High-sensitivity troponin assays for the early rule-out or diagnosis of acute myocardial infarction in people with acute chest pain: a systematic review and cost-effectiveness analysis

Abbott ARCHITECT high-sensitivity troponin I assay

The Abbott ARCHITECT^® hs-cTnI STAT assay (Abbott Laboratories, Chicago, IL, USA) can be used with the Abbott ARCHITECT^® i2000SR and i1000SR analysers (Abbott Laboratories). The assay is a quantitative, chemiluminescent microparticle immunoassay (CMIA) for serum or plasma samples. Results are available within 16 minutes. The ARCHITECT hs-cTnI STAT assay can detect cTnI in 96% of the reference population, and has a recommended 99th percentile cut-off of 26.2 ng/l, with a CV of 4%. 15 The assay is CE marked and available to the NHS.

AccuTnI+3 troponin I assay (Beckman Coulter)

The AccuTnI+3 hs-cTnI assay is approved for use on both the Beckman Coulter Access 2 and DxI analysers (Brea, CA, USA) and has recently received CE mark approval. The assay is a quantitative, two-site paramagnetic particle chemiluminescent sandwich immunoassay for serum or plasma samples. The AccuTnI+3 assay has a recommended 99th percentile cut-off of 40 ng/l, with a CV of < 10%. 16 A recent conference abstract reported data suggesting that the assay can detect cTnI in 88% of the reference population when used on the Access II analyser and in 58% of the reference population when used on the DxI analyser. 17 The same study17 reported a difference in the 99th centile upper reference limit between the two analysers (41 ng/l for the Access II and 34 ng/l for the DxI).

Roche Elecsys high-sensitivity troponin T assay

The Roche Elecsys^® cTnT-hs (high-sensitive troponin T assay) and Roche Elecsys^® cTnT-hs STAT assays (Roche Diagnostics GmbH, Mannheim, Germany) can be used on the Roche Elecsys^® 2010 analyser (Roche Diagnostics GmbH) and the cobas Modular Analytics e series immunoassay analysers, e411 platform. The assay is a quantitative, sandwich electrochemiluminescence immunoassay (ECLIA) for serum and plasma samples. Results are available within 18 minutes with the standard assay and within 9 minutes if the STAT assay is used. Both versions of the assay can detect cTnT in 61% of the reference population and have a recommended 99th percentile cut-off of 14 ng/l, with a CV of < 10%. 18 Both versions of the assay are CE marked and available to the NHS.

A summary of the product properties of hs-cTnI and hs-cTnT assays available to the NHS in England and Wales is provided in Table 1.

The hs-cTn assays can be used as single diagnostic tests, or in combination with other cardiac biomarkers, for example heart fatty acid binding protein (H-FABP) and copeptin. The use of combinations of cardiac biomarkers may increase sensitivity, when a positive result on either test is considered to be indicative of AMI, although this increase may be achieved at the expense of decreased specificity. Conversely, if a positive result on both tests is required before AMI is diagnosed, increased specificity and reduced sensitivity are likely. It is currently unclear which, if any, of the available cardiac biomarkers could add clinical benefit if used in combination with hs-cTnI and hs-cTnT, compared with hs-cTnI and hs-cTnT alone. A recent systematic review reported some data for combination testing, but none of the identified studies of Tns combined with other biomarkers used high-sensitivity methods. 7 Retrospective analysis of data from one arm of a randomised controlled trial (RCT) by the same authors provided some indication that the use of H-FABP in combination with hs-cTn, on admission, may increase sensitivity for AMI without decreasing specificity. 19 This increase was equivalent to the sensitivity achieved by serial hs-cTn testing on admission and at 90 minutes. 19 However, these tests are not readily available for analytical platforms in routine use in the NHS and discussions at the scoping stage of this assessment concluded that practical applications of H-FABP and copeptin assays and evidence for their effectiveness are not yet sufficiently developed to justify their inclusion.

This assessment will consider hs-cTn assays used singly or in series, up to 4 hours after the onset of chest pain or up to 4 hours after presentation (as reported); for serial Tn measurements, both data on change in Tn levels and peak Tn will be considered (as reported).

