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Validation of the (Troponin-only) Manchester Acute Coronary Syndromes decision aid with a contemporary cardiac troponin I assay
SHORT TITLE:
The MACS decision aid with contemporary troponin
AUTHORS:
Patricia Van Den Berga; Gillian Burrowsb; Philip Lewisb; Simon Carleyc, d; Richard Bodyc, d, e
Affiliations:
a: Maastricht University, Maastricht, The Netherlands
b: Stockport NHS Foundation Trust, Poplar Grove, Stockport, United Kingdom
c: Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, M13
9WL
d: Manchester Metropolitan University
e: The University of Manchester, Manchester Academic Health Science Centre, Oxford Road,
Manchester, M13 9PL
Corresponding author and address:
Prof. Richard Body
Professor and Consultant in Emergency Medicine; Research Director, Emergency Medicine and
Intensive Care Research Group; and Honorary Senior Lecturer in Cardiovascular Medicine
Emergency Department, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, United
Kingdom
Email: [email protected]
Telephone: 00 44 7880 712 929
Key words: Acute Coronary Syndromes; Clinical Decision Rules; Cardiac Troponin; Sensitivity and
Specificity
Word count:
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Declarations
Siemens donated reagents for the purposes of this research without charge.
Funding sources and sponsorship
Siemens donated reagents for the purposes of this research without charge. The study was funded through a research grant from the Royal College of Emergency Medicine and supported by the National Institute for Health Research Clinical Research Network.
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Abstract
Objectives
The Manchester Acute Coronary Syndromes (MACS) decision aid can ‘rules in’ and ‘rule out’ acute
coronary syndromes (ACS) by combining a patient’s symptoms with the results of a single blood test
taken at the time of arrival in the Emergency Department (ED). The original model (MACS) included
two biomarkers: high sensitivity cardiac troponin T (hs-cTnT) and heart-type fatty acid binding
protein (h-FABP). A refined model without h-FABP was found to have comparable sensitivity but
greater specificity. We sought to validate MACS and T-MACS using the contemporary Siemens Advia
Centaur cardiac troponin I assay to increase usability in practice.
Methods
This is a secondary analysis from prospective diagnostic cohort study at Stepping Hill Hospital, United
Kingdom. Patients presenting with chest pain of suspected cardiac nature warranting rule out for ACS
were included. All patients underwent hs-cTnT testing at least 12 hours after peak symptoms. The
primary outcome was a diagnosis of ACS, defined as either prevalent acute myocardial infarction
(AMI) or incident major adverse cardiac events (death, AMI or coronary revascularization) within 30
days.
Results
Of 405 included patients, 76 (18.8%) had ACS. MACS and T-MACS had similar C-statistics (0.94 for
each, p=0.36) and sensitivity (difference 1.3%, 95% CI -1.3 to 3.9%, p=1.00) but T-MACS had
significantly greater specificity (difference 16.7%, 95% CI 14.6 – 18.9%, p<0.0001). T-MACS and MACS
would have allowed 36.3% and 22.5% patients to be immediately discharged respectively. Of patients
classified as ‘very low risk’, none had ACS when MACS was used compared to one (0.7%) with T-
MACS.
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Conclusion
Both MACS and T-MACS effectively ruled out ACS even with a contemporary troponin I assay and
could be used to reduce unnecessary hospital admissions.
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BackgroundPatients presenting with chest pain to the emergency department (ED) are the group most
commonly requiring emergency hospital admission [1]. Serial troponin testing for rule out of acute
coronary syndromes (ACS) remains the standard of care with the latest high sensitivity troponin
assays still lacking sufficient diagnostic sensitivity to rule out ACS with a single blood test on arrival to
the ED using conventional diagnostic thresholds [2,3].
