Professional Documents
Culture Documents
J Jacc 2023 04 040
J Jacc 2023 04 040
1, 2023
PUBLISHED BY ELSEVIER
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 Fred S. Apple, PHD,n,o on behalf of the IFCC Committee on
Cardiac Bio-Markers
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 regu-
lations 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.
(J Am Coll Cardiol 2023;82:60–69) © 2023 by the American College of Cardiology Foundation.
Manuscript received March 14, 2023; revised manuscript received April 5, 2023, accepted April 10, 2023.
gram can effectively exclude acute MI. SINGLE-SAMPLE RULE-OUT MI = myocardial infarction
100.0
99.5
Negative Predictive Value (95% CI)
99.0
98.5
98.0
97.5
1 2 3 4 5 6 7 8 9 10 11 12 13 14
100
90
80
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Troponin Concentration on Presentation, ng/L
Troponin Concentration, ng/L ≤1 2 3 4 5 6 7 8 9 10 11 12 13 14
Cumulative Events, n 3 4 6 9 18 28 30 36 40 48 55 60 68 73
Cumulative Events, % 0.5 0.3 0.3 0.4 0.7 1.0 1.0 1.2 1.3 1.5 1.7 1.9 2.1 2.2
Cumulative Number, n 649 1,422 1,946 2,302 2,550 2,740 2,890 3,006 3,106 3,166 3,172 3,235 3,284 3,340
Cumulative Number, % 17 37 51 61 67 72 76 79 81 83 83 85 86 88
(Top) Negative predictive value of a range of high-sensitivity cardiac troponin I concentrations (ARCHITECT STAT, Abbott) on presentation for the composite outcome
of index myocardial infarction (MI) and MI or cardiac death at 30 days. (Bottom) Proportion of patients with suspected acute coronary syndrome with troponin
concentrations below each threshold. Reprinted with permission from Body et al.20
JACC VOL. 82, NO. 1, 2023 Jaffe et al 63
JULY 4, 2023:60–69 Single Troponin to Rule Out MI
reasons for MI and few traditional risk factors, for patients. The incidence of MI or cardiac death was
example, those with microvascular dysfunction, very low in both groups. Length of ED stay was
vasospasm, spontaneous coronary artery spasm, significantly lower in the single-sample group.
and/or coronary embolic disease.19 Furthermore, the proportion of patients discharged
increased from 50% with standard care to 71% with
CLINICAL STUDIES the single-sample rule-out. This strategy was
deployed only in those who presented $3 hours after
The metrics for the use of this approach vary symptom onset. The incidence of MI or cardiac death
tremendously.2 Although the initial study used the at 30 days was low (0.3% with the early rule-out
LoB, 6 this threshold has not been adopted because of strategy and 0.4% with standard care). This small
the high degree of assay imprecision at LoB concen- difference did not meet the prespecified criteria to
trations. Therefore, the LoD, for which imprecision conclude that it was noninferior to standard care.
is <20% to 25%, is preferred. 6 The LoD does not Nonetheless, the frequency of events was so low that
guarantee high precision, and it is for that reason that it met the metrics desired for adequate identification
the U.S. Food and Drug Administration (FDA) has of these patients. Follow-up at 1 year also demon-
restricted the reporting of hs-cTn concentrations to strated no increase in cardiac events, suggesting that
the limit of quantitation (LoQ), which is the lowest discharge did not compromise care.9
concentration with a coefficient of analytical varia- The second randomized trial was called RAPID-TnT
tion of 20%. 29 (Rapid Assessment of Possible Acute Coronary
Result reporting is further complicated because for Syndrome in the Emergency Department With
some hs-cTn assays, there is variability in precision High-Sensitivity Troponin T). 35 It was designed with
depending upon the analytical platform and the so-called masked and unmasked groups. The masked-
sample matrix. 30 For many hs-cTn assays, it is not group clinicians were not informed of hs-cTnT
necessary to use concentrations as low as the LoD or concentrations that were very low and therefore
even the LoQ. Studies have documented that for treated patients as if they were using a less sensitive
many hs-cTn assays, concentrations greater than the cTn assay. In the unmasked group, the concentrations
LoD can establish an NPV of >99.5%. These higher were shared, and single-sample rule-out was per-
concentrations allow the rule-out of a larger number mitted. The analysis was more complicated because
of patients and increase effectiveness (Figure 1). The the early rule-out strategy involved both a 0/1-hour
International Federation of Clinical Chemistry and protocol as well as the single-sample rule-out. It
Laboratory Medicine Committee on Clinical Applica- should be noted that 13% of patients came back to the
tions of Cardiac Bio-Markers and the American Asso- ED because of chest pain, and readmission was more
ciation for Clinical Chemistry Academy advocate that common in the unmasked (4.0%) than the masked
reporting below the 20% coefficient of analytical arm (2.7%). During long-term follow-up, there was
variation concentration is likely of value and should an increased signal for mortality in patients who
not negatively affect safety.31 This issue most directly had elevations of hs-cTnT in the unmasked group.36
affects the hs-cTnT assay from Roche Diagnostics, One explanation might be that when clinicians
whose LoD is 3 or 5 ng/L depending on the analyzer. did not have hs-cTn concentrations, they were more
Yet the FDA allows reporting only to a concentration conservative.