Diagnostic assessment

The assessment of patients with suspected ACS is described in the National Institute for Health and Care Excellence (NICE) clinical guideline 95 (CG95)11 ‘Chest pain of recent onset: Assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin’. The guideline11 specifies that initial assessment should include a resting 12-lead ECG along with a clinical history, a physical examination and biochemical marker analysis. For people in whom a regional ST segment elevation or presumed new left branch bundle block is seen on ECG, management should follow NICE clinical guideline 167 (CG167)20 ‘The acute management of AMI with ST segment elevation’. People without persistent ST-elevation changes on ECG [i.e. with suspected non-ST segment elevation acute coronary syndrome (NSTE-ACS)], should receive further investigation using cardiac biomarkers, with the aim of distinguishing NSTEMI from UA. NICE CG9511 makes the following recommendations on the use of cardiac biomarkers:

• Take a blood sample for cTnI or cTnT on initial assessment in hospital. These are the preferred biochemical markers to diagnose AMI.

• Take a second blood sample for cTnI or cTnT measurement 10–12 hours after the onset of symptoms.

• Do not use biomarkers such as natriuretic peptides and high-sensitivity C-reactive protein to diagnose an ACS.

• Do not use biomarkers of myocardial ischaemia (such as ischaemia-modified albumin) as opposed to markers of necrosis when assessing people with acute chest pain.

• Take into account the clinical presentation, from the time of onset of symptoms and the resting 12-lead ECG findings, when interpreting Tn measurements.

Clinical guideline 9511 recommends that a diagnosis of NSTEMI should be made using the universal definition of AMI. 8 However, the third universal definition of AMI has been updated since the publication of CG95. 21 The most recent version states that AMI is defined as ‘The detection of a rise and/or fall of cardiac biomarker values (preferably cardiac Tn) with at least one value above the 99th percentile upper reference limit and with at least one of the following: symptoms of ischaemia, new or presumed new significant ST segment T wave changes or new left branch bundle block, development of pathological Q waves in the ECG, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or identification of an intracoronary thrombus by angiography or autopsy’.

The Scottish Intercollegiate Guidelines Network guideline 93 (SIGN 93)12 provides similar recommendations on the diagnostic work-up of people with suspected ACS, stating:

• immediate assessment with a 12-lead ECG

• repeat 12-lead ECG if there is diagnostic uncertainty or change in clinical status, and at discharge

• serum Tn measurement on arrival at hospital

• repeat serum Tn measurement 12 hours after the onset of symptoms

• Tn concentrations should not be interpreted in isolation but with regard to clinical presentation.

Guidelines from the ESC22 on the diagnostic assessment of people with a suspected NSTE-ACS are consistent with those of NICE and SIGN, but additionally acknowledge the use of high-sensitivity Tn assays and make recommendations on a fast-track rule-out protocol. The guidelines22 state that hs-cTn assays have a negative predictive value (NPV) of > 95% for AMI on admission; including a second sample of hs-cTn at 3 hours can increase this to 100%.

Management/treatment

The NICE clinical guideline 94 (CG94), ‘Unstable angina and NSTEMI: The early management of unstable angina and non-STEMI’,23 provides recommendations on the management of people with suspected NSTE-ACS. The guideline23 states that initial treatment should include a combination of antiplatelet (aspirin, clopidogrel and glycoprotein IIb/IIIa inhibitors) and antithrombin therapy, and should take into account contraindications, risk factors and the likelihood of percutaneous coronary intervention. SIGN 9312 makes similar recommendations. It is recommended that people with a diagnosis of NSTEMI, who are assessed as being at low risk of future complications, receive conservative treatment with aspirin and/or clopidogrel, or aspirin in combination with ticagrelor. People at a higher risk of future complications should be offered coronary angiography (within 96 hours of admission), with subsequent coronary revascularisation by percutaneous coronary intervention or coronary artery bypass grafting where indicated. 23 Additional testing to quantify inducible ischaemia may also be used, before discharge, to identify those who may need further intervention23 and SIGN 9312 also recommends functional testing to identify people at higher risk. SIGN 9312 states that people in whom an elevated Tn level is not observed may be discharged for further follow-up according to clinical judgement and, in some cases, the results of ischaemia testing. 12

Longer-term follow-up of people who have had an AMI is described in full in NICE clinical guideline 48 (CG48)24 ‘Secondary prevention in primary and secondary care for patients following a myocardial infarction’. This includes recommendations on lifestyle changes, cardiac rehabilitation programmes, drug therapy [including a combination of angiotensin-converting enzyme (ACE) inhibitors, aspirin, beta-blockers and statins], and further cardiological assessment to determine whether coronary revascularisation is required.

