Randomised Assessment of Treatment using Panel Assay of Cardiac markers - Contemporary Biomarker Evaluation (RATPAC CBE)

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Chapter 1 Background

Chapter 2 Research objectives and research questions

The objectives of this study were:

1. to test the diagnostic accuracy for an AMI of highly sensitive troponin assays and a range of new cardiac biomarkers of plaque destabilisation, myocardial ischaemia and necrosis

2. to test the prognostic accuracy for adverse cardiac events of highly sensitive troponin assays and this range of new cardiac biomarkers

3. to estimate the potential cost-effectiveness of using highly sensitive troponin assays or this range of new cardiac biomarkers instead of admission and 12-hour troponin measurements.

These objectives were addressed with the following research questions:

1. Is a panel of cardiac markers, as currently available, required for early diagnosis of myocardial infarction?

2. Do novel cytoplasmic markers of myocardial damage contribute to the early differential diagnosis of patients presenting with chest pain?

3. Are all high-sensitivity cardiac troponin markers of equivalent diagnostic efficiency?

4. Do markers of myocardial dysfunction contribute to the early differential diagnosis of patients presenting with chest pain?

5. Do markers of vascular dysfunction contribute to the early differential diagnosis of patients presenting with chest pain?

6. What is the prognostic role of cytoplasmic markers of myocardial damage compared with troponin measurement?

7. What is the prognostic role of high-sensitivity troponin assays?

8. What is the prognostic role of myocardial dysfunction compared with troponin measurement?

9. What is the cost-effectiveness of the identified strategies?

Chapter 3 Methods

Economic analysis

Economic analysis was predicated by two different scenarios. In the first scenario it was assumed that a number of biomarkers would have equivalent diagnostic and prognostic efficiency or that one single biomarker would be superior to all other single biomarkers or combinations of biomarkers. Cost minimisation analysis was used for economic modelling for this scenario. In the second scenario it was assumed that a single biomarker or combinations of biomarkers at different time points or combinations of markers at different time points would be used to achieve optimal diagnostic and prognostic patient categorisation. For this scenario a decision-analysis cost-effectiveness approach was utilised.

The decision-analysis model developed for a related Health Technology Assessment (HTA) project ‘Cost-effectiveness of diagnostic strategies for suspected acute coronary syndrome (ACS)’ (HTA 09/22/21) was used. 241Full details of the model are given in the HTA journal publication for this project, but the essential details are as follows.

A decision tree model was developed using Simul8 software (Simul8 Corporation, Boston, MA, USA) to explore the costs and health outcomes associated with different diagnostic strategies. The model took an economic perspective of the NHS in England and Wales and a lifetime horizon with mean life expectancy based on UK interim lifetables. 242The basic model structure is shown inFigure 1.

FIGURE 1.

Basic model structure. MI, myocardial infarction.

The model applied different testing strategies for myocardial infarction to a hypothetical cohort of patients presenting to hospital with symptoms suggestive of myocardial infarction but with no diagnostic ECG changes (ST deviation > 1 mm or T-wave inversion > 3 mm), no known history of coronary heart disease and no major comorbidities requiring inpatient treatment (such as heart failure or arrhythmia). Each patient entering the model had the following characteristics defined by sampling from the RATPAC trial population: age, gender, myocardial infarction present or not, time delay between onset of worst pain and arrival at hospital, and time of day.

The following diagnostic strategies were applied to each patient:

1. no testing: discharge all patients without treatment

2. high-sensitivity troponin at presentation: discharge home if test is negative or admit to hospital for troponin testing at 10–12 hours if positive

3. high-sensitivity troponin and a combination of cytoplasmic or neurohormone biomarkers at presentation: discharge home if both tests are negative or admit to hospital for troponin testing at 10–12 hours if either test is positive

4. high-sensitivity troponin at presentation and at 90 minutes as in the RATPAC protocol: discharge home if both tests are negative or admit to hospital for troponin testing at 10–12 hours if either test is positive

5. standard troponin testing at 10–12 hours.

Strategy 1 is a theoretical ‘zero option’ strategy designed to test whether or not any of the testing strategies are cost-effective. Strategy 5 is current standard practice as recommended in guidance from the National Institute for Health and Care Excellence (NICE). 243

It was assumed that blood tests performed at presentation were undertaken in the emergency department and that results would be available and a decision made within 2 hours of sampling. Subsequent time delays are likely to depend on the system in place for managing admissions with chest pain and, so, three different scenarios with regard to troponin measurement at 10–12 hours were tested:

1. the ‘doctor-on-demand’ scenario in which medical staff were available 24 hours a day to make a disposition decision within 1 hour of the results being available

2. the twice-daily ward round scenario in which medical staff were available only during twice-daily ward rounds (e.g. 0900 and 1800 hours) to make disposition decisions

3. the once-daily ward round scenario in which medical staff were available only during one daily ward round (e.g. 1400 hours) to make disposition decisions.

It was assumed that standard troponin measurement at 10–12 hours was the reference standard for myocardial infarction and was therefore effectively 100% sensitive and specific. All patients who were not discharged after presentation testing received testing at 10–12 hours to confirm or refute the diagnosis of myocardial infarction. Those with myocardial infarction were admitted to hospital and treated. Those without myocardial infarction were discharged home without treatment.

The sensitivity and specificity of presentation biochemical testing was estimated using data from this study. It was assumed that true-positives would be confirmed at 10–12 hours and admitted for treatment, false-positives would be admitted until a 10- to 12-hour troponin test ruled out myocardial infarction, and true-negatives and false-negatives would be discharged without treatment. Costs were accrued throughout the diagnostic process dependent on length of stay in hospital, number of biochemical tests received and receipt of treatment for myocardial infarction. It was assumed that all biochemical tests would cost £20 per test regardless of current availability or price. Current availability and price depend on current usage, which in turn depends on evidence of effectiveness and cost-effectiveness. It was assumed that any biochemical test that was shown convincingly to be effective and cost-effective would become widely available at a reasonable cost, regardless of current availability and cost.

Following diagnosis and treatment it was assumed that patients would die, suffer reinfarction or survive without reinfarction over the following year, depending on (1) whether or not they had myocardial infarction and (2) whether or not myocardial infarction was treated. The rates of death and reinfarction up to 1 year for patients with treated myocardial infarction, untreated myocardial infarction and no myocardial infarction were estimated using data from a cohort study of patients before and after implementation of a change of operational threshold. 244The parameters used in the model are shown inTable 5.

TABLE 5 - Parameters used in the economic model and their derivation

IQR, interquartile range; MI, myocardial infarction; SD, standard deviation; SE, standard error.

Parameter	Estimate	Distribution	Source
Population characteristics
Age (years), mean (SD)	53.0 (13.5)	SE 0.30	Goodacreet al.245
Male (%)	58.1	n/N = 1138/1958
MI prevalence (%)	7.0	n/N = 137/1958
Time delay (minutes), median (IQR)	132 (80–255)
1-year probabilities of death and non-fatal MI (%)
Death, treated MI	11	n/N = 9/80	Millset al.244
Death, untreated MI	21	n/N = 19/90
Reinfarction, treated MI	11	n/N = 9/80
Reinfarction, untreated MI	29	n/N = 26/90
Costs of tests, hospital stay and treatment (£)
Treatment of MI (index or reinfarction)	3587	(3000,4000)	NHS reference costs246
Hospital stay (per hour) for testing	22	(20,30)	NHS reference costs for general medical ward246
Biochemical testing (per test)	20	(18,25)	Goodacreet al.245

It was assumed that survival and cardiac events after the first year would be independent of the diagnostic testing strategy at initial hospital admission, but that additional health-care costs and quality-adjusted life-years (QALYs) would be accrued by survivors and influenced by whether or not they suffered myocardial infarction and reinfarction. Table 6shows lifetime costs and QALYs for those with myocardial infarction. Patients without myocardial infarction were assumed to have normal quality-adjusted life expectancy and no additional health-care costs.

TABLE 6 - Lifetime cost and QALY estimates after myocardial infarction

Age (years)	Cost (£)	QALYs	QALYs with reinfarction
30–44	4012.5	12.20	9.76
45–54	3115	9.47	7.58
55–64	2215	6.73	5.39
65–74	1530	4.65	3.72
≥ 75	800	2.43	1.95

Chapter 4 Results

A total of 2263 participants were successfully recruited between 30 January 2007 and 2 June 2008; 1125 patients were successfully randomised to the point-of-care testing arm and 18 did not complete the 3-month follow-up. In the point-of-care testing arm there were 36 patients with events (3%): death 6 (1%); non-fatal myocardial infarction 5 (< 1%); hospitalisation for ACS (without myocardial infarction) 18 (2%); life-threatening arrhythmia 6 (1%), emergency revascularisation 10 (1%). Event rates between the point-of-care testing arm and the central laboratory testing arm were not statistically different, although slightly more patients with an AMI were detected in the point-of-care testing arm (90/1125 vs 72/1118). Study enrolment is summarised inFigure 2.

FIGURE 2.

Trial enrolment. CHD, coronary heart disease. a, Patients were sampled on pre-determined screening days to assess the number of patients not recruited.

Estimated number of patients not recruited=number not recruited on screening days×total days recruitingtotal days screening.

Percentages are out of the total number of non-recruited patient notes screened (n = 9109).

Sample and result availability for the point-of-care arm and samples available from the subsequent extended biomarker phase are summarised inFigures 3and4respectively.

FIGURE 3.

Sample and result availability for patients enrolled in the point-of-care arm of the study. MI, myocardial infarction.

FIGURE 4.

Samples available from the extended biomarker phase of the study. MI, myocardial infarction; POCT, point-of-care testing.

Demographics and patient characteristics in the point-of-care testing arm are summarised inTable 7.

The patient characteristics of the original data and the biomarker subset were not statistically significantly different. The diagnostic categorisation of patients on admission, following final diagnostic categorisation in the point-of-care arm of the RATPAC study and following review using the 99th percentile from the local laboratory and core laboratory troponin data are summarised inTable 8. In total, 847 out of 850 patients had laboratory troponin measurements performed. Median time from onset of chest pain to the last troponin measurement performed in the laboratory was 495 minutes [range 95–46,600 minutes, interquartile range (IQR) 310–738 minutes]. In total, 285 out of 850 of these samples (33.5%) were taken < 6 hours from onset of chest pain, 556 (65.4%) were taken ≥ 6 hours from onset of chest pain and 364 (42.8%) were taken ≥ 10 hours from onset of chest pain. Hence, the majority of patients had a troponin measurement performed in accordance with the current recommendations of the European Society of Cardiology. Following a review of the laboratory troponin results and measurement of the admission and 90-minute samples using the Siemens Ultra assay three patients were reclassified as having an AMI.