The Manchester Acute Coronary Syndromes (MACS) decision aid is a prospectively validated rule out
and risk stratification strategy for ACS based on a single blood test on arrival in patients presenting
with suspected cardiac chest pain to the ED. The computer based MACS model consists of a
combination of five patient symptoms (worsening angina, vomiting, observed diaphoresis, pain
radiating to the right arm and hypotension with a systolic blood pressure <100 mmHg), ischaemia on
the ECG and two biomarker concentrations: high sensitivity cardiac troponin T (hs-cTnT) and heart-
type fatty acid binding protein (h-FABP) [4]. As h-FABP is not commonly used in practice, its inclusion
was considered by some to be a barrier to clinical implementation. We therefore recently derived
and validated the refined T-MACS model in which hs-cTnT is the only biomarker [5].
Both models predicted major adverse cardiac events (MACE) at 30 days at 97.9%, 98.2% and 100%
sensitivity for MACS and 96.3% and 98.1% sensitivity for T-MACS in the respective (external)
validation studies [5–9]. One limitation of the (T-)MACS rule is that has only been validated with the
Roche Diagnostics Elecsys hs-cTnT assay to date.
High sensitivity cardiac troponin assays are not uniformly available at all hospitals. This highlights a
pressing need to validate the MACS rule with contemporary cardiac troponin assays that do not meet
criteria for being labelled as ‘high sensitivity’ [10]. One of the more commonly used contemporary
assays is the cardiac troponin I Ultra assay manufactured by Siemens (cTnI; Siemens ADVIA Centaur).
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We sought to validate the MACS and T-MACS rule for the Siemens Advia Centaur cTnI assay. In doing
so, we aimed to evaluate the diagnostic accuracy of both the original MACS rule and the refined T-
MACS model.
Methods
Design and setting
This work shows a secondary analysis of data collected in a prospective diagnostic cohort study
conducted between April and July 2010 in the ED of Stepping Hill Hospital, Stockport, United
Kingdom, a district general hospital with approximately 80,000 patients annually attending the ED.
The Research Ethics Committee granted ethical approval (reference 09/H1014/74) and all
participants provided written informed consent. We have published several separate analyses from
this study [4,6,11,12].
Study participants
Patients aged >25 years presenting to the ED with chest pain which the treating physician suspects to
be cardiac in nature, warranting investigations to rule out ACS were included if peak symptom onset
was reported within the last 24 hours. Patients were asked to provide initial verbal consent to the
treating ED physician at the time of their initial presentation to the ED. Written informed consent was
later sought by a member of the research team approaching the patient either in hospital or
requesting written informed consent by post. If patients were unable to provide written informed
consent they were not eligible for inclusion in the study.
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We excluded patients if they required hospital admission for another medical condition, needed
dialysis due to renal failure, presented with significant chest trauma suspicious for myocardial
contusion, were pregnant, did not speak English, were prisoners and those for whom follow up
would be impossible by any means.
Data collection and laboratory analysis
All clinical data was prospectively collected by the initial treating ED physician using a custom-
designed case report form documenting absence and presence of relevant symptoms and findings on
physical examination, ECG interpretation, ED diagnosis, disposition from the ED, as well as patient
characteristics including past medical history and current medication use.
Serum blood samples were routinely taken on arrival and at least 12 hours after peak symptom onset
in all patients presenting with suspected cardiac chest pain to the ED. The serum samples were
stored at ≤-70⁰C and further analysed in subsequently thawed batches for hs-cTnT (Roche
Diagnostics Elecsys, 5th generation, 99th percentile 14ng/L, coefficient of variation <10% at 13ng/L),
cTnI (Siemens troponin I Ultra, ADVIA Centaur, 99th percentile 40 ng/L, coefficient of variation <10%
at 30 ng/L) and H-FABP (Randox Laboratories, County Antrim, Northern Ireland, automated
immunoturbidimetric assay, 99th percentile 6.32 ng/mL, total coefficient of variation 6.85% at 5.47
ng/mL and an assay range from 0.747 to 120 ng/mL). In this report we have only included reference
to hs-cTnT measurements from samples that were re-tested using a batch of reagents unaffected by
a calibration shift noted by the manufacturer [13]. Subsequent results reported are from the analysis
with the unaffected batch.