of the LoQ of 6 ng/L. Only recently have data been These conflicting data caused ambivalence about
published to suggest that this concentration can be the strategy in the United States, where the ability of
relied on for the single-sample rule-out. 32 some hs-cTn assays to report the concentrations
Many observational studies have validated the associated with success of the single-sample strategy
single-sample rule-out, as have systematic reviews was precluded by the FDA’s prohibition. This has led
and individual patient–level meta-analyses.2,33 to controversy over whether this approach should be
Recently, 3 randomized trials have provided more used with hs-cTnT. Four studies have probed the use
robust validation. The first, a stepped-wedge ran- of hs-cTnT concentrations of <6 ng/L. Two small tri-
domized controlled trial called HiSTORIC (High- als used hs-cTnT with 0-hour and 3-hour sampling.
Sensitivity Cardiac Troponin on Presentation to Rule Both suggested that the approach was successful.37,38
Out Myocardial Infarction), used the Abbott hs-cTnI Both studies used a higher 99th percentile (19 ng/L, as
assay.34 In this noninferiority trial, standard care recommended in the U.S. package insert) for diag-
with serial sampling was compared with the single- nosing MI compared with those used in Europe
sample rule-out using a validated optimized cutoff (common cutoffs of 14 ng/L, 9 ng/L in women, and
of <5 ng/L,13 well above the 1.9 ng/L LoD, in >31,000 17 ng/L in men) and in the Universal Sample Bank.39
JACC VOL. 82, NO. 1, 2023 Jaffe et al 65
JULY 4, 2023:60–69 Single Troponin to Rule Out MI
C ENTR AL I LL U STRA T I O N Single-Sample Rule-Out for Myocardial Infarction With Cardiac Troponin
The metrics and application of the single-sample rule-out approach for myocardial infarction (MI). The figure emphasizes the need for safety first while attempting to
maximize efficiency, thus the application of clinical judgement and the presence of nonischemic electrocardiographic findings. Areas where additional information
would be helpful are listed in boxes on the left. *Negative predictive value (NPV) can be misleading in smaller datasets or when the prevalence of MI is low.
Accordingly, all studies should report both NPV and sensitivity and their respective CIs. CVa ¼ coefficient of analytical variation; NPV ¼ negative predictive value.
A third trial, in Canada, used lower 99th-percentile group vs 37% with standard care; adjusted OR: 1.58;
concentrations (<8 ng/L in men and <7 ng/L in 95% CI: 0.84-2.98). Although the difference in the
women) and showed sensitivity of 98.5% for 7-day proportion discharged between arms was almost
outcomes. 40 Finally, a recent large study with a very identical to that observed in RAPID-TnT, the CIs were
small number of MIs (2.1%) also demonstrated that wide, and the study may have been underpowered.
single-sample rule-out was worthwhile. 41 However, LoDED suggests that the approach using the LoD
the low incidence of MI raises the question of cutoff is safe, but the effectiveness of the strategy
whether such an effect would be seen if the incidence cannot be taken for granted. Hospitals must work to
of MI were higher. ensure protocol adherence and alter their clinical
The LoDED (Limit of Detection in the ED) ran- work flow to maximize the benefits.