The distribution of diagnoses in the final and review diagnosis groups was not statistically different.

Evaluation of the diagnostic accuracy for acute myocardial infarction of highly sensitive troponin assays and a range of new cardiac biomarkers of plaque destabilisation, myocardial ischaemia and necrosis

Is a panel of cardiac markers required for the early diagnosis of chest pain?

The cardiac troponin assay used in the RATPAC trial was the Stratus CS analyser. Although this is not considered to be a high-sensitivity troponin assay, it meets the criteria proposed as a guideline-acceptable assay. 84The 10% CV is below the 99th percentile according to the manufacturer's data sheet. The need for additional cytoplasmic biomarkers as well as troponin is based on the argument that these will rise earlier than troponin as they are more readily released. The ability to detect troponin values around the 99th percentile may supersede the need for earlier markers as the time point for diagnostic insensitivity of troponin (the period of ‘troponin blindness’) may no longer occur. The markers traditionally suggested have been myoglobin and CK-MB. The first phase of the evaluation was therefore to assess the comparative diagnostic efficiency of cTnI measured on the Stratus CS alone utilising all of the available data for simultaneous real-time measurement of cTnI, myoglobin and CK-MB. The diagnostic efficiency of the panel approach was compared with that of single markers and single marker combinations utilising the final clinical diagnosis derived from the RATPAC study to allow comparison against the independent diagnostic standard used for patient management during the trial. The following diagnostic strategies were compared: individual marker values (cTnI > 99th percentile, CK-MB > 5μg/l20and myoglobin > 95th percentile), delta CK-MB > 1.5μg/l20and myoglobin (defined as percentage change from admission measurement > 25%). These were then compared with the combination of individual markers at presentation, the combination of individual markers at 90 minutes and the combination of admission and 90-minute marker values or delta values. For each combination, rule-in diagnosis of an AMI (specificity and positive predictive value) and rule-out diagnosis of an AMI (sensitivity and negative predictive value) were calculated.

Full data were available for 84 out of 90 patients of AMI and for 987 out of 1035 patients in whom an AMI was excluded. There were no interpretable results for cTnI in 45 patients (five AMI), for CK-MB in 47 patients (six AMI) and for myoglobin in 40 patients (six AMI). In the admission sample measurement of cTnI was the most diagnostically efficient, with an area under the ROC curve (95% confidence intervals in parentheses) of 0.96 (0.93 to 0.98) compared with 0.85 (0.80 to 0.90) for CK-MB and 0.75 (0.68 to 0.81) for myoglobin, and was statistically significantly greater than all other analytes, with a sensitivity of 0.845 (0.750 to 0.915) and a specificity of 0.976 (0.964 to 0.984). At 90 minutes, cTnI measurement had the highest AUC – 0.95 (0.87 to 1.00) compared with 0.86 (0.77 to 0.94) for CK-MB, 0.78 (0.65 to 0.91) for myoglobin, 0.83 (0.65 to 1.00) for delta CK-MB and 0.58 (0.35 to 0.81) for delta myoglobin – but was statistically significantly different only from delta myoglobin (p = 0.0035) and delta CK-MB (p = 0.0064). Comparison of final diagnoses showed that in one case there was no diagnostic elevation of cTnI, CK-MB or myoglobin on admission or at 90 minutes, although there was a clinical diagnosis of myocardial infarction and the patient was admitted. In one case CK-MB and myoglobin were elevated, but cTnI was not. The data are summarised inTable 9.

TABLE 9 - Diagnostic efficiencies of individual markers on admission and at 90 minutes

MI, myocardial infarction; N, no; NPV, negative predictive value; NS, not significant; PPV, positive predictive value; Y, yes.

Diagnosis	Positive test	cTnI	CK-MB	Myoglobin	cTnI or CK-MB	cTnI or myoglobin	Triple test	CK-MB or myoglobin
On admission
Ml (n)	Y	71	33	30	72	74	74
	N	13	51	54	11	9	8
No Ml (n)	Y	24	31	50	47	67	82
	N	966	959	942	933	912	889
Sensitivity (95% Cl)		0.845 (0.750 to 0.915)	0.393 (0.288 to 0.505)	0.357 (0.256 to 0.469)	0.867 (0.775 to 0.932)	0.892 (0.804 to 0.949)	0.902 (0.817 to 0.957)
p-value			< 0.0001	< 0.0001	NS	NS	NS
Specificity (95% Cl)		0.976 (0.964 to 0.984)	0.969 (0.956 to 0.979)	0.950 (0.934 to 0.962)	0.952 (0.937 to 0.965)	0.932 (0.914 to 0.947)	0.916 (0.896 to 0.932)
p-value			NS	0.003	0.0069	< 0.0001	< 0.0001
PPV (95% Cl)		0.747 (0.648 to 0.831)	0.516 (0.387 to 0.642)	0.375 (0.269 to 0.490)	0.605 (0.517 to 0.693)	0.525 (0.442 to 0.607)	0.474 (0.396 to 0.553)
NPV (95% Cl)		0.987 (0.977 to 0.993)	0.950 (0.934 to 0.962)	0.946 (0.930 to 0.959)	0.988 (0.979 to 0.994)	0.990 (0.982 to 0.996)	0.991 (0.982 to 0.996)
At 90 minutes
MI (n)	Y	16	3	4	12	11	11
	N	1	9	7	0	0	0
No MI (n)	Y	13	16	28	27	41	51
	N	814	809	798	789	775	756
Sensitivity (95% CI)		0.941 (0.713 to 0.999)	0.250 (0.055 to 0.572)	0.364 (0.109 to 0.692)	1.000 (0.735 to 1.000)	1.000 (0.715 to 1.000)	1.000 (0.715 to 1.000)
p-value			0.0004	0.004	NS	NS	NS
Specificity (95% Cl)		0.984 (0.973 to 0.992)	0.981 (0.969 to 0.989)	0.966 (0.951 to 0.977)	0.967 (0.952 to 0.978)	0.950 (0.932 to 0.964)	0.937 (0.918 to 0.953)
p-value			NS	0.03	0.0337	0.0002	< 0.0001
PPV (95% CI)		0.552 (0.357 to 0.736)	0.158 (0.034 to 0.396)	0.125 (0.035 to 0.290)	0.308 (0.170 to 0.476)	0.212 (0.111 to 0.347)	0.177 (0.092 to 0.295)
NPV (95% CI)		0.999 (0.993 to 1.000)	0.989 (0.979 to 0.995)	0.991 (0.982 to 0.996)	1.000 (0.995 to 1.000)	1.000 (0.995 to 1.000)	1.000 (0.995 to 1.000)
Peak or delta
MI (n)	Y	83	33	33	84	84	84	43
	N	2	51	51	1	1	1	42
No MI (n)	Y	37	31	127	60	155	170	145
	N	958	963	874	941	849	834	857
Sensitivity (95% CI)		0.976 (0.918 to 0.997)	0.393 (0.288 to 0.505)	0.393 (0.288 to 0.505)	0.988 (0.936 to 1.000)	0.988 (0.936 to 1.000)	0.988 (0.936 to 1.0)	0.506 (0.395 to 0.616)
p-value			< 0.0001	< 0.0001	NS	NS	NS	< 0.0001
Specificity (95% CI)		0.963 (0.949 to 0.974)	0.969 (0.969 to 0.979)	0.873 (0.853 to 0.894)	0.940 (0.924 to 0.954)	0.846 (0.823 to 0.868)	0.831 (0.807 to 0.861)	0.855 (0.834 to 0.877)
p-value			NS	0.003	0.0239	< 0.0001	< 0.0001	< 0.0001
PPV (95% CI)		0.692 (0.609 to 0.774)	0.516 (0.387 to 0.643)	0.206 (0.144 to 0.269)	0.583 (0.503 to 0.664)	0.351 (0.291 to 0.412)	0.331 (0.273 to 0.389)	0.229 (0.169 to 0.289)
NPV (95% CI)		0.998 (0.992 to 1.000)	0.950 (0.934 to 0.962)	0.945 (0.928 to 0.959)	0.999 (0.994 to 1.000)	0.999 (0.994 to 1.000)	0.999 (0.993 to 1.000)	0.953 (0.937 to 0.966)

Optimal diagnostic performance for all markers was achieved by 90 minutes. Both on admission and at 90 minutes, measurement of cTnI was diagnostically significantly more sensitive (hence, would allow rule-out of an AMI) than CK-MB or myoglobin but was more specific (rule-in of an AMI) only than myoglobin. Examining the combination of peak values and peak values plus change (delta) showed that cTnI was superior to both CK-MB and myoglobin alone or in combination. Delta cTnI was less sensitive (12/16) than peak cTnI (83/85), but was more sensitive than CK-MB (p = 0.018) or myoglobin (p = 0.018).

Do cytoplasmic markers of myocardial damage contribute to the early differential diagnosis of patients presenting with chest pain?

The measurement of H-FABP has been proposed as a more sensitive marker because of the cytoplasmic location of H-FABP and its low molecular weight. However, the molecular weight (15 kDa) is not substantially less than that of myoglobin (16.7 kDa), although the tissue concentration is higher. The diagnostic performance of H-FABP was therefore compared with that of the other cytoplasmic markers of myocardial necrosis and cTnI measured using the Stratus CS analyser. H-FABP measurement was also compared with the other high-sensitivity cTnI and cTnT methods. ROC analysis used the diagnosis of myocardial infarction based on the review diagnosis utilising the cTnI Ultra assay as the reference standard to provide a degree of independence of the diagnostic classification from the biomarkers undergoing evaluation. ROC curves were constructed for markers measured on admission and for peak values (admission or 90 minutes from admission) and are shown inFigures 5–8. AUCs and comparison of AUCs are provided inTables 10and11.

FIGURE 5.