Search strategy

Search strategies were based on intervention (high-sensitivity Tn assays) and target condition, as recommended in the CRD guidance for undertaking reviews in health care25 and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. 27

Candidate search terms were identified from target references, browsing database thesauri [e.g. MEDLINE medical subject heading (MeSH) and EMBASE Emtree], existing reviews identified during the rapid appraisal process and initial scoping searches. These scoping searches were used to generate test sets of target references, which informed text mining analysis of high-frequency subject-indexing terms using EndNote X4 reference management software (Thomson Reuters, CA, USA). Strategy development involved an iterative approach testing candidate text and indexing terms across a sample of bibliographic databases, aiming to reach a satisfactory balance of sensitivity and specificity.

The following databases were searched for relevant studies from 2005 to October 2013:

• MEDLINE (OvidSP): 2005–2013/10/wk1.

• MEDLINE In-Process Citations and Daily Update (OvidSP): up to 2013/10/1.

• EMBASE (OvidSP): 2005–2013/10/10.

• Cochrane Database of Systematic Reviews (CDSR) (Wiley): Cochrane Library Issue 10 2005–2013/10/11.

• Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley): Cochrane Library Issue 9 2005–2013/10/11.

• Database of Abstracts of Reviews of Effects (DARE) (Wiley): Cochrane Library Issue 3 2005–July 2013.

• Health Technology Assessment (HTA) Database (Wiley): Cochrane Library Issue 3 2005–July 2013.

• Science Citation Index (SCI) (Web of Science): 2005–2013/10/14.

• Conference Proceedings Citation Index – Science (CPCI) (Web of Science): 2005–2013/10/14.

• Latin American and Caribbean Health Sciences Literature (LILACS) (Internet): 2005–2013/10/11 (http://regional.bvsalud.org/php/index.php?lang = en).

• International Network of Agencies for Health Technology Assessment (INAHTA) Publications (Internet): 2005–2013/10/15 (www.inahta.org/).

• BIOSIS Previews (Web of Knowledge): 2005–2013/10/11.

• National Institute for Health Research (NIHR) Health Technology Assessment programme (Internet): 2005–2013/10/14.

• Aggressive Research Intelligence Facility (ARIF) database (Internet): 2005–2013/10/16 (www.birmingham.ac.uk/research/activity/mds/projects/HaPS/PHEB/ARIF/index.aspx).

• Medion database (Internet): 2005–2013/10/16 (www.mediondatabase.nl/).

• PROSPERO (International Prospective Register of Systematic Reviews) (Internet): up to 2013/10/10 (www.crd.york.ac.uk/prospero/).

Completed and ongoing trials were identified by searches of the following resources (2005 to October 2013):

• National Institutes of Health (NIH) ClinicalTrials.gov (Internet): up to 2013/10/1 (www.clinicaltrials.gov/).

• Current Controlled Trials (CCT) (Internet): up to 2013/10/10 (www.controlled-trials.com/).

• World Health Organization International Clinical Trials Registry Platform (ICTRP) (Internet): up to 2013/10/10 (www.who.int/ictrp/en/).

No restrictions on language or publication status were applied. Date restrictions were applied based on expert advice on the earliest appearance of literature of high-sensitivity Tn assays. Searches took into account generic and other product names for the intervention. The main EMBASE strategy for each set of searches was independently peer reviewed by a second Information Specialist, using the Canadian Agency for Drugs and Technologies in Health (CADTH) Peer Review Checklist. 28 Search strategies were developed specifically for each database and the keywords associated with high-sensitivity Tn T/I were adapted according to the configuration of each database. Full search strategies are reported in Appendix 1.

Electronic searches were undertaken for the following conference abstracts (selected based on advice from expert committee members):

• American Heart Association (AHA) Scientific Sessions (Internet): 2009–13 (http://my.americanheart.org/professional/Sessions/ScientificSessions/Archive/Archive-Scientific-Sessions_UCM_316935_SubHomePage.jsp).

• American Association for Clinical Chemistry (AACC) (Internet): 2009–13 (www.aacc.org/resourcecenters/meet_abstracts_archive/abstracts_archive/annual_meeting/Pages/default.aspx#).

• European Society of Cardiology (ESC) (Internet): 2009–13 (http://spo.escardio.org/abstract-book/search.aspx).