domized trial included 632 low-risk patients with A more definitive observational validation for hs-
suspected MI and normal electrocardiographic find- cTnT has recently been published. 32 In approxi-
ings at 8 hospitals in the United Kingdom.42 In that mately 86,000 patients studied at multiple sites, the
trial, patients were individually randomized to MI frequency with which those who had concentrations
rule-out on the basis of an initial hs-cTnI or hs-cTnT of hs-cTnT <6 ng/L developed myocardial injury (a
concentration less than the LoD of the assay in use subsequent concentration greater than the sex-
or to standard care. No patients who met the criteria specific 99th-percentile upper reference limit) was
for single-sample rule-out had major adverse cardiac roughly 1%. It was lower in men, and the only signal
events within 30 days. However, there was not a of possible concern was in women who were older
statistically significant increase in early discharges (>65 years) and had comorbidities for cardiac disease,
from the ED (46% within 4 hours in the intervention who had a lower NPV (97%). When this approach was
66 Jaffe et al JACC VOL. 82, NO. 1, 2023
T A B L E 2 Single-Sample Rule-Out Threshold Values for Commercially Available High-Sensitivity Cardiac Troponin Assays
Rule-Out Performance
Proportion Outcome
Threshold, Ruled Out, Prevalence, NPV Sensitivity
Assay ng/L n % % (95% CI) (95% CI) TN FN TP FP Outcome First Author
a
Analysis population restricted to patients with a presentation concentration of high-sensitivity cardiac troponin below the sex-specific 99th-percentile threshold.
FN ¼ false negative; FP ¼ false positive; MI ¼ myocardial infarction; NPV ¼ negative predictive value; NSTEMI ¼ non–ST-segment elevation myocardial infarction; TN ¼ true negative; TP ¼ true positive.
applied to an extensively adjudicated cohort of nearly artery disease, for which the European Society of
2,000 patients with nonischemic electrocardiographic Cardiology 0/1 hour algorithm had an NPV of only
findings, it was more robust. Thus, it is clear the 96.6% and sensitivity of 93.2% using hs-cTnT. It is
single-sample approach works with hs-cTnT as well unclear whether the problems were with the single-
as most of the hs-cTnI assays.32,43,44 The proportion sample rule-out using a value <6 ng/L or the change
of patients in whom this strategy is applicable varies in values over 1 hour or both. The data call attention
by study but ranges from 29% to 74% depending on to the need for clinical oversight when implementing
the study cited and the approach used.32-35,43,44 this strategy. 46
It is notable however, that the concern with regard Point-of-care (POC) assays have been touted as
to older patients is similar to that reported from useful for the single-sample rule-out, but most have
Israel.45 These patients had lower NPVs when they relied on stored plasma samples and not fresh whole
were older and had higher GRACE (Global Registry of blood.47-51 Recently, a novel hs-cTnI POC assay
45
Acute Coronary Events) scores. No study has spe- (Atellica VTLi, Siemens Healthineers; <8 minutes)
cifically addressed whether sex-specific thresholds has been validated on whole blood. It derived (fresh
would improve this strategy in women. The concept whole blood) and validated (stored plasma) a cutoff
that those with a high pretest probability of cardio- concentration (<4 ng/L) to identify patients at low
vascular disease are those in whom this approach may risk for index MI and low risk at 30 days (<1%). Up to
fail is supported by a recent evaluation comparing 40% of patients presenting with symptoms sugges-
patients with and those without known coronary tive of ischemia might be discharged. 51 We are likely
JACC VOL. 82, NO. 1, 2023 Jaffe et al 67
JULY 4, 2023:60–69 Single Troponin to Rule Out MI
to see more reports on POC hs-cTn assays as they are FUNDING SUPPORT AND AUTHOR DISCLOSURES
evaluated and validated for single-sample rule-out
strategies for MI. Given the rapid turnaround time of 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
these assays, this could provide further efficiencies
Research Excellent Award (RE/18/5/34216). Dr Jaffe has consulted for
for crowded EDs. Abbott, Beckman Coulter, Siemens, Roche, Ortho Diagnostics, ET