Outcomes
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The primary outcome for this analysis was the diagnosis of ACS. ACS was defined as either AMI
occurring during the initial hospital admission (prevalent AMI) or incident major adverse cardiac
events (MACE) occurring within 30 days. MACE included death (all cause), incident AMI and urgent
coronary revascularization. The diagnosis of AMI was allocated by two independent investigators
(blinded for MACS group outcome) in accordance with the third universal definition of AMI [14]
based on clinical information and the requirement of patients having a rise and/or fall of hs-cTnT
with at least one troponin level above the 99th percentile (14 ng/L). Disagreement (n=2) was resolved
by discussion and were both explained by errors in reading or interpreting hs-cTnT concentrations.
Secondary outcomes included the diagnosis of AMI alone and the identification of a new coronary
stenosis (>50%) on coronary angiography.
Follow up
All patients were followed up after 30 days, including assessment of (a) the mortality status by using
the National Health Strategic Tracing Service (NSTS) database, (b) checking electronic patient hospital
records, and (c) personal contact by telephone or in hospital for in-patients. In case patients
remained persistently uncontactable their general practitioner (GP) was contacted. Follow up was
considered appropriate if the patients GP had been in contact with the patient during the follow up
period and was able to provide sufficient information regarding ED attendances, hospital admissions,
investigations and episodes of chest pain. In case patients required attention at another hospital in
the follow up period, relevant records were obtained in copy from that hospital.
Statistical analysis
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Statistical analysis was undertaken using SPSS version 23.0 (SPSS Inc, Chicago, Illinois) and MedCalc
version 13.1.2.0 (Mariakerke, Belgium). We summarized baseline characteristics using descriptive
statistics.
We applied the previously derived formulae for the MACS and T-MACS models to estimate the
probability of ACS, entering cTnI concentrations (Supplementary Appendix). Consistent with our
approach in the original model derivation, patients with cTnI concentrations below the limit of
detection of the assay (6ng/L) were considered to have concentrations of 5ng/L. The model classified
patients into four distinct risk groups based on their calculated risk probability according to the cut
offs applied in the derivation of the original MACS rule. The four risk groups with associated
suggestion for patient disposition include: (1) very low risk (p<0.02; patients eligible for immediate
discharge); (2) low risk (0.02<p<0.05; suitable for serial cardiac troponin sampling in ED observation
ward or comparable alternatives); (3) moderate risk (0.05<p<0.95; serial cardiac troponin sampling
required in general ward such as Acute Medical Ward); and (4) p>0.95; ACS considered ruled best
managed in a high dependency unit or specialist ward).
Test characteristics including sensitivity, specificity, positive predictive value (PPV) and, negative
predictive value (NPV), positive likelihood ratio and negative likelihood ratio, together with
respective 95% confidence intervals (95% CI) were calculated to assess the diagnostic accuracy of the
various strategies. Paired comparison of diagnostic accuracy measures was performed with
McNemar’s test. Additionally, we calculated the area under the receiver operating characteristic
(ROC) curves for the MACs and T-MACS rule in conjunction with cTnI, which were compared
according to the method described by De Long [15]. Statistical analyses were undertaken using
MedCalc, version 17.1 (Mariakerke, Belgium).
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Results
We included 405 patients in this study, of whom 66 (16.3%) had AMI and 76 (18.8%) had one or more
MACE within 30 days. Patient baseline characteristics are summarised in Table 1.