Identified references were downloaded in EndNote X4 software for further assessment and handling. References in retrieved articles were checked for additional studies. The final list of included papers was checked on PubMed for retractions, errata and related citations. 29–31

Inclusion and exclusion criteria

Inclusion criteria for each of the clinical effectiveness questions are summarised in Table 2. Studies that fulfilled these criteria were eligible for inclusion in the review.

Inclusion screening and data extraction

Two reviewers (MW and PW) independently screened the titles and abstracts of all of the reports identified by searches, and any discrepancies were discussed and resolved by consensus. Full copies of all of the studies that were deemed potentially relevant were obtained and the same two reviewers independently assessed these for inclusion; any disagreements were resolved by consensus. Details of studies excluded at the full paper screening stage are presented in Appendix 4.

Studies cited in materials provided by the manufacturers of hs-cTn assays were first checked against the project reference database, in EndNote X4; any studies not already identified by our searches were screened for inclusion following the process described above.

Data were extracted on the following: study details, inclusion and exclusion criteria, participant characteristics (demographic characteristics and cardiac risk factors), target condition (NSTEMI or AMI), details of the hs-cTnT or hs-cTnI test (manufacturer, timing, and definition of positive diagnostic threshold), details of reference standard [manufacturer, timing, diagnostic threshold for conventional Tn T or I testing, clinical and imaging components of the reference standard, method of adjudication (e.g. two independent clinicians)] and test performance outcome measures [numbers of true-positive (TP), false-positive (FP), false-negative (FN) and true-negative (TN) test results]. Data were extracted by one reviewer, using a piloted, standard data extraction form and checked by a second (MW and PW); any disagreements were resolved by consensus. Full data extraction tables are provided in Appendix 2.

Quality assessment

The methodological quality of included diagnostic test accuracy (DTA) studies was assessed using QUADAS-2. 33 Quality assessments was undertaken by one reviewer and checked by a second (MW and PW); any disagreements were resolved by consensus.

The results of the quality assessments are summarised and presented in tables and graphs in the results of the systematic review and are presented in full, by study, in Appendix 3.

Methods of analysis/synthesis

Sensitivity and specificity were calculated for each set of 2 × 2 data, and plotted in receiver operating characteristic (ROC) space. The bivariate/hierarchical summary receiver operating characteristic (HSROC) model was used to estimate summary sensitivity and specificity with 95% confidence intervals (CIs) and prediction regions around the summary points, and to derive HSROC curves for meta-analyses involving four or more studies. 34–36 This approach allows for between-study heterogeneity in sensitivity and specificity, and for the trade-off (negative correlation) between sensitivity and specificity commonly seen in diagnostic meta-analyses. For meta-analyses with fewer than four studies we estimated separate pooled estimates of sensitivity and specificity, using random-effects logistic regression. 37 Heterogeneity was assessed visually using summary receiver operating characteristic (SROC) plots and statistically using the variance of logit (sensitivity) and logit (specificity), where ‘logit’ indicates the logistic function: the smaller these values, the less heterogeneity between studies. Summary positive and negative likelihood ratios (LR+ and LR–) were derived from the summary estimates of sensitivity and specificity. Analyses were performed in Stata 10 (StataCorp LP, College Station, TX, USA), mainly using the metandi command. For analyses that would not run in Stata we used MetaDiSc version 1.4 (freeware, available to download from www.hrc.es/investigacion/metadisc_en.htm). 38

Analyses were conducted separately for each of the three hs-cTn assays. Analyses were stratified according to whether the study evaluated the prediction of AMI or MACE, timing of collection of blood sample for testing, and the threshold used to define a positive hs-cTn result. We investigated possible sources of heterogeneity using stratified analyses based on the following variables:

• population – studies included mixed populations compared with those that excluded patients with STEMI

• age > 70 years compared with age ≤ 70 years

• patients with pre-existing CAD at baseline compared with patients without pre-existing CAD

• time from symptom onset to presentation < 3 hours compared with > 3 hours

• time from symptom onset to presentation < 6 hours compared with > 6 hours

• low to moderate pre-test probability of disease compared with high pre-test probability of disease.