Healthcare, SphingoTec, Radiometer, SpinChip, LumiraDX, Astellas,
CONCLUSIONS Amgen, Novartis, and RCE Technologies; and holds patent
20210401347 along with others. Dr Body has received consulting fees
The data presented herein and summarized in the from Roche, Aptamer Group, Abbott, Psyros Diagnostics, Siemens
Healthineers, Beckman Coulter, and Radiometer; and has partici-
Central Illustration lead to the following
pated on advisory boards for the FORCE Trial (funded by the National
recommendations. Institute for Health and Care Research), the REWIRE trial (Queen
First, the evidence-based studies demonstrate that Mary University), the PRONTO trial (funded by the National Institute
the single-sample rule-out strategy on the basis of for Health and Care Research), and LumiraDx. Dr Mills has received
research grants from Abbott Diagnostics and Siemens Healthineers;
low concentrations of hs-cTn and nonischemic elec-
and has received personal fees for participation on advisory boards or
trocardiographic findings is a safe way to exclude MI. speaking from Abbott Diagnostics, Roche Diagnostics, Siemens
Recent data suggest that perhaps a low HEART (his- Healthineers, LumiraDx, and Psyros Diagnostics. Dr Aakre is an
tory, electrocardiogram, age, risk factors, and initial associate editor of Clinical Biochemistry; is chair of the International
52 Federation of Clinical Chemistry and Laboratory Medicine Committee
troponin) score may help as well.
on Clinical Applications of Cardiac Bio-Markers; has served on advi-
Second, at present, this strategy should be used sory boards for Roche Diagnostics and SpinChip; has received
only in patients presenting >2 hours after symptom consulting honoraria from CardiNor; has received lecture honorarium
from Siemens Healthineers and Snibe Diagnostics; and has received
onset.
research grants from Siemens Healthineers and Roche Diagnostics. Dr
Third, clinical judgment, not hs-cTn concentration Collinson is an associate editor of the Journal of Applied Laboratory
alone, must be used to safely implement the single- Medicine; is an advisory board member for Psyros Diagnostics; and
sample rule-out strategy. Particular care in older pa- has previously advised LumiraDX, Radiometer, and Siemens. Dr
Saenger has received consulting fees from Radiometer. Dr Ham-
tients, women, and those with cardiac comorbidities
marsten has stock options with Aligned Bio. Dr Omland has received
is advised. consulting fees from Roche, Bayer, and CardiNor; has received hon-
Fourth, for each hs-cTn assay and the analytical oraria from Roche; has a patent pending with Roche; has participated
platform that is used, individualized cutoff con- on advisory boards for Bayer and Roche; has a fiduciary role with
CardiNor; holds stock in CardiNor; and has received equipment and
centrations should be derived and validated that
material from Novartis and Abbott. Dr Sandoval has been on advisory
optimize the performance of the assay by main- boards and has served as a speaker for Abbott Diagnostics and Roche
taining an NPV of >99.5%. NPV can be misleading Diagnostics; and holds patent 20210401347 along with others. Dr
in smaller datasets or when the prevalence of MI is Ordonez-Llanos has received consulting fees from AWE Medical and
Hemcheck. Dr Apple has received consulting fees from HyTest and
low. Accordingly, all studies should report both
AWE Medical; has received advisory fees from Werfen, Siemens
NPV and sensitivity and their respective CIs. When Healthineers, and Qorvo Biotechnology; has received nonsalaried
incorporated into a clinical pathway for 30-day risk grant support through the Hennepin Healthcare Research Institute
for MI or death, this will maximize the proportion from Abbott Diagnostics, Abbott POC, Roche Diagnostics, Siemens
Healthineers, Quidel/Ortho, Becton Dickinson, and Beckman Coulter;
of patients eligible for early discharge (29%-74%)
and has received fees for serving as associate editor for Clinical
(Table 2). Chemistry. Dr Wereski has reported that he has no relationships
Fifth, POC hs-cTn assays must be validated using relevant to the contents of this paper to disclose.
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