Receiver operating characteristic curves for cytoplasmic biomarkers compared with cTnI for the diagnosis of an AMI: markers measured on admission. cTnI CS 1, Stratus CS admission sample; CK-MB 1, CK-MB admission sample; Myo 1, myoglobin admission sample; FABP 1, H-FABP admission sample.

FIGURE 6.

Receiver operating characteristic curves for cytoplasmic biomarkers compared with cTnI for the diagnosis of an AMI. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI CS peak, Stratus CS peak value; CK-MB peak, CK-MB peak value; Myo peak, myoglobin peak value; FABP peak, H-FABP peak value.

FIGURE 7.

Receiver operating characteristic curves for cytoplasmic biomarkers compared with cTnI and cTnT for the diagnosis of an AMI: markers measured on admission. cTnI CS 1, Stratus CS admission sample; cTnT 1, Roche high-sensitivity cTnT admission value; cTnI B1, Beckman AccuTnl admission sample; CK-MB 1, CK-MB admission sample; Myo 1, myoglobin admission sample; FABP 1, H-FABP admission sample.

FIGURE 8.

Receiver operating characteristic curves for cytoplasmic biomarkers compared with cTnI and cTnT for the diagnosis of an AMI. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI B peak, Beckman AccuTnI peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cTnT peak value; CK-MB peak, CK-MB peak value; Myo peak, myoglobin peak value; FABP peak, H-FABP peak value.

TABLE 10 - Area under the ROC curve and comparisons of AUCs for cytoplasmic biomarkers compared with cTnI and cTnT for the diagnosis of an AMI: markers measured on admission

CI, confidence interval; CK-MB 1, CK-MB admission sample; cTnI B 1, Beckman AccuTnI admission sample; cTnI CS 1, Stratus CS admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission sample; FABP 1, H-FABP admission sample; Myo 1, myoglobin admission sample.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.94 (0.90 to 0.98)	cTnI CS 1 vs CK-MB 1	0.10 (0.04 to 0.16)	0.0023
CK-MB 1	0.84 (0.79 to 0.90)	cTnI CS 1 vs Myo 1	0.18 (0.10 to 0.26)	< 0.0001
Myo 1	0.76 (0.69 to 0.84)	cTnI CS 1 vs FABP 1	0.10 (0.02 to 0.18)	0.0115
FABP 1	0.84 (0.77 to 0.90)	CK-MB 1 vs Myo 1	0.08 (0.02 to 0.14)	0.0107
cTnI B 1	0.92 (0.88 to 0.96)	CK-MB 1 vs FABP 1	0.00 (−0.05 to 0.05)	0.8579
cTnT 1	0.92 (0.88 to 0.96)	Myo 1 vs FABP 1	−0.08 (−0.14 to −0.01)	0.0146
cTnI S 1	0.90 (0.85 to 0.95)	cTnI B 1 vs CK-MB 1	0.08 (0.02 to 0.13)	0.0049
		cTnI B 1 vs Myo 1	0.16 (0.09 to 0.23)	< 0.0001
		cTnI B 1 vs FABP 1	0.08 (0.02 to 0.14)	0.0054
		cTnI S 1 vs CK-MB 1	0.06 (0.01 to 0.11)	0.0267
		cTnI S 1 vs Myo 1	0.14 (0.07 to 0.21)	0.0002
		cTnI S 1 vs FABP 1	0.07 (0.01 to 0.12)	0.0317
		cTnT 1 vs CK-MB 1	0.08 (0.03 to 0.13)	0.0018
		cTnT 1 vs Myo 1	0.16 (0.09 to 0.23)	< 0.0001
		cTnT 1 vs FABP 1	0.08 (0.03 to 0.14)	0.0036

TABLE 11 - Area under the ROC curve and comparisons of AUCs for cytoplasmic biomarkers compared with cTnI and cTnT for the diagnosis of an AMI: peak value of measurement on admission or 90 minutes from admission

CI, confidence interval; CK-MB peak, CK-MB peak value; cTnI B peak, Beckman AccuTnI peak value; cTnI CS peak, Stratus CS peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cTnT peak value; FABP peak, H-FABP peak value; Myo peak, myoglobin peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS peak	0.98 (0.96 to 1.00)	cTnI CS peak vs CK-MB peak	0.13 (0.08 to 0.19)	< 0.0001
CK-MB peak	0.85 (0.80 to 0.90)	cTnI CS peak vs Myo peak	0.24 (0.16 to 0.32)	< 0.0001
Myo peak	0.74 (0.67 to 0.82)	cTnI CS peak vs FABP peak	0.16 (0.09 to 0.23)	< 0.0001
FABP peak	0.82 (0.75 to 0.89)	CK-MB peak vs Myo peak	0.11 (0.04 to 0.17)	0.0008
cTnI B peak	0.93 (0.88 to 0.97)	CK-MB peak vs FABP peak	0.03 (–0.03 to 0.08)	0.3328
cTnI S peak	0.94 (0.90 to 0.97)	Myo peak vs FABP peak	–0.08 (–0.15 to –0.02)	0.0109
cTnT peak	0.92 (0.88 to 0.97)	cTnI B peak vs CK-MB peak	0.08 (0.02 to 0.13)	0.0041
		cTnI B peak vs Myo peak	0.18 (0.11 to 0.26)	< 0.0001
		cTnI B peak vs FABP peak	0.10 (0.04 to 0.16)	0.0005
		cTnI S peak vs CK-MB peak	0.09 (0.04 to 0.13)	0.0006
		cTnI S peak vs Myo peak	0.19 (0.12 to 0.26)	< 0.0001
		cTnI S peak vs FABP peak	0.11 (0.06 to 0.17)	< 0.0001
		cTnT peak vs CK-MB peak	0.07 (0.02 to 0.12)	0.0046
		cTnT peak vs Myo peak	0.18 (0.11 to 0.25)	< 0.0001
		cTnT peak vs FABP peak	0.10 (0.04 to 0.16)	0.0019

Cardiac troponin measurement was diagnostically superior to all of the other markers on admission as assessed by comparison of areas under the ROC curve. Both H-FABP and CK-MB were superior to myoglobin on admission. The diagnostic efficiencies of CK-MB and H-FABP were equivalent. The following diagnostic strategies were also compared: individual marker values [(cTnI > 99th percentile (0.07μg/l), CK-MB > 5μg/l20myoglobin > 95th percentile (66 mg/l), hFABP > 95th percentile (2.5 mg/l)]; delta CK-MB > 1.6μg/l20and myoglobin (defined as % change from admission measurement > 25%); the combination of presentation or 90-minute value and the combination of presentation or 90-minute value plus delta value. These results are summarised inTable 12. As found previously, the diagnostic sensitivity of troponin was superior to that of all of the other biomarkers examined but its diagnostic specificity was not significantly different from that of CK-MB, although it was superior to that of the other two biomarkers. The use of a delta value for CK-MB, myoglobin and H-FABP did not significantly improve sensitivity but significantly worsened the specificity for myoglobin and H-FABP.

TABLE 12 - Diagnostic efficiencies of individual markers on admission, individual markers at 90 minutes, peak values of individual markers and peak values of individual markers plus delta (change) for the diagnosis of an AMI

CI, confidence interval; MI, myocardial infarction; N, no; NPV, negative predictive value; NS, not significant, Y, yes.

p-values are significance for diagnostic categorisation for each marker or marker combination compared with the diagnostic performance of cTnI measurement on the Stratus CS alone.

Diagnosis	Positive test	cTnl	CK-MB	Myoglobin	H-FABP
On admission
MI (n)	Y	53	26	36	43
	N	13	40	30	23
No MI (n)	Y	16	23	81	48
	N	749	739	684	717
Sensitivity (95% CI)		0.803 (0.6867 to 0.891)	0.394 (0.276 to 0.522)	0.546 (0.418 to 0.669)	0.652 (0.524 to 0.765)
p-valuea			< 0.0001	0.0027	NS
Specificity (95% Cl)		0.979 (0.966 to 0.988)	0.970 (0.955 to 0.981)	0.894 (0.870 to 0.915)	0.937 (0.918 to 0.953)
p-valuea			NS	< 0.0001	< 0.0001
NPV (95% Cl)		0.983 (0.971 to 0.991)	0.949 (0.931 to 0.963)	0.958 (0.941 to 0.971)	0.969 (0.954 to 0.980)
At 90 minutes
MI (n)	Y	13	2	6	7
	N	1	8	5	4
No MI (n)	Y	9	14	57	20
	N	646	638	589	626
Sensitivity (95% CI)		0.929 (0.661 to 0.998)	0.200 (0.0252 to 0.556)	0.546 (0.234 to 0.833)	0.636 (0.308 to 0.891)
p-valuea			0.0010	NS	NS
Specificity (95% CI)		0.986 (0.974 to 0.994)	0.979 (0.964 to 0.988)	0.912 (0.887 to 0.933)	0.969 (0.953 to 0.981)
p-valuea			NS	< 0.0001	NS
NPV (95% CI)		0.998 (0.991 to 1.000)	0.988 (0.976 to 0.995)	0.992 (0.980 to 0.997)	0.994 (0.984 to 0.998)
Peak value
MI (n)	Y	64	27	38	44
	N	3	39	30	24
No MI (n)	Y	24	25	107	58
	N	742	740	673	722
Sensitivity (95% CI)		0.955 (0.875 to 0.991)	0.409 (0.289 to 0.537)	0.559 (0.433 to 0.679)	0.647 (0.522 to 0.759)
p-valuea			< 0.0001	< 0.0001	< 0.0001
Specificity (95% CI)		0.969 (0.954 to 0.980)	0.967 (0.952 to 0.979)	0.863 (0.839 to 0.887)	0.926 (0.905 to 0.943)
p-valuea			NS	< 0.0001	0.0003
Peak value or delta
MI (n)	Y	64	27	38	46
	N	3	39	30	22
No MI (n)	Y	24	25	246	213
	N	742	740	534	567
Sensitivity (95% CI)		0.955 (0.875 to 0.991)	0.409 (0.289 to 0.537)	0.559 (0.433 to 0.679)	0.676 (0.552 to 0.785)
p-valuea			< 0.0001	< 0.0001	< 0.0001
Specificity (95% CI)		0.969 (0.954 to 0.980)	0.967 (0.952 to 0.979)	0.680 (0.647 to 0.713)	0.727 (0.696 to 0.758)
p-valuea			NS	< 0.0001	< 0.0001

Are all high-sensitivity cardiac troponin methods of equivalent diagnostic efficiency?

