a b s t r a c t

Objectives: The Manchester Acute Coronary Syndromes (MACS) decision aid can ‘rules in’ and ‘rule out’ acute cor- onary 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 prac- tice.

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 in- cluded. All patients underwent hs-cTnT testing at least 12 h 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 b 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.

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.

(C) 2017

Background

Patients presenting with chest pain to the emergency department (ED) are the group most commonly requiring emergency hospital ad- mission [1]. Serial Troponin testing for rule out of acute coronary syn- dromes (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 con- ventional 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

* Corresponding author at: Emergency Department, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom.

E-mail address: [email protected] (R. Body).

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 b 100 mm Hg), ischae- mia on the ECG and two biomarker concentrations: high sensitivity car- diac 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 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.

https://doi.org/10.1016/j.ajem.2017.09.032 0735-6757/(C) 2017

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 com- monly used contemporary assays is the cardiac troponin I Ultra assay manufactured by Siemens (cTnI; Siemens ADVIA Centaur).

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 diagnos- tic 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 prospec- tive 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 N 25 years presenting to the ED with chest pain which the treating physician suspects to be cardiac in nature, warranting in- vestigations to rule out ACS were included if peak symptom onset was reported within the last 24 h. Patients were asked to provide initial ver- bal consent to the treating ED physician at the time of their initial pre- sentation 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.

We excluded patients if they required hospital admission for anoth- er 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 ab- sence and presence of relevant symptoms and findings on physical ex- amination, ECG interpretation, ED diagnosis, disposition from the ED, as well as patient characteristics including past medical history and cur- rent medication use.

Serum blood samples were routinely taken on arrival and at least 12 h after peak symptom onset in all patients presenting with suspected cardiac chest pain to the ED. The serum samples were stored at <=-70 ?C and further analysed in subsequently thawed batches for hs-cTnT (Roche Diagnostics Elecsys, 5th generation, 99th percentile 14 ng/L, co- efficient of variation b 10% at 13 ng/L), cTnI (Siemens troponin I Ultra, ADVIA Centaur, 99th percentile 40 ng/L, coefficient of variation b 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 in- cluded 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

The primary outcome for this analysis was the diagnosis of ACS. ACS was defined as either AMI occurring during the initial hospital admis- sion (prevalent AMI) or incident Major adverse cardiac events 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 dis- cussion 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 (N 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 re- cords, 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 ap- propriate if the patients GP had been in contact with the patient during the follow up period and was able to provide sufficient information re- garding ED attendances, hospital admissions, investigations and epi- sodes 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

Statistical analysis was undertaken using SPSS version 23.0 (SPSS Inc., Chicago, Illinois) and MedCalc version 13.1.2.0 (Mariakerke, Belgium). We summarised 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 concen- trations [4,5]. Consistent with our approach in the original model deri- vation, patients with cTnI concentrations below the limit of detection of the assay (6 ng/L) were considered to have concentrations of 5 ng/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 asso- ciated suggestion for patient disposition include: (1) very low risk (p b 0.02; patients eligible for immediate discharge); (2) low risk (0.02 b p b 0.05; suitable for serial cardiac troponin sampling in ED observation ward or comparable alternatives); (3) moderate risk (0.05 b p b 0.95; serial cardiac troponin sampling required in general ward such as Acute Medical Ward); and (4) p N 0.95; ACS considered ruled best man- aged in a high dependency unit or specialist ward.

Test characteristics including sensitivity, specificity, positive predic- tive value (PPV), negative predictive value (NPV), positive likelihood ratio and negative likelihood ratio, together with respective 95% confi- dence intervals (95% CI) were calculated to assess the diagnostic accura- cy of the various strategies. Paired comparison of diagnostic accuracy measures was performed with McNemar’s test. Additionally, we calcu- lated the area under the receiver operating characteristic curves for the MACs and T-MACS rule in conjunction with cTnI, which were compared according to the method described by De Long [15]. Statisti- cal analyses were undertaken using MedCalc, version 17.1 (Mariakerke, Belgium).

Table 1 Baseline characteristics of included patients.
	Total (n = 405)	ACS at 30 days (n = 76)	No ACS at 30 days (n = 329)
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)
0-3 h	185 (45.7)	33 (43.4)	152 (6.2)
3-6 h	82 (20.2)	20 (26.3)	62 (18.8)
6-12 h	60 (14.8)	9 (11.8)	51 (15.5)
N 12 h	78 (19.3)	14 (18.4)	64 (19.5)
Components of the (T-)MACS rule Acute 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 b 100 mm Hg (%)	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 N 40 ng/L (%)	66 (16.3)	55 (72.4)	11 (3.3)
h-FABP N 6.32 ng/L (%)	163 (40.2)	64 (84.2)	99 (30.1)
Outcomes Number 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)

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. A participant flow diagram is shown in Fig. 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

Fig. 1. Flow chart of study participants.

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)

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 circum- flex 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 statistical- ly significant. Specificity between the models however differed by 16.72% (95% CI 14.55 to 18.89, p b 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 perfor- mance 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 be- tween the areas of 0.005 (95% CI -0.006 to 0.017), p = 0.360. A visual representation is shown in Fig. 2.

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 N 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 vali- dation studies using hs-cTnT [7,9]. With T-MACS the percentage of pa- tients 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 physi- cians 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 gen- erally considered acceptable, decision will remain up to local depart- mental 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 clini- cians consider acceptable [19].

MACS and T-MACS both had a diagnostic performance similar to al- ternative rule out strategies. The HEART score, combining patient histo- ry, 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 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 provid- ing 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 provid- ing guidance on patient disposition to high dependency units, increas- ing 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 tropo-

nin 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 algo- rithm 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

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.

Fig. 2. ROC curve for MACS and T-MACS.

0/3-hours serial troponin testing, had 100% sensitivity in a randomized controlled trial with 0% of missed MACE within 30 days [23], supporting the need to combine cTnI with additional diagnostic features.

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 analy- sis should be of acceptable size to answer our objectives and the data, although analysed retrospectively, address the question in a valid fash- ion. We acknowledge that ideally the cTnI assay should be validated prospectively in clinical practice with both models to support the find- ings 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 Sie- mens Ultra cTnI assay effectively ruled out ACS and risk stratified the re- maining 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 dis- charge at the 0.7% risk of missing ACS within 30 days.

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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