Stratified analyses were conducted for all time points and thresholds for which sufficient data were available. To investigate the influence of risk of bias on the studies, we restricted analyses to studies conducted in patients at low or unclear risk of bias for the two QUADAS items considered to have the greatest potential to have introduced bias into these studies: the item on patient spectrum (1) and the item on patient flow (4). As the focus of this review was the diagnosis of NSTEMI, we conducted these analyses in studies that excluded patients with STEMI. We used SROC plots to display summary estimates from the various primary and stratified analyses.

We compared the accuracy of the three different hs-cTn assays by tabulating summary estimates from analyses for common time points and thresholds assessed for all assays. Only one study39 provided a direct comparison of all three assays. Estimates of sensitivity, specificity, and LR+ and LR– for each assay derived from this study were included in the summary tables.

Overview of included studies

Based on the searches and inclusion screening described above, 37 publications19,39,40–74 of 18 studies19,39,40,42,44,46,48,49,51,54,55,57,58,63,64,67,70,73 were included in the review; the results sections of this report cites studies using the primary publication and, where this is different, the publication in which the referenced data were reported. Fifteen studies19,39,40,42,44,46,49,51,54,55,57,58,64,67,70 reported accuracy data for the Roche Elecsys hs-cTnT assay, four studies39,48,58,63 reported accuracy data for the Abbott ARCHITECT hs-cTnI assay, and two studies39,73 reported accuracy data for the Beckman Coulter Access hs-cTnI assay; two studies39,58 reported data for more than one assay. No RCTs or current controlled trials (CCTs) were identified; no studies provided data on the effects on patient-relevant outcomes of management based on hs-cTn assays within 4 hours of presentation compared with management based on standard cTn assays at presentation and after 10–12 hours. All studies included in the systematic review were diagnostic cohort studies, which reported data on the diagnostic or prognostic accuracy hs-cTn assays.

Thirteen19,39,40,42,44,48,49,51,55,57,64,67,73 of the 18 included studies19,39,40,42,44,46,48,49,51,54,55,57,58,63,64,67,70,73 were conducted in Europe (two in the UK19,67), four were conducted in Australia and New Zealand,46,54,58,63 and one was conducted in the USA. 70 Thirteen39,40,42,46,48,49,51,54,55,57,63,64,70 of the 18 included studies19,39,40,42,44,46,48,49,51,54,55,57,58,63,64,67,70,73 reported receiving some support from test manufacturers, including supply of assay kits; two studies58,73 did not report any information on funding.

Full details of the characteristics of study participants, study inclusion and exclusion criteria, and hs-cTn assay used and reference standard, and detailed results are reported in the data extraction tables presented in Appendix 2.

Study quality

The main potential sources of bias in the 18 studies19,39,40,42,44,46,48,49,51,54,55,57,58,63,64,67,70,73 included in this assessment relate to patient spectrum and patient flow. There were also concerns regarding the applicability of the patient population and the reference standard in some of the included studies. The results of QUADAS-2 assessments are summarised in Table 3 and Figure 2; full QUADAS-2 assessments for each study are provided in Appendix 3. A summary of the risks of bias and applicability concerns within each QUADAS-2 domain is provided in Table 3.

FIGURE 2.

Summary of QUADAS-2 results for studies of hs-cTn assays.

Diagnostic accuracy of the Roche Elecsys high-sensitivity cardiac troponin T assay

Presentation samples

The summary estimates of sensitivity and specificity, where the diagnostic threshold was defined as the 99th centile for the general population, were 89% (95% CI 85% to 92%) and 82% (95% CI 77% to 86%), based on data from 13 studies;19,39,40,44,46,49,51,54,57,58,64,68,70 the SROC curve for this analysis is shown in Figure 3. The LR+ and LR– were 4.94 (95% CI 3.84 to 6.39) and 0.13 (95% CI 0.10 to 0.19), respectively. These estimates were similar when the analysis was restricted to studies that excluded participants with STEMI; summary estimates of sensitivity and specificity were 88% (95% CI 78 to 93%) and 84% (95% CI 74 to 90%), respectively (SROC curve shown in Figure 4) and the LR+ and LR– were 5.41 (95% CI 3.40 to 8.63) and 0.15 (95% CI 0.08 to 0.26), respectively, based on six studies. 19,40,44,46,51,64 The only study40 conducted in a population which excluded participants with STEMI, which was rated as ‘low or unclear risk of bias’ on all QUADAS domains, reported similar sensitivity and negative LR (see Table 4) to the summary estimates, but lower estimates of specificity [71% (95% CI 66% to 76%)] and LR+ [3.11 (95% CI 2.55 to 3.79)]. Results were also similar when the analysis was restricted to eight studies39,41,49,54,57,58,67,70 with a mixed population (i.e. where the target condition was any AMI); summary estimates of sensitivity and specificity were 89% (95% CI 86% to 91%) and 81% (95% CI 76% to 85%), respectively (SROC curve shown in Figure 5) and the LR+ and LR– were 4.64 (95% CI 3.73 to 5.76) and 0.14 (95% CI 0.11 to 0.17), respectively. Based on these data, it is unlikely that hs-cTnT testing on a single admission sample, using the 99th centile diagnostic threshold, would be considered adequate for either rule-out or rule-in of any AMI or NSTEMI. Although there was little apparent variation in the estimates of test performance derived from the three meta-analyses described above, the result of the second analysis (studies that excluded participants with STEMI) was selected to inform our cost-effectiveness analyses, as it best matched the main population of interest for this assessment (i.e. the target condition was NSTEMI rather than any AMI). The approach of, where possible, selecting data based on a population that excluded STEMI rather than a mixed population to inform cost-effectiveness modelling was applied throughout.