The diagnostic performance of four methods of measuring cardiac troponin was compared utilising the review diagnosis as the gold standard. The four methods were cTnI measured using the Stratus CS analyser, the Beckman AccuTnI method and the Siemens Ultra assay and cTnT measured using the Roche high-sensitivity assay. Diagnosis was initially compared using the admission sample alone and then using the peak value of the admission or the 90-minute sample. The ROC curves obtained are shown inFigures 9and10with comparison of the AUCs inTable 13. Diagnosis based on classification using the 99th percentile value is summarised inTable 14.

FIGURE 9.

Receiver operating characteristic curves for troponin measurement for the diagnosis of an AMI: markers measured on admission. cTnI CS 1, Stratus CS admission sample; cTnI B 1, Beckman AccuTnI admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission sample.

FIGURE 10.

Receiver operating characteristic curves for troponin measurement for the diagnosis of an AMI: peak values on admission or at 90 minutes from admission. cTnI CS peak, Stratus CS peak value; cTnI B peak, Beckman AccuTnI peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cTnT peak value.

TABLE 13 - Area under the ROC curve and comparison of AUCs for cardiac troponin measurements for the diagnosis of an AMI: markers measured on admission (1) or peak value of measurement on admission or at 90 minutes from admission (peak)

CI, confidence interval; cTnI B 1, Beckman AccuTnI admission sample; cTnI B peak, Beckman AccuTnI peak value; cTnI CS 1, Stratus CS admission sample; cTnI CS peak, Stratus CS peak value; cTnI S 1, Siemens Ultra admission sample; cTnI S peak, Siemens Ultra peak value; cTnT 1, Roche high-sensitivity cTnT admission sample; cTnT peak, Roche high-sensitivity cTnT peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.94 (0.90 to 0.98)	cTnI CS 1 vs cTnI B 1	0.02 (−0.02 to 0.07)	0.3752
cTnI B 1	0.92 (0.88 to 0.96)	cTnI CS 1 vs cTnI S 1	0.04 (−0.01 to 0.08)	0.0947
cTnI S 1	0.90 (0.85 to 0.95)	cTnI CS 1 vs cTnT 1	0.02 (−0.03 to 0.07)	0.4610
cTnT 1	0.92 (0.88 to 0.96)	cTnI B 1 vs cTnI S 1	0.02 (−0.01 to 0.05)	0.2117
		cTnI B 1 vs cTnT 1	0.00 (−0.04 to 0.04)	0.9317
		cTnI S 1 vs cTnT 1	−0.02 (−0.05 to 0.01)	0.2494
cTnI CS peak	0.98 (0.96 to 1.00)	cTnI CS peak vs cTnI B peak	0.05 (0.02 to 0.09)	0.0056
cTnI B peak	0.93 (0.88 to 0.97)	cTnI CS peak vs cTnI S peak	0.05 (0.01 to 0.08)	0.0152
cTnI S peak	0.94 (0.90 to 0.97)	cTnI CS peak vs cTnT peak	0.06 (0.01 to 0.11)	0.0134
cTnT peak	0.92 (0.88 to 0.97)	cTnI B peak vs cTnI S peak	−0.01 (−0.02 to 0.01)	0.2340
		cTnI B peak vs cTnT peak	0.00 (−0.04 to 0.04)	0.8454
		cTnI S peak vs cTnT peak	0.01 (−0.02 to 0.05)	0.4760

TABLE 14 - Diagnostic efficiencies of cardiac troponin measurements on admission and of peak values of individual markers for the diagnosis of an AMI

CI, confidence interval; cTnI B, Beckman AccuTnI sample; cTnI CS, Stratus CS sample; cTnI S, Siemens Ultra sample; cTnT, Roche high-sensitivity cTnT sample; MI, myocardial infarction; NPV, negative predictive value; NS, not significant.

p-values are significance for diagnostic categorisation for each marker compared with the diagnostic performance of cTnI measured using the Stratus CS.

Diagnosis	cTnl CS	cTnl B	cTnl S	cTnT
On admission
MI (n)	53	44	49	53
	13	22	17	14
No MI (n)	16	11	19	33
	749	758	751	733
Sensitivity (95% CI)	0.803 (0.687 to 0.891)	0.667 (0.540 to 0.778)	0.742 (0.620 to 0.842)	0.791 (0.674 to 0.881)
p-valuea		NS	NS	NS
Specificity (95% CI)	0.979 (0.966 to 0.988)	0.986 (0.975 to 0.993)	0.975 (0.962 to 0.985)	0.957 (0.940 to 0.970)
p-valuea		NS	NS	0.021
NPV (95% CI)	0.983 (0.971 to 0.991)	0.972 (0.958 to 0.982)	0.978 (0.965 to 0.987)	0.981 (0.969 to 0.990)
Peak value
MI (n)	64	53	57	57
	3	15	11	11
No MI (n)	24	15	31	43
	742	766	751	736
Sensitivity (95% CI)	0.955 (0.875 to 0.991)	0.779 (0.662 to 0.871)	0.838 (0.729 to 0.916)	0.838 (0.729 to 0.916)
p-valuea		0.005	0.048	0.048
Specificity (95% CI)	0.969 (0.954 to 0.980)	0.981 (0.969 to 0.989)	0.960 (0.944 to 0.973)	0.945 (0.926 to 0.960)
p-valuea		NS	NS	0.029

There were no statistically significant differences between the AUCs or diagnostic categorisation for the admission samples for any of these troponin methods. For peak value, the Stratus CS seemed to be diagnostically superior to all of the other troponin methods. There were no differences between any of the other methods. This may well represent a selection bias in the analysis as patients with an elevated Stratus CS troponin level were admitted and a second sample was not taken.

The individual methods missed varying numbers of patients with a final diagnosis of myocardial infarction. The Stratus CS cTnI missed three patients. One was diagnosed on ECG criteria, but had an elevated cTnT. The other two patients had elevated cTnI by the Siemens assay and elevated cTnT. The Beckman cTnI assay missed 15 patients. In 13 patients there was no second sample but six showed elevation of cTnI measured by the Siemens assay and seven showed elevation of cTnT. The Siemens cTnI assay missed 11 patients, eight of whom had no second sample, but showed elevation of cTnI on the Beckman assay (two patients) and elevation of cTnT (four patients). Measurement of cTnT missed 11 patients, 10 of whom did not have a second sample. Three patients had an elevated cTnI on the Beckman and Siemens assays and one had an elevated cTnI on the Siemens assay alone.

Increased sensitivity of troponin methods is at the expense of specificity due to the detection of myocardial injury in a range of other non-ACS conditions. In the population where AMI was excluded, elevation of all four troponins occurred in three cases, two of which had myocarditis. Three patients showed elevation of all three of the troponin methods under investigation but not of cTnI measured by the Stratus CS. One of these patients had myocarditis. Elevation of cTnI measured by the Stratus CS occurred in 24/766 (3.1%) of cases with a final diagnosis that excluded myocardial infarction, two also showed elevation of cTnI by the Siemens Ultra, 1 by the Beckman method and eight showed elevation of cTnT. Elevation of troponin in patients without a final diagnosis of myocardial infarction occurred in 15/781 (1.9%) patients for cTnI measured by the Beckman method, 31 (31/782, 4.0%) patients for cTnI measured by the Siemens Ultra assay and 43/779 (5.5%) patients for cTnT. One in 15 with elevated cTnI by the Beckman method had elevation by the Stratus CS alone and 9/15 by the Siemens Ultra alone and 11/15 had an elevated cTnT. For the Siemens method, 16/31 also had elevation of cTnT. Detailed information on missed diagnosis of myocardial infarction for all four troponin methods and elevations in patients without a final diagnosis of myocardial infarction is summarised inAppendices 1and2.

Do markers of vascular dysfunction contribute to the early differential diagnosis of patients presenting with chest pain?

Measurement of cardiac troponin was compared with measurement of copeptin and NTproBNP on admission and for the peak of the admission or 90 minutes from admission value. The diagnostic efficiency was compared by ROC curve analysis using the review final diagnosis as above. The ROC curves are shown inFigures 11and12with the areas under the ROC curve and comparisons inTable 15. Measurement of NTproBNP was superior to copeptin measurement in the admission and peak samples. Measurement of cardiac troponin was superior to both NTproBNP and copeptin measurement on admission and in the peak sample.

FIGURE 11.

Receiver operating characteristic curves for vascular dysfunction markers compared with troponin measurements for the diagnosis of an AMI: markers measured on admission. cTnI CS 1, Stratus CS admission sample; cTnI B1, Beckman AccuTnl admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission value; copeptin 1, copeptin admission sample; NTproBNP 1, NTproBNP admission sample

FIGURE 12.