Risk stratification of patients over the four distinctive risk groups with MACS and T-MACS is shown in
Table 2. Using the MACS rule with cTnI, 91 patients (22.5%) were categorised as very low risk with no
missed ACS or prevalent AMI in this group. Using the contemporary assay with T-MACS increased the
number of patients identified as very low risk to 147 (36.3%). One patient (0.7%,95% CI 0.02 – 3.8%)
developed MACE within 30 days. This patient developed an AMI 8 days after initial presentation to
the ED, following which a severe stenosis to the circumflex artery was noted at angiography. This was
managed medically without coronary intervention. No prevalent AMIs would have been missed,
resulting in 100.0% sensitivity (95%CI 94.6 to 100.0%).
The sensitivity for predicting ACS within 30 days was 100.0% (95% CI: 94.6 to 100.0%) and 98.7%
(95% CI 92.9 to 100.0%) for MACS and T-MACS respectively. The absolute difference in sensitivity of
1.32% (95% CI -1.25 to 3.89), p=1.00 between the two models was not statistically significant.
Specificity between the models however differed by 16.72% (95% CI 14.55 to 18.89, p<0.0001),
favouring T-MACS with a specificity of 44.4% (95% CI 38.9 to 49.9) versus 27.7% (95% CI 22.9 to 32.8)
for MACS. Both models provided high NPVs for ACS within 30 days with 100% (95% CI 96.0 to 100)
and 99.3% (95% CI 96.3 to 100) for MACS and T-MACS, respectively. Additional diagnostic
performance characteristics are summarised in Table 3.
The AUC was 0.943 (95% CI 0.916 to 0.964) for MACS and 0.938 (95% CI 0.909 to 0.959) for T-MACS,
resulting in an absolute difference between the areas of 0.005 (95% CI -0.006 to 0.017), p=0.360. A
visual representation is shown in Figure 2.
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Discussion
In this secondary analysis we have addressed a limitation of the (T-)MACS rule, which had until now
only been validated with one assay: hs-cTnT (Roche Diagnostics Elecsys, 5th generation). The
contemporary cTnI assay we evaluated in our study meets the precision criteria for being a high-
sensitivity troponin assay but cannot quantify troponin levels in more than 50% of apparently healthy
volunteers [16]. This assay has been shown to provide comparable diagnostic accuracy to high-
sensitivity assays at the 99th percentile cut-off [17]. The results of our analysis support those earlier
findings suggesting that both models, MACS and T-MACS, provide sufficient diagnostic accuracy when
used with the cTnI assay for ‘ruling out’ ACS within 30 days. With the MACS rule the cTnI assay
identified 22.5% of patients as eligible for immediate discharge, which is comparable to findings from
the two external validation studies using hs-cTnT [7,9]. With T-MACS the percentage of patients
eligible for immediate discharge rises to 36.5% at the cost of missing 1 patient (0.7%) who developed
ACS within 30 days. Neither model missed any prevalent AMIs in the very low risk group.
According to a survey study by Than et al 40% of emergency physicians would be reluctant to
discharge a patient if the risk of missing MACE exceeds 1% [18]. Our findings for MACS and T-MACS
were within this range but with a clear definition of what risk of missing ACS is generally considered
acceptable, decision will remain up to local departmental standards and the risk individual physician
are willing to take. Shared decision making might provide an important avenue for further research
taking into account patient preferences alongside what clinicians consider acceptable [19].
MACS and T-MACS both had a diagnostic performance similar to alternative rule out strategies. The
HEART score, combining patient history, ECG, age, risk factors and troponin, was mainly validated in
studies using contemporary troponin assays, making findings comparable to our analysis. The HEART
score was reported with an average sensitivity of 96.7% in a recent meta-analysis and an average of
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1.6% (95% CI 1.2-2.0) ‘missed’ MACE in patients categorised as low risk with a HEART score of 0 to 3
points [20]. Both models in our analysis have reached a similar and even slightly better diagnostic
accuracy for ruling out ACS in patients identified as being low risk.
Furthermore, MACS and T-MACS rule have the advantage of providing effective risk stratification of
patients not classified as ‘very low risk’. The HEART score potentially could be used in a similar
fashion but has so far not been evaluated for this aspect. Our analysis demonstrated a high positive
predictive value for the patients identified as ‘high risk’, empowering emergency physicians to not
only rule out ACS but providing guidance on patient disposition to high dependency units, increasing
the efficient use of the most judicious resources.