FIGURE 3.

Summary receiver operating characteristic for the Roche Elecsys hs-cTnT assay using the 99th centile threshold and a presentation sample (13 studies19,39–41,46,49,51,54,57,58,64,67,70).

FIGURE 4.

Summary receiver operating characteristic for the Roche Elecsys hs-cTnT assay using the 99th centile threshold and a presentation sample (six studies19,40,44,46,51,64 that excluded participants with STEMI).

FIGURE 5.

Summary receiver operating characteristic for the Roche Elecsys hs-cTnT assay using the 99th centile threshold and a presentation sample (eight studies39,41,49,54,57,58,67,70 with a mixed population, target condition any AMI).

Limited data were identified on additional clinical subgroups (age > 70 years vs. ≤ 70 years,39,53 without pre-existing CAD compared with pre-existing CAD,39,46 and high pre-test probability compared with low to moderate pre-test probability (determined by clinical judgement based on cardiovascular risk factors, type of chest pain, physical findings and ECG abnormalities49). None of these studies excluded participants with STEMI. The study that stratified participants by age39,52 reported a higher estimate of sensitivity [97% (95% CI 92% to 99%)] and a lower estimate of LR– [0.05 (95% CI 0.02 or 0.18)] in participants > 70 years of age than for patients ≤ 70 years of age [88% (95% CI 78% to 94%) and 0.14 (95% CI 0.07 to 0.28), respectively]; the estimates of sensitivity and LR– for people > 70 years of age were also higher and lower, respectively, than the corresponding summary estimates derived from all 13 studies19,39,40,44,46,49,51,52,57,58,64,67,70 that used the 99th centile diagnostic threshold. A similar pattern was apparent for people with a high pre-test probability compared with those with a low to moderate pre-test probability49 and for participants without pre-existing CAD compared with those with pre-existing CAD39,47 (see Table 4). As with the age stratification, the estimates of sensitivity and LR– were higher and lower, respectively, than the corresponding summary estimates derived from all 13 studies19,39,40,44,46,49,51,54,57,58,64,67,70 which used the 99th centile diagnostic threshold, for people with a high pre-test probability and for people without pre-existing CAD. Figure 6 illustrates the variation in performance characteristics of a single admission sample, using the 99th centile diagnostic threshold, when used in different clinical subgroups. These data provide some indication that hs-cTnT testing on a single admission sample, using the 99th centile diagnostic threshold, may be adequate for rule-out of AMI in certain selected populations [older people (≥ 70 years), those without pre-existing CAD, and people classified by clinical judgement as having a high pre-test probability].

FIGURE 6.

Receiver operating characteristic space plot for the Roche Elecsys hs-cTnT assay using the 99th centile threshold and a presentation sample in different clinical subgroups.