Receiver operating characteristic curves for vascular dysfunction markers compared with troponin measurements for the diagnosis of an AMI. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI CS peak, Stratus CS peak sample; cTnI B peak, Beckman AccuTnI peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cardiac cTnT peak value; copeptin peak, copeptin peak value; NTproBNP peak, NTproBNP peak value

TABLE 15 - Area under the ROC curve and comparisons of AUCs for vascular dysfunction markers and cardiac troponin measurements for the diagnosis of an AMI on admission (1) and for peak values (peak)

CI, confidence interval; copeptin 1, copeptin admission sample; copeptin peak, copeptin peak value; cTnI B 1, Beckman AccuTnI admission sample; cTnI B peak, Beckman AccuTnI peak value; cTnI CS 1, Stratus CS admission sample; cTnI CS peak, Stratus CS peak value; cTnI S 1, Siemens Ultra admission sample; cTnI S peak, Siemens Ultra peak value; cTnT 1, Roche high-sensitivity cTnT admission sample; cTnT peak, Roche high-sensitivity cTnT peak value; NTproBNP 1, NTproBNP admission sample; NTproBNP peak, NTproBNP peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.94 (0.90 to 0.98)	cTnI CS 1 vs copeptin 1	0.32 (0.26 to 0.38)	< 0.0001
cTnI B 1	0.92 (0.88 to 0.96)	cTnI CS 1 vs NTproBNP 1	0.09 (0.03 to 0.14)	0.0029
cTnI S 1	0.90 (0.85 to 0.95)	cTnI B 1 vs copeptin 1	0.30 (0.23 to 0.36)	< 0.0001
cTnT 1	0.92 (0.88 to 0.96)	cTnI B 1 vs NTproBNP 1	0.07 (0.02 to 0.12)	0.0101
Copeptin 1	0.62 (0.57 to 0.68)	cTnI S 1 vs copeptin 1	0.28 (0.22 to 0.34)	< 0.0001
NTproBNP 1	0.85 (0.80 to 0.9)	cTnI S 1 vs NTproBNP 1	0.05 (0.01 to 0.09)	0.0273
		cTnT 1 vs copeptin 1	0.30 (0.24 to 0.36)	< 0.0001
		cTnT 1 vs NTproBNP 1	0.07 (0.03 to 0.11)	0.0010
		Copeptin 1 vs NTproBNP 1	−0.23 (−0.30 to −0.16)	< 0.0001
cTnI CS peak	0.98 (0.96 to 1.00)	cTnI CS peak vs copeptin peak	0.42 (0.35 to 0.48)	< 0.0001
cTnI B peak	0.93 (0.88 to 0.97)	cTnI CS peak vs NTproBNP peak	0.14 (0.08 to 0.21)	< 0.0001
cTnI S peak	0.94 (0.90 to 0.97)	cTnI B peak vs copeptin peak	0.36 (0.29 to 0.43)	< 0.0001
cTnT peak	0.92 (0.88 to 0.97)	cTnI B peak vs NTproBNP peak	0.09 (0.03 to 0.15)	0.0044
Copeptin peak	0.56 (0.50 to 0.62)	cTnI S peak vs copeptin peak	0.37 (0.30 to 0.44)	< 0.0001
NTproBNP peak	0.84 (0.78 to 0.90)	cTnI S peak vs NTproBNP peak	0.10 (0.04 to 0.16)	0.0014
		cTnT peak vs copeptin peak	0.36 (0.30 to 0.42)	< 0.0001
		cTnT peak vs NTproBNP peak	0.08 (0.04 to 0.13)	0.0002
		Copeptin peak vs NTproBNP peak	−0.27 (−0.35 to −0.20)	< 0.0001

Do combinations of biomarkers allow earlier rule-in or rule-out of an acute myocardial infarction in patients presenting with chest pain?

The rationale for the selection of other cytoplasmic biomarkers of cardiac necrosis or neurohormones is that they may provide earlier information or supplementary information to measurement of cardiac troponin alone. A number of studies have suggested that the combination of either H-FABP or copeptin measurement with measurement of cardiac troponin on admission would allow very early diagnostic categorisation and potentially discharge solely on the basis of admission measurement. The combination of the different troponins with H-FABP or copeptin for rule-in or rule-out diagnosis was examined by construction of contingency tables utilising 99th percentile cut-offs for troponin and the 95th percentile cut-off for H-FABP. For copeptin, none of the values obtained exceeded the 95th percentile. In view of this an ROC optimised cut-off of 7.4 mg/l was used. The results of the analysis are summarised inTable 16. Measurement of H-FABP improved diagnostic sensitivity of all of the troponin measurements, but significantly reduced specificity. The increase in sensitivity obtained from combined measurement was equivalent to the sensitivity obtained from the combination of the measurement of troponin alone on admission and at 90 minutes from admission.

TABLE 16 - Comparison of sensitivity and specificity of single biomarkers on admission and combination of measurements on admission with troponin measurement on admission and combined measurement of troponin on admission and 90 minutes from admission for the diagnosis of an AMIa

CI, confidence interval; cTnI B, cTnI Beckman sample; cTnI CS, cTnI Stratus CS sample; cTnI S, cTnI Siemens Ultra sample; cTnT, Roche high-sensitivity cTnT sample; MI, myocardial infarction; N, no; NPV, negative predictive value; NS, not significant; Y yes.

Each combination of troponin plus second marker measured on admission (H-FABP, copeptin or NTproBNP) is compared with troponin alone measured on admission for each of the individual troponin methods.

Diagnosis	Positive test	Admission sample	H-FABP	Combined	Copeptin	Combined	NTproBNP	Combined	Peak troponin sample
cTnl CS
MI (n)	Y	50	41	58	34	57	44	56	60
	N	13	22	5	29	6	19	7	3
No MI (n)	Y	15	46	57	291	303	48	71	23
	N	725	694	683	449	437	692	669	717
Sensitivity (95% CI)		0.794 (0.673 to 0.885)	0.651 (0.520 to 0.767)	0.921 (0.824 to 0.974)	0.540 (0.409 to 0.666)	0.905 (0.804 to 0.964)	0.698 (0.570 to 0.808)	0.889 (0.784 to 0.954)	0.952 (0.867 to 0.990)
p-value			NS	NS	0.0043	NS		NS	NS
Specificity (95% CI)		0.980 (0.967 to 0.989)	0.938 (0.918 to 0.954)	0.923 (0.901 to 0.941)	0.607 (0.571 to 0.642)	0.591 (0.555 to 0.626)	0.935 (0.915 to 0.952)	0.904 (0.881 to 0.924)	0.969 (0.954 to 0.980)
p-value			< 0.0001	< 0.0001	< 0.0001	< 0.0001		< 0.0001
NPV (95% CI)		0.982 (0.970 to 0.991)	0.969 (0.954 to 0.981)	0.993 (0.983 to 0.998)	0.939 (0.914 to 0.959)	0.986 (0.971 to 0.995)	0.973 (0.959 to 0.984)	0.990 (0.979 to 0.996)	0.996 (0.988 to 0.999)
cTnl S
MI (n)	Y	46		54		52		52	52
	N	17		9		11		11	11
No MI (n)	Y	14		52		297		55	26
	N	726		688		443		685	714
Sensitivity (95% CI)		0.730 (0.603 to 0.834)		0.857 (0.746 to 0.933)		0.825 (0.709 to 0.909)		0.825 (0.709 to 0.909)	0.825 (0.709 to 0.909)
p-value				NS		NS		NS	NS
Specificity (95% CI)		0.981 (0.968 to 0.990)		0.930 (0.909 to 0.947)		0.599 (0.563 to 0.634)		0.926 (0.904 to 0.944)	0.965 (0.949 to 0.977)
p-value				< 0.0001		< 0.0001		< 0.0001	< 0.0001
NPV (95% CI)		0.977 (0.964 to 0.987)		0.987 (0.976 to 0.994)		0.976 (0.957 to 0.988)		0.984 (0.972 to 0.992)	0.985 (0.973 to 0.992)
cTnT
MI (n)	Y	49		54		53		53	52
	N	14		9		10		10	11
No MI (n)	Y	28		62		299		65	38
	N	712		678		441		675	702
Sensitivity (95% CI)		0.778 (0.655 to 0.873)		0.857 (0.746 to 0.933)		0.841 (0.727 to 0.921)		0.841 (0.727 to 0.921)	0.825 (0.709 to 0.909)
p-value				NS		NS		NS	NS
Specificity (95% CI)		0.962 (0.946 to 0.975)		0.916 (0.894 to 0.935)		0.596 (0.561 to 0.631)		0.912 (0.889 to 0.932)	0.949 (0.930 to 0.963)
p-value				0.0003		< 0.0001		< 0.0001	< 0.0001
NPV (95% CI)		0.981 (0.968 to 0.989)		0.987 (0.975 to 0.994)		0.978 (0.969 to 0.989)		0.985 (0.973 to 0.993)	0.985 (0.974 to 0.993)
cTnl B
MI (n)	Y	42		49		51		49	49
	N	21		14		12		14	14
No MI (n)	Y	11		53		296		53	15
	N	729		687		444		687	725
Sensitivity (95% CI)		0.667 (0.537 to 0.780)		0.778 (0.655 to 0.873)		0.841 (0.727 to 0.921)		0.778 (0.665 to 0.873)	0.778 (0.655 to 0.873)
p-value				NS		NS		NS	NS
Specificity (95% CI)		0.985 (0.974 to 0.993)		0.928 (0.907 to 0.946)		0.596 (0.561 to 0.631)		0.928 (0.907 to 0.946)	0.980 (0.980 to 0.989)
p-value				< 0.0001		< 0.0001		< 0.0001	< 0.0001
NPV (95% CI)				0.980 (0.967 to 0.989)		0.974 (0.955 to 0.986)			0.981 (0.968 to 0.990)

The prognostic accuracy for adverse cardiac events of highly sensitive troponin assays and the range of new cardiac biomarkers

What is the prognostic role of cytoplasmic markers of myocardial damage when compared with troponin measurement?

Receiver operating characteristic curves using the combined MACE of death, readmission with myocardial infarction, readmission with unstable angina or the need for urgent revascularisation as the dichotomous variable were constructed using the admission sample measurement and peak of the admission or 90-minute sample measurement comparing cytoplasmic markers with the four troponin measurement methods. The results are summarised inFigures 13–16with the AUCs and comparison of the AUCs inTables 17and18.

FIGURE 13.

Receiver operating characteristic curves for cytoplasmic markers and troponin measurements for the prediction of MACE: markers measured on admission cTnI CS 1, Stratus CS admission sample; CK-MB 1, CK-MB admission sample; Myo 1, myoglobin admission sample; FABP 1, H-FABP admission sample.

FIGURE 14.

Receiver operating characteristic curves for troponin measurements for the prediction of MACE: markers measured on admission. cTnI CS 1, Stratus CS admission sample; cTnI B 1, Beckman AccuTnI admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission sample.

FIGURE 15.

Receiver operating characteristic curves for cytoplasmic markers and troponin measurements for the prediction of MACE. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI CS peak, Stratus CS peak value; CK-MB peak, CK-MB peak value; Myo peak, myoglobin peak value; FABP peak, H-FABP peak value.

FIGURE 16.

Receiver operating characteristic curves for troponin measurements for the prediction of MACE. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI CS peak, Stratus CS peak value; cTnI B peak, Beckman AccuTnI peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cTnT peak value.