Another rule out strategy relying on a single blood test on arrival to the ED in combination with ECG
changes, the limit of detection (LoD) rule out, requires the diagnostic precision of high sensitivity
troponin assays and therefore is not directly comparable to findings from this analysis. In a recent
study evaluating this cTnI assay for ruling out AMI we showed that using the assay at the LoD
together with ECG changes was insufficient to rule out prevalent AMI and subsequent MACE [21].
Other promising strategies usually require some form of serial troponin testing. In a recent derivation
and validation study cTnI was shown to potentially rule out AMI with 93.3% sensitivity in a 0/1-hour
algorithm and 94.5% sensitivity in a 0/2-hours algorithm in the validation cohort. Patients wrongly
classified as ‘rule out’ usually had ECG changes suggestive of AMI or a previous history of coronary
artery disease [22]. The HEART pathway, a modified version of the HEART score relying on 0/3-hours
serial troponin testing, had 100% sensitivity in a randomised controlled trial with 0% of missed MACE
within 30 days [23], supporting the need to combine cTnI with additional diagnostic features.
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Limitations
Our results were limited by the fact that this is a secondary analysis of prospective data, and
therefore we did perform a power calculation specifically for this analysis. Nevertheless, the sample
size in our analysis should be of acceptable size to answer our objectives and the data, although
analysed retrospectively, address the question in a valid fashion. We acknowledge that ideally the
cTnI assay should be validated prospectively in clinical practice with both models to support the
findings from this analysis. Future research is required to validate the MACS and T-MACS model for
additional contemporary and high-sensitivity troponin assays commonly used in clinical practice.
Conclusion
Both, MACS and T-MACS when used with the contemporary Siemens Ultra cTnI assay effectively
ruled out ACS and risk stratified the remaining patients and therefore could be used in clinical
practice. Clinicians need to consider if using T-MACS with cTnI is acceptable to them, considering the
higher percentages of patients eligible for discharge at the 0.7% risk of missing ACS within 30 days.
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5 Body R, Carlton E, Sperrin M, Lewis PS, Burrows G, Carley S, et al. Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid: single biomarker re-derivation and external validation in three cohorts. Emerg Med J Published Online First: 26 August 2016. doi:10.1136/emermed-2016-205983
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9 Greenslade JH, Nayer R, Parsonage W, Doig S, Young J, Pickering JW, et al. Validating the Manchester Acute Coronary Syndromes (MACS) and Troponin-only Manchester Acute Coronary Syndromes (T-MACS) rules for the prediction of acute myocardial infarction in patients presenting to the emergency department with chest pain. Emerg Med J Published Online First: 31 March 2017. doi:10.1136/emermed-2016-206366
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11 Body R, Cook G, Burrows G, Carley S, Lewis PS, Jarvis J, et al. Can emergency physicians ‘rule in’ and ‘rule out’ acute myocardial infarction with clinical judgement? Emergency Medicine Journal 2014;31:872–6.