Time from onset of chest pain to presentation was inconsistently reported across studies; when reported, the median time from onset ranged from 2.7 hours to 8.25 hours. Full details of all information reported is provided in Appendix 2 (see Baseline study details). Two studies39,67 specifically investigated variation in test performance according to time from symptom onset to presentation. Both of these studies39,67 were conducted in a mixed population (i.e. the target condition was any AMI). Study participants were stratified by presentation before or after 3 hours,39,67 and before or after 6 hours. 67 Summary estimates for the 3-hour stratification indicated that a presentation sample using the 99th centile threshold had higher sensitivity [94% (95% CI 92% to 96%)] and lower specificity [77% (95% CI 75% to 79%)] for any AMI, when used to assess people presenting at > 3 hours after the onset of chest pain than when used to assess early presenters [sensitivity 78% (95% CI 71% to 83%) and specificity 84% (95% CI 81% to 86%)] (see Table 4). The LR– was also lower when the test was used in people presenting after 3 hours from the onset of chest pain [0.08 (95% CI 0.05 to 0.11)] than in early presenters [0.26 (95% CI 0.178 to 0.39)]. Test performance in people presenting after 6 hours from the onset of chest pain was similar to that observed in people presenting after 3 hours (see Table 4). Figure 7 illustrates the variation in performance characteristics of a single admission sample, using the 99th centile diagnostic threshold, when used in people presenting at different times from the onset of chest pain. These data provide some indication that hs-cTnT testing on a single admission sample, using the 99th centile diagnostic threshold, may be adequate for rule-out of AMI when people present after 3 hours from the onset of chest pain, but that longer delays in presentation did not appear to further improve rule-out performance.

FIGURE 7.

Receiver operating characteristic space plot for the Roche Elecsys hs-cTnT assay using the 99th centile threshold and a presentation sample in people presenting at different times after symptom onset.

Five studies39,46,53,54,57,67 considered the performance of a presentation sample using a threshold equivalent to the LoD (5 ng/l) or LoB (3 ng/l) of the assay for the diagnosis of AMI. Three studies39,46,53,54 reported data for the 5 ng/l threshold; one of these studies39,52 reported data at this threshold only for participants > 70 years of age. When this study39,52 was excluded, the summary estimates of sensitivity and specificity were 95% (95% CI 92% to 97%) and 54% (95% CI 51% to 58%), respectively, and the LR+ and LR– were 2.06 (95% CI 1.40 to 2.64) and 0.09 (95% CI 0.07 to 0.17), respectively (see Table 4). Three studies reported data for the 3 ng/l threshold. 42,46,67 The summary estimates of sensitivity and specificity derived from these studies were 98% (95% CI 95% to 99%) and 40% (95% CI 38% to 43%), respectively, and the LR+ and LR– were 1.63 (95% CI 1.24 to 1.86) and 0.05 (95% CI 0.02 to 0.21), respectively (see Table 4). Only one study46 was conducted in a population that excluded people with STEMI; however, estimates of test performance from this study were similar to the summary estimates. For the 3-ng/l threshold, sensitivity and specificity derived from this study were 95% (95% CI 92% to 98%) and 48% (95% CI 44% to 51%), respectively, and the LR+ and LR– were 1.83 (95% CI 1.70 to 1.97) and 0.10 (95% CI 0.05 to 0.18), respectively (see Table 4). 46 For the 5-ng/l threshold, sensitivity and specificity derived from this study were 93% (95% CI 89% to 96%) and 58% (95% CI 55% to 62%), respectively, and the LR+ and LR– were 2.20 (95% CI 2.00 to 2.50) and 0.11 (95% CI 0.07 to 0.19), respectively (see Table 4). 46 These data provide some indication that hs-cTnT testing on a single admission sample may be adequate to rule out any AMI or NSTEMI, where a lower diagnostic threshold (5 ng/l or 3 ng/l) is used.