TABLE 17 - Area under the ROC curve and comparison of AUCs for cytoplasmic markers and cardiac troponin measurements for the prediction of MACE on admission

CI, confidence interval; CK-MB 1, CK-MB admission sample; cTnI B 1, Beckman AccuTnI admission sample; cTnI CS 1, Stratus CS admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission sample; FABP 1, H-FABP admission sample; Myo 1, myoglobin admission sample.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.73 (0.60 to 0.85)	cTnI CS 1 vs CK-MB 1	0.02 (−0.08 to 0.12)	0.6798
CK-MB 1	0.71(0.58 to 0.84)	cTnI CS 1 vs Myo 1	0.05 (−0.07 to 0.17)	0.4471
Myo 1	0.68 (0.56 to 0.80)	cTnI CS 1 vs FABP 1	0.01 (−0.10 to 0.12)	0.8484
FABP 1	0.72 (0.59 to 0.84)	CK-MB 1 vs Myo 1	0.03 (−0.07 to 0.12)	0.5908
cTnI B 1	0.83 (0.74 to 0.93)	CK-MB 1 vs FABP 1	−0.01 (−0.08 to 0.06)	0.7965
cTnI S 1	0.80 (0.70 to 0.90)	Myo 1 vs FABP 1	−0.04 (−0.12 to 0.05)	0.4295
cTnT 1	0.79 (0.68 to 0.89)	cTnI B 1 vs CK-MB 1	0.13 (0.06 to 0.19)	0.0001
		cTnI B 1 vs Myo 1	0.15 (0.07 to 0.24)	0.0004
		cTnI B 1 vs FABP 1	0.12 (0.05 to 0.19)	0.0012
		cTnI S 1 vs CK-MB 1	0.09 (0.02 to 0.16)	0.0093
		cTnI S 1 vs Myo 1	0.12 (0.03 to 0.21)	0.0126
		cTnI S 1 vs FABP 1	0.08 (0.01 to 0.16)	0.0337
		cTnT 1 vs CK-MB 1	0.08 (−0.01 to 0.18)	0.0810
		cTnT 1 vs FABP 1	0.07 (−0.01 to 0.16)	0.0982
		cTnT 1 vs Myo 1	0.11 (0.01 to 0.21)	0.0363

TABLE 18 - Area under the ROC curve and comparison of AUCs for cytoplasmic markers and cardiac troponin measurements for the prediction of MACE for peak values (peak)

CI, confidence interval; CK-MB peak, CK-MB peak value; cTnI B peak, Beckman AccuTnI peak value; cTnI CS peak, Stratus CS peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cTnT peak value; FABP peak, H-FABP peak value; Myo peak, myoglobin peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS peak	0.86 (0.77 to 0.94)	cTnI CS peak vs CK-MB peak	0.15 (0.07 to 0.24)	0.0003
CK-MB peak	0.70 (0.57 to 0.83)	cTnI CS peak vs Myo peak	0.20 (0.09 to 0.32)	0.0003
Myo peak	0.65 (0.53 to 0.78)	cTnI CS peak vs FABP peak	0.15 (0.06 to 0.23)	0.0009
FABP peak	0.71 (0.58 to 0.84)	CK-MB peak vs Myo peak	0.05 (−0.05 to 0.15)	0.3486
cTnI B peak	0.82 (0.71 to 0.92)	CK-MB peak vs FABP peak	−0.01 (−0.08 to 0.06)	0.8263
cTnI S peak	0.81 (0.71 to 0.91)	Myo peak vs FABP peak	−0.06 (−0.15 to 0.03)	0.2153
cTnT peak	0.78 (0.67 to 0.89)	cTnI B peak vs CK-MB peak	0.12 (0.05 to 0.18)	0.0004
		cTnI B peak vs Myo peak	0.17 (0.08 to 0.25)	0.0003
		cTnI B peak vs FABP peak	0.11 (0.05 to 0.17)	0.0005
		cTnI S peak vs CK-MB peak	0.11 (0.04 to 0.17)	0.0021
		cTnI S peak vs Myo peak	0.16 (0.06 to 0.25)	0.0011
		cTnI S peak vs FABP peak	0.10 (0.04 to 0.16)	0.0018
		cTnT peak vs CK-MB peak	0.08 (−0.01 to 0.17)	0.0936
		cTnT peak vs Myo peak	0.13 (0.02 to 0.23)	0.0168
		cTnT peak vs FABP peak	0.07 (−0.02 to 0.16)	0.1108

Differences between the admission value and the peak value were observed. In the case of the admission measurement, cTnI measured on the Stratus CS was equivalent to all of the cytoplasmic markers (CK-MB, myoglobin and H-FABP) for outcome prediction. The three sensitive troponin methods demonstrated a greater AUC than the cytoplasmic markers, which was statistically significant for both cTnI methods but just failed to reach significance for cTnT for CK-MB and H-FABP. All of the cytoplasmic markers had equivalent ability to predict outcome on the admission sample measurement. When peak values were examined, troponin measurement was overall a significantly better outcome predictor than the cytoplasmic markers. Measurement of cTnI on the Stratus CS for the peak values was significantly better than measurement of all three cytoplasmic markers. The other cTnI methods also demonstrated improved outcome prediction with an increase in significance. Measurement of cTnT showed improvement in diagnostic performance only when compared with measurement of myoglobin when peak values were examined.

What is the prognostic role of high-sensitivity troponin assays?

Receiver operating characteristic curves using the combined MACEs of death, readmission with myocardial infarction, readmission with unstable angina or the need for urgent revascularisation as the dichotomous variable were constructed using the admission sample measurement and peak of the admission or 90-minute sample measurement comparing the four troponin measurement methods. The results are summarised inFigures 14and16with the AUCs and comparison of the AUCs inTable 19.

TABLE 19 - Area under the ROC curve and comparison of AUCs for cardiac troponin measurements for the prediction of MACE on admission (1) and for peak values (peak)

CI, confidence interval; cTnI B 1, Beckman AccuTnI admission sample; cTnI B peak, Beckman AccuTnI peak value; cTnI CS 1, Stratus CS admission sample; cTnI CS peak, Stratus CS peak value; cTnI S 1, Siemens Ultra admission sample; cTnI S peak, Siemens Ultra peak value; cTnT 1, Roche high-sensitivity cTnT admission sample; cTnT peak, Roche high-sensitivity cTnT peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.73 (0.60 to 0.85)	cTnI CS 1 vs cTnI B 1	−0.11 (−0.22 to 0.00)	0.0523
cTnI B 1	0.83 (0.74 to 0.93)	cTnI CS 1 vs cTnI S 1	−0.07 (−0.16 to 0.01)	0.1054
cTnI S 1	0.80 (0.70 to 0.90)	cTnI CS 1 vs cTnT 1	−0.06 (−0.16 to 0.04)	0.2112
cTnT 1	0.79 (0.68 to 0.89)	cTnI B 1 vs cTnI S 1	0.04 (−0.02 to 0.10)	0.2231
		cTnI B 1 vs cTnT 1	0.04 (−0.04 to 0.13)	0.3295
		cTnI S 1 vs cTnT 1	0.01 (−0.06 to 0.07)	0.8215
cTnI CS peak	0.86 (0.77 to 0.94)	cTnI CS peak vs cTnI B peak	0.04 (−0.02 to 0.10)	0.1791
cTnI B peak	0.82 (0.71 to 0.92)	cTnI CS peak vs cTnI S peak	0.05 (−0.01 to 0.11)	0.1109
cTnI S peak	0.81 (0.71 to 0.91)	cTnI CS peak vs cTnT peak	0.08 (−0.03 to 0.18)	0.1454
cTnT peak	0.78 (0.67 to 0.89)	cTnI B peak vs cTnI S peak	0.01 (−0.04 to 0.06)	0.6676
		cTnI B peak vs cTnT peak	0.04 (−0.06 to 0.13)	0.4538
		cTnI S peak vs cTnT peak	0.03 (−0.06 to 0.11)	0.5406

There was no statistically significant difference between the ability of the different troponin methods to predict MACEs on either admission or for peak sample measurements. Although cTnI measurement using the Stratus CS showed superior performance for the diagnosis of an AMI when assessed using peak values, the ability of the different troponin methods to predict MACEs was not statistically significantly different between admission values and peak values. The apparent superiority of the Stratus CS method for detecting an AMI may reflect selection bias in the population. A positive cTnI measured using the Stratus CS was used to select patients for admission. When an independent measure of performance was utilised, the ability to predict an adverse prognosis, this apparent discrepancy between the methods disappears.

What is the prognostic role of myocardial dysfunction markers compared with troponin measurement?

Receiver operating characteristic curves using the combined MACE of death, readmission with myocardial infarction, readmission with unstable angina or the need for urgent revascularisation as the dichotomous variable were constructed using the admission sample measurement and the peak of the admission or 90-minute sample measurement comparing the four troponin methods with neurohormone measurement. The results are summarised inFigures 17and18with the AUCs and comparison of the AUCs inTable 20.

FIGURE 17.

Receiver operating characteristic curves for troponin and neurohormone measurements for the prediction of MACE: markers measured on admission cTnI CS 1, Stratus CS admission sample; cTnI B1, Beckman AccuTnl admission sample; cTnI S 1, Siemens Ultra admission sample; cTnT 1, Roche high-sensitivity cTnT admission value; copeptin 1, copeptin admission sample; NTproBNP 1, NTproBNP admission sample.

FIGURE 18.

Receiver operating characteristic curves for troponin and neurohormone measurements for the prediction of MACE. Markers are peak values of measurement on admission or 90 minutes from admission. cTnI CS peak, Stratus CS peak sample; cTnI B peak, Beckman AccuTnI peak value; cTnI S peak, Siemens Ultra peak value; cTnT peak, Roche high-sensitivity cardiac cTnT peak value; copeptin peak, copeptin peak value; NTproBNP peak, NTproBNP peak value

TABLE 20 - Area under the ROC curve and comparison of AUCs for cardiac troponin and neurohormone measurements for the prediction of MACE on admission (1) and for peak values (peak)

Copeptin 1, copeptin admission sample; copeptin peak, copeptin peak value; cTnI B 1, Beckman AccuTnI admission sample; cTnI B peak, Beckman AccuTnI peak value; cTnI CS 1, Stratus CS admission sample; cTnI CS peak, Stratus CS peak value; cTnI S 1, Siemens Ultra admission sample; cTnI S peak, Siemens Ultra peak value; cTnT 1, Roche high-sensitivity cTnT admission sample; cTnT peak, Roche high-sensitivity cTnT peak value; NTproBNP 1, NTproBNP admission sample; NTproBNP peak, NTproBNP peak value.

