476-87.