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Legends to figures
Figure 1: Flow chart of study participants
Figure 2: ROC curve for MACS and T-MACS
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Tables
Table 1: Baseline characteristics of included patients Total (n=405) ACS at 30 days
(n=)No ACS at 30 days
(n=)Age in years, mean (SD) 64 (16) 71 (13) 62 (16)Men (%) 233 (57.5) 47 (61.8) 186 (56.5)Previous angina (%) 172 (42.5) 22 (28.9) 150 (45.6)Previous myocardial infarction (%) 127 (31.4) 25 (32.9) 102 (31.0)Previous coronary intervention (%) 15 (19.7) 79 (24.0)Hypertension (%) 166 (41.0) 35 (46.1) 124 (37.7)Hyperlipidaemia (%) 159 (39.3) 39 (51.3) 127 (38.6)Diabetes mellitus (%) 71 (17.5) 20 (26.3) 51 (15.5)Current smoking (%) 86 (21.2) 16 (21.1) 70 (21.3)Time from symptom onset to arrival in the ED (median, IQR):
0 – 3h3 – 6h6 – 12h>12h
185 (45.7)82 (20.2)60 (14.8)78 (19.3)
33 (43.4)20 (26.3)9 (11.8)
14 (18.4)
152 (6.2)62 (18.8)51 (15.5)64 (19.5)
Components of the (T-)MACS ruleAcute ECG ischaemia (%) 93 (23.0) 39 (51.3) 54 (16.4)Worsening angina (%) 86 (21.2) 20 (26.3) 66 (20.1)Pain associated with vomiting (%) 31 (7.7) 10 (13.2) 21 (6.4)Sweating observed (%) 20 (4.9) 9 (11.8) 11 (3.3)Systolic blood pressure <100mmHg (%)
17 (4.2) 3 (3.9) 14 (4.3)
Pain radiating to right arm or shoulder (%)
51 (12.6) 19 (25.0) 32 (9.7)
cTnI >40 ng/L (%) 66 (16.3) 55 (72.4) 11 (3.3)h-FABP >6.32 ng/L (%) 163 (40.2) 64 (84.2) 99 (30.1)OutcomesNumber of patients with any MACE (including prevalent AMI) at 30 days (%)
83 (20.5)
Number of patients with incident AMI at 30 days (%)
11 (2.7)
Number of patients with coronary revascularization at 30 days (%)
39 (9.6)
Number of patients with death at 30 days (%)
4 (1.0)
Number of patients with prevalent AMI at ED presentation (%)
67 (16.5)
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Table 2: Proportion of patients with MACE and AMI in the four risk groups for the MACS and T-MACS models
Very low risk Low risk Moderate risk High risk
MACS Total number of patients (%)
91 (22.5) 83 (20.5) 175 (43.2) 56 (13.8)
Number (%) with ACS
0 (0.0) 2 (2.4) 25 (14.3) 49 (87.5)
Number (%) with AMI
0 (0.0) 0 (0.0) 18 (10.3) 48 (85.7)
T-MACS Total number of patients (%)
147 (36.3) 64 (15.8) 141 (34.8) 53 (13.1)
Number (%) with ACS
1 (0.7) 2 (3.1) 26 (18.4) 47 (88.7)
Number (%) with AMI
0 (0.0) 1 (1.6) 19 (13.5) 46 (86.8)
Table 3: Diagnostic performance of the MACS and T-MACS models as ‘rule out’ strategies (i.e. ‘very low risk’ versus all other risk groups; 95% confidence intervals in parentheses)
MACS T-MACS
For ACS For AMI For ACS For AMI
Sensitivity 100.0(94.6 – 100.0)
100.0(95.3 – 100.0)
98.7(92.9 – 100.0)
100.0(94.6 – 100.0)
Specificity 27.7(23.0 – 32.9)
27.7(22.9 – 32.8)
44.4(38.9 – 49.9)
43.4(38.0 – 48.8)
PPV 21.8(17.3 – 26.9)
24.2(19.6 – 29.3)
29.1(23.6 – 35.0)
25.6(20.4 – 31.4)
NPV 100.0(96.0 – 100.0)
100.0(96.0 – 100.0)
99.3(96.3 – 100.0)
100.0(97.5 – 100.0)
LR+ 1.38(1.29 – 1.48)
1.38(1.29 – 1.48)
1.77(1.61 – 1.96)
1.77(1.61 – 1.94)
LR- 0.00(N/A)
0.00(N/A)
0.03(0.00 – 0.21)
0.00(N/A)
PPV= positive predictive value, NPV= negative predictive value, LR+= positive likelihood ratio, LR-= negative likelihood ration, ACS= acute coronary syndromes, AMI= acute myocardial infarction