Test	Area (95% CI)	Contrast	Difference (95% CI)	p-value
cTnI CS 1	0.73 (0.60 to 0.85)	cTnI CS 1 vs copeptin 1	0.15 (0.02 to 0.28)	0.0291
cTnI B 1	0.83 (0.74 to 0.93)	cTnI CS 1 vs NTproBNP 1	−0.04 (−0.15 to 0.07)	0.4431
cTnI S 1	0.80 (0.70 to 0.90)	cTnI B 1 vs copeptin 1	0.25 (0.13 to 0.37)	< 0.0001
cTnT 1	0.79 (0.68 to 0.89)	cTnI B 1 vs NTproBNP 1	0.06 (−0.04 to 0.17)	0.2496
Copeptin 1	0.58 (0.47 to 0.69)	cTnI S 1 vs copeptin 1	0.22 (0.10 to 0.34)	0.0004
NTproBNP 1	0.77 (0.65 to 0.89)	cTnI S 1 vs NTproBNP 1	0.03 (−0.07 to 0.13)	0.5951
		cTnT 1 vs copeptin 1	0.21 (0.09 to 0.33)	0.0006
		cTnT 1 vs NTproBNP 1	0.02 (−0.08 to 0.12)	0.6860
		Copeptin 1 vs NTproBNP 1	−0.19 (−0.30 to −0.09)	0.0004
cTnI CS peak	0.98 (0.96 to 1.00)	cTnI CS peak vs copeptin peak	0.42 (0.35 to 0.48)	< 0.0001
cTnI B peak	0.93 (0.88 to 0.97)	cTnI CS peak vs NTproBNP peak	0.14 (0.08 to 0.21)	< 0.0001
cTnI S peak	0.94 (0.90 to 0.97)	cTnI B peak vs copeptin peak	0.36 (0.29 to 0.43)	< 0.0001
cTnT peak	0.92 (0.88 to 0.97)	cTnI B peak vs NTproBNP peak	0.09 (0.03 to 0.15)	0.0044
Copeptin peak	0.56 (0.50 to 0.62)	cTnI S peak vs copeptin peak	0.37 (0.30 to 0.44)	< 0.0001
NTproBNP peak	0.84 (0.78 to 0.90)	cTnI S peak vs NTproBNP peak	0.10 (0.04 to 0.16)	0.0014
		cTnT peak vs copeptin peak	0.36 (0.30 to 0.42)	< 0.0001
		cTnT peak vs NTproBNP peak	0.08 (0.04 to 0.13)	0.0002
		Copeptin peak vs NTproBNP peak	−0.27 (−0.35 to −0.20)	< 0.0001

When measured on admission, all four troponin methods and NTproBNP were significantly better outcome predictors than copeptin. On the admission sample, none of the four troponin methods predicted adverse events significantly better than measurement of NTproBNP. A different pattern was seen when examining measurements of peak value. All four troponin methods were significantly better outcome predictors than NTproBNP when measured as the peak of the admission or 90-minute sample. Again, copeptin performed poorly and was significantly worse than NTproBNP.

Estimation of the potential economic impact (clinical effectiveness and cost-effectiveness) of using highly sensitive troponin assays or the range of new cardiac biomarkers instead of an admission and 12-hour troponin measurement

Economic impact of measuring a panel of contemporary cardiac markers compared with the measurement of cardiac troponin alone for early differential diagnosis in chest pain patients

Currently, the costs of performing troponin, CK-MB and myoglobin measurements are equivalent. All utilise the same equipment and measurement is performed by immunoassay. The measurement of troponin is required by the universal definition of myocardial infarction. Measurement of CK-MB and myoglobin in addition could be justified only if there was superior diagnostic performance of the panel of assays. As there was no diagnostic efficiency to be gained in measuring a panel compared with a single test, Cost minimisation analysis shows that measurement of cardiac troponin alone was the most cost-effective diagnostic strategy.

Economic impact of combining a novel biomarker of myocardial injury with cardiac troponin measurement

Objective

The objective was to estimate the potential cost-effectiveness of using highly sensitive troponin assays (at presentation alone or at presentation and 90 minutes later) and new cardiac biomarkers instead of a 10- to 12-hour troponin measurement.

After review of the results of the analytical part of the project, the following diagnostic strategies were applied to each patient:

1. no testing: discharge all patients without treatment

2. high-sensitivity troponin at presentation: discharge home if test is negative or admit to hospital for troponin testing at 10–12 hours if positive

3. high-sensitivity troponin and H-FABP at presentation: discharge home if both tests are negative or admit to hospital for troponin testing at 10–12 hours if either test is positive

4. high-sensitivity troponin at presentation and at 90 minutes: discharge home if both tests are negative or admit to hospital for troponin testing at 10–12 hours if either test is positive

5. standard troponin testing at 10–12 hours.

The cTnT and H-FABP data from this study were used to estimate the sensitivity and specificity of strategies 2–4. Only H-FABP in combination with troponin was tested because this combination was both more sensitive and more specific than other biomarker combinations (troponin with copeptin or troponin with NTproBNP) and so it would clearly dominate them if the costs of all biomarkers were assumed to be the same.

The main analysis used data from cTnT to estimate the sensitivity and specificity of cTnT at presentation, cTnT and H-FABP at presentation and cTnT at presentation and at 90 minutes. In a secondary analysis the same strategies were tested but using data from cTnI (Stratus CS), which analysis suggested may have superior diagnostic accuracy. The estimates used are presented inTables 21and22.

TABLE 21 - Sensitivity and specificity of strategies tested

Strategy	Sensitivity (95% CI)	Specificity (95% CI)
No testing	0	1
High-sensitivity cTnT at presentation	0.778 (0.655 to 0.873)	0.962 (0.946 to 0.975)
High-sensitivity cTnT and H-FABP at presentation	0.857 (0.746 to 0.933)	0.916 (0.894 to 0.935)
High-sensitivity cTnT at presentation and at 90 minutes	0.825 (0.709 to 0.909)	0.949 (0.930 to 0.963)
Troponin at 10–12 hours	1	1

TABLE 22 - Sensitivity and specificity of strategies tested using cTnI Stratus CS instead of cTnT

Strategy	Sensitivity (95% CI)	Specificity (95% CI)
No testing	0	1
High-sensitivity cTnI at presentation	0.794 (0.673 to 0.885)	0.980 (0.967 to 0.989)
High-sensitivity cTnI and H-FABP at presentation	0.921 (0.824 to 0.974)	0.923 (0.901 to 0.941)
High-sensitivity cTnI at presentation and at 90 minutes	0.952(0.867 to 0.990)	0.969 (0.954 to 0.980)
Troponin at 10–12 hours	1	1

Main analysis deterministic results

The results of the main deterministic analysis for cTnT strategies in a hypothetical cohort of patients (n = 2240) in the three scenarios tested, that is, doctor on demand, twice-daily ward round and once-daily ward round, are shown inTable 23. As expected, the effectiveness of the strategies (as measured by the total QALYs) increases in accordance with the strategy sensitivity, as an increase in sensitivity results in more patients of myocardial infarction being detected and treated. The total costs for each testing strategy increase as the specificity decreases and more patients require 10-hour troponin testing. However, the direct costs of measuring troponin at baseline and at 90 minutes exceed the costs of measuring troponin and H-FABP at baseline, so the former strategy is more expensive and thus dominated by the latter. The incremental cost-effectiveness ratio (ICER) reports the additional cost required using the strategy to accrue 1 additional QALY compared with the next most effective alternative. NICE decision-making suggests that a threshold of £20,000–30,000 per QALY is usually used, so a strategy is unlikely to be considered cost-effective if the ICER exceeds £20,000–30,000 per QALY.

TABLE 23 - Main analysis: deterministic results of the cost-effectiveness analysis using cTnT

	Doctor-on-demand scenario			Twice-daily ward round scenario			Once-daily ward round scenario
	Total costs (£)	Total QALYs	ICER (£)	Total costs (£)	Total QALYs	ICER (£)	Total costs (£)	Total QALYs	ICER (£)
No testing	965,994	26,226.68	–	965,994	26,226.68	–	965,994	26,226.68	–
High-sensitivity cTnT at presentation	1,581,263	26,349.42	5012	1,614,048	26,349.42	5280	1,638,450	26,349.42	5479
High-sensitivity cTnT at presentation and at 90 minutes	1,715,256	26,354.37	Dominated	1,755,642	26,354.37	Dominated	1,785,754	26,354.37	Dominated
High-sensitivity cTnT and H-FABP at presentation	1,682,362	26,358.72	11,026	1,736,440	26,358.72	13,160	1,776,146	26,358.72	14,806
10-hour troponin	2,016,540	26,386.36	12,090	2,416,409	26,386.36	24,600	2,705,696	26,386.36	33,630

At the £20,000 per QALY threshold, 10-hour troponin testing is cost-effective (£12,090 per QALY) in the doctor-on-demand scenario (if a decision can be made and the patient discharged as soon as a negative troponin result is available) but not in the other scenarios, where the ICER for 10-hour troponin, compared with high-sensitivity cTnT and H-FABP at presentation, exceeds £20,000 per QALY. In the other two scenarios (once-daily ward round and twice-daily ward rounds), the analysis shows that the strategies based on high-sensitivity cTnT and H-FABP at presentation are likely to be considered cost-effective compared with the next most effective alternative using a £20,000 per QALY threshold.

If a £30,000 per QALY threshold is used then 10-hour troponin testing is cost-effective in the doctor-on-demand scenario (£12,090 per QALY) and the twice-daily ward round scenario (£24,600 per QALY), whereas the high-sensitivity cTnT and H-FABP at presentation strategy is considered cost-effective in the once-daily ward round scenario (£14,806 per QALY).

Secondary analysis deterministic results

The results of the secondary analysis using cTnI are reported inTable 24. High-sensitivity cTnI at presentation and at 90 minutes was cost-effective in all three scenarios at the £20,000 per QALY threshold. At the £30,000 per QALY threshold, the 10-hour troponin strategy is cost-effective only in the doctor-on-demand scenario (£24,327 per QALY), with its ICER substantially exceeding the threshold in the other scenarios. High-sensitivity cTnI at presentation and at 90 minutes is cost-effective in the once-daily ward round scenario (£8310 per QALY) and the twice-daily ward round scenario (£7929 per QALY) at the £30,000 per QALY threshold.

TABLE 24 - Secondary analysis: deterministic results of the cost-effectiveness analysis using cTnI

	Doctor-on-demand scenario			Twice-daily ward round scenario			Once-daily ward round scenario
	Total costs (£)	Total QALYs	ICER (£)	Total costs (£)	Total QALYs	ICER (£)	Total costs (£)	Total QALYs	ICER (£)
No testing	965,994	26,226.68	–	965,994	26,226.68	–	965,994	26,226.68	–
High-sensitivity cTnI at presentation	1,576,820	26,350.78	4922	1,609,240	26,350.78	5183	1,628,460	26,350.78	5338
High-sensitivity cTnI and H-FABP at presentation	1,711,921	26,370.19	6960	1,764,695	26,370.19	Extendedly dominated	1,803,022	26,370.19	Extendedly dominated
High-sensitivity cTnI at presentation and at 90 minutes	1,773,748	26,376.38	9988	1,812,245	26,376.38	7929	1,841,210	26,376.38	8310
10-hour troponin	2,016,540	26,386.36	24,327	2,416,409	26,386.36	60,537	2,705,696	26,386.36	86,621

Main probabilistic results

Probabilistic analysis incorporated uncertainty in the parameter estimates to provide estimates of the probability that each cTnT strategy would be cost-effective at different thresholds for willingness to pay for health gain. Figure 19shows the probability in the probabilistic sensitivity analyses that each strategy is optimal at thresholds of willingness to pay ranging from zero to £50,000 per QALY in the doctor-on-demand, twice-daily ward round and once-daily ward round scenarios. Tables containing the probabilities of cost-effectiveness of each cTnT strategy for the three scenarios at different willingness-to-pay thresholds are presented inAppendix 3.

FIGURE 19.

Cost-effectiveness acceptability curves of cTnT strategies. (a) Doctor-on-demand scenario; (b) twice-daily ward round scenario; (c) once-daily ward round scenario. MAICER, maximum acceptable incremental cost-effectiveness ratio; High Sens Trop T, high-sensitivity TnT at presentation; High Sens Trop T + H-FABP, high-sensitivity TnT and H-FABP at presentation; High Sens Trop T + 90 minutes, high-sensitivity TnT at presentation and 90 minutes; 10 hour Trop, 10-hour troponin.

In the doctor-on-demand scenario the high-sensitivity cTnT and H-FABP at presentation strategy has the highest probability of being optimal at thresholds between £6000 and £14,000 per QALY, whereas above £14,000 per QALY 10-hour troponin testing has the highest probability of being optimal. In the twice-daily ward round scenario, high-sensitivity cTnT and H-FABP at presentation has the highest probability of being optimal at thresholds between £8000 and £27,000 per QALY, whereas above £27,000 per QALY 10-hour troponin testing has the highest probability of being optimal. In the once-daily ward round scenario, high-sensitivity cTnT and H-FABP at presentation has the highest probability of being optimal at thresholds between £8000 and £37,000 per QALY, whereas 10-hour troponin testing is optimal only above thresholds of £37,000 per QALY. These results reflect the deterministic analysis and suggest that high-sensitivity cTnT and H-FABP at presentation has the highest probability of being cost-effective in most scenarios and at typically used thresholds for willingness to pay.

Secondary analysis probabilistic results

The secondary probabilistic analysis for cTnI strategies using the doctor-on-demand, twice-daily ward round and once-daily ward round scenarios is shown inFigure 20. Tables containing the probabilities of cost-effectiveness of each cTnI strategy for the three scenarios at different willingness-to-pay thresholds are presented inAppendix 4.

FIGURE 20.

Cost-effectiveness acceptability curves of cTnI strategies. (a) Doctor-on-demand scenario; (b) twice-daily ward round scenario; (c) once-daily ward round scenario. MAICER, maximum acceptable incremental cost-effectiveness ratio; High Sens Trop I, high-sensitivity TnI at presentation; High Sens Trop I + H-FABP, high-sensitivity TnI and H-FABP at presentation; High Sens Trop I + 90 minutes, high-sensitivity TnI at presentation and 90 minutes; 10 hour Trop, troponin at 10–12 hours.

In the doctor-on-demand scenario the high-sensitivity cTnI and H-FABP at presentation strategy has the highest probability of being optimal at thresholds between £5000 and £12,000 per QALY; the high-sensitivity cTnI at presentation and at 90 minutes strategy is optimal between £12,000 and £28,000 per QALY; and 10-hour troponin testing is optimal above thresholds of £28,000 per QALY. In the twice-daily ward round and once-daily ward round scenarios, the high-sensitivity cTnI at presentation and at 90 minutes strategy has the highest probability of being optimal at all thresholds tested above £8000 per QALY and £7000 per QALY respectively. Again, these results reflect the deterministic analysis results inTable 24and suggest that the strategy using high-sensitivity cTnI on presentation and at 90 minutes has the highest probability of being cost-effective in most scenarios and at typically used thresholds for willingness to pay.

Chapter 5 Discussion

Acknowledgements

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Appendix 1 Detailed results of missed acute myocardial infarction cases by troponin measurement method

Detailed results of missed acute myocardial infarction cases by troponin measurement method (PDF download)

Appendix 2 Detailed results of troponin elevation in non-acute coronary syndrome patients

Detailed results of troponin elevation in non-acute coronary syndrome patients (PDF download)

Appendix 3 Probabilistic sensitivity analysis results for troponin T strategies

Probabilistic sensitivity analysis results for troponin T strategies (PDF download)

Appendix 4 Probabilistic sensitivity analysis results for troponin I strategies

Probabilistic sensitivity analysis results for troponin I strategies (PDF download)

Appendix 5 Study protocol

Study protocol (PDF download)

Glossary

Area under the curve

The calculated integral underneath a plot of test sensitivity against (1 – test specificity).

Biomarker

A metabolic intermediary molecule, signal molecule, enzyme or protein that significantly changes in response to a disease state and can be used to monitor onset or progress of disease, or predict outcome in response to treatment.

Cost-effectiveness acceptability curve

A way of illustrating cost-effectiveness results by plotting the probability that the intervention is cost-effective (y-axis) against the maximum that society is willing to pay for an improvement in health (x-axis).

Cost-effectiveness plane

A way of illustrating cost-effectiveness results by plotting the mean incremental cost and effectiveness on a four-quadrant graph. Interventions that are more costly and more effective fall in the north-east quadrant.

Dalton

Unit of atomic mass.

False-negative

A test result erroneously indicating that a patient with a condition does not have that condition.

False-positive

A test result erroneously indicating that a patient without a condition does have that condition.

Incremental cost-effectiveness ratio

The difference in costs between one intervention and an alternative, divided by the difference in outcomes.

Likelihood ratio

Describes how many times more likely a person with a disease is to receive a particular test result than a person without the disease. A likelihood ratio of a positive test result is usually a number > 1; a likelihood ratio of a negative test result usually lies between 0 and 1.

Quality-adjusted life-year

A measure of the benefit of health care combining the impact of both expected length of life and quality of life.

Receiver operating characteristic curve

Graphical representation of the relationship between ‘true-positive fraction’ (sensitivity) and ‘false-positive fraction’ (1 – specificity). It displays the trade-offs between sensitivity and specificity as a result of varying the cut-off value for positivity in case of a continuous test result.

Reference standard

Established test(s) against which the accuracy of a new test for detecting a particular condition can be evaluated.

Sensitivity (true-positive rate)

The proportion of individuals with the target condition in a population who are correctly identified by a diagnostic test.

Specificity (true-negative rate)

The proportion of individuals free of the target condition in a population who are correctly identified by a diagnostic test.

Test accuracy

The proportion of test results that are correctly identified by the test.

True-negative

A test result correctly identifying that a patient without a condition does not have that condition.

True-positive

A test result correctly identifying that a patient with a condition has that condition.

List of abbreviations

ACS

acute coronary syndrome

AM

adrenomedullin

AMI

acute myocardial infarction

ANP

atrial natriuretic peptide

AUC

area under the curve

AVP

arginine vasopressin

BNP

B-type natriuretic peptide

CK

creatine kinase

CK-MB

creatine kinase MB isoenzyme

CRP

C-reactive protein

cTnI

cardiac troponin I

cTnT

cardiac troponin T

CTU

Clinical Trials Unit

CV

coefficient of variation

ECG

electrocardiogram

ED

emergency department

EDTA

ethylenediaminetetraacetic acid

FABP

fatty acid-binding protein

GDF15

growth differentiation factor 15

GRACE

Global Registry of Acute Coronary Events

H-FABP

heart-type fatty acid-binding protein

HTA

Health Technology Assessment

ICER

incremental cost-effectiveness ratio

IL

interleukin

IL-1

interleukin 1

IL-1β

interleukin 1 beta

IL-33

interleukin 33

IL-6

interleukin 6

IL-6R

interleukin-6 receptor

IMA

ischaemia-modified albumin

IQR

interquartile range

MACE

major adverse cardiac event

MMP

matrix metalloproteinase

MPO

myeloperoxidase

NICE

National Institute for Health and Care Excellence

NSTEMI

non-ST-segment elevation myocardial infarction

NTproBNP

N-terminal pro-B-type natriuretic peptide

NYHA

New York Heart Association

PAPP-A

pregnancy-associated plasma protein A

QALY

quality-adjusted life-year

RATPAC

Randomised Assessment of Treatment using Panel Assay of Cardiac markers

RATPAC-CBE

Randomised Assessment of Treatment using Panel Assay of Cardiac markers – Contemporary Biomarker Evaluation

RCV

relative change value

ROC

receiver operating characteristic

sIL-6R

soluble interleukin-6 receptor

STEMI

ST-segment elevation myocardial infarction

TIMP

tissue inhibitor of metalloproteinase

TnC

troponin C

TnI

troponin I

TnT

troponin T

WHO

World Health Organization