Multiple samples

Six studies39,40,46,50,52,58,65,70 (data reported in multiple publications) provided data on the performance of a variety of diagnostic strategies involving multiple sampling, most commonly involving a combination of a peak hs-cTn value above the 99th centile diagnostic threshold and a 20% change in hs-cTnT over 2 or 3 hours following presentation (see Table 4). Figure 8 shows the results of these studies plotted in ROC space. One study46,50 reported data for this combination over 2 hours in a population that excluded people with STEMI, and this study46,50 was used in cost-effectiveness modelling. It is important to give full consideration to the optimal way of interpreting combination data of this type. As can be seen from the values reported in Table 4, a positive result from the ‘AND’ combination (defined as both a peak value above the 99th centile AND a change of > 20% over 2 hours) provides the optimum rule-in performance [LR+ 8.42 (95% CI 6.11 to 11.60)]; conversely, a negative result from the ‘OR’ combination (defined as both no value above the 99th centile AND a change of < 20% over 2 hours) provides the optimum rule-out performance [LR– 0.04 (95% CI 0.02 to 0.10)]. Where a patient has a negative result from the ‘AND’ combination/positive result from the ‘OR’ combination (defined as either a peak value above the 99th centile OR a change of > 20% over 2 hours), further investigation is likely to be needed. This optimal interpretation strategy is illustrated in Figure 9, along with a potential initial rule-out step, based on a presentation sample below the LoB threshold (3 ng/l); this strategy is included in cost-effectiveness modelling. Figure 9 shows the application of this two-stage approach to a theoretical cohort of 1000 people presenting with symptoms suggestive of ACS (STEMI excluded); the estimated number of people with AMI and a negative test result who would be erroneously discharged based on this testing strategy is 14 (nine at the first stage and five at the second stage). The prevalence of NSTEMI was estimated to be 17%, based on data from three studies40,46,64 conducted in populations that excluded people with STEMI. Four studies were excluded from the estimate of prevalence because they were considered to have unrepresentative populations: three studies44,51,55 were conducted in coronary care unit populations and one study76 was conducted in a low-risk population. It was assumed that the diagnostic performance of ‘AND’/’OR’ combinations of peak values of hs-cTnT and change over 2 hours, using the 99th centile diagnostic threshold, are the same for people in whom NSTEMI is not ruled out by the initial test (hs-cTnT > LoB) as for the initial population; this was because no test performance data were available for the combination of initial hs-cTnT test using the LoB diagnostic threshold followed by combined peak hs-cTnT and change over 2 hours using the 99th centile threshold.

FIGURE 8.

Receiver operating characteristic space plot of the Roche Elecsys hs-cTnT assay using multiple sampling strategies.

FIGURE 9.

Testing pathway for the Roche Elecsys hs-cTnT assay used in cost-effectiveness modelling.

Diagnostic accuracy of the Abbott ARCHITECT high-sensitivity cardiac troponin I assay

Study details

Four diagnostic cohort studies39,48,58,63 provided data on the diagnostic performance of the Abbott ARCHITECT hs-cTnI assay. Three of these studies39,48,58 assessed the accuracy of the Abbott ARCHITECT hs-cTnI assay for the detection of AMI, and the remaining study63 assessed accuracy for the prediction of MACE within 30 days of the index presentation. None of the studies in this section provided data specific to the population of interest for this assessment; participants with STEMI excluded (i.e. the target condition was NSTEMI rather than any AMI). All four studies39,48,58,63 were conducted in mixed populations. Full details of the baseline characteristics of study populations, including baseline cardiac risk factors, are provided in Appendix 2 (see Baseline study details).

Where a single diagnostic threshold was used to define a positive test result for AMI, all studies in this section39,48,58,63 reported data for the 99th centile for the general population and a single sample taken at presentation. Table 5 provides summary estimates of diagnostic performance for this testing strategy. All other combinations of diagnostic threshold and hs-cTnI test timing were assessed by only one study. Figure 10 shows the diagnostic performance of all testing strategies assessed plotted in ROC space. Diagnostic performance estimates derived from these studies are also provided. Key results used in the cost-effectiveness modelling conducted for this assessment are highlighted in bold text. Full results (including numbers of TP, FP, FN and TN test results) for all studies and all data sets are provided in Appendix 2 (see Study results).

TABLE 5 - Accuracy of the Abbott ARCHITECT hs-cTnI assay: summary estimates (95% CIs)

Key results, used in cost-effectiveness modelling, are highlighted in bold text.

Grouping	Population	Risk of bias	n	Sensitivity (%)	Specificity (%)	LR+	LR–
Prediction of AMI
Presentation samples, 99th centile threshold	Mixed	Mixed	3 39 , 48 , 58	80 (77 to 83)	93 (92 to 94)	11.47 (9.04 to 16.19)	0.22 (0.16 to 0.27)
Presentation sample, LoD threshold	Mixed	High risk for patient flow	1 48	100 (98 to 100)	35 (32 to 38)	1.54 (1.47 to 1.62)	0.01 (0.00 to 0.08)
3 hours after presentation, 99th centile threshold	Mixed	High risk for patient flow	1 48	98 (96 to 99)	90 (88 to 92)	10.16 (8.38 to 12.31)	0.02 (0.01 to 0.05)
Presentation and 2–3 hours, peak above 99th centile threshold	Mixed	Unclear risk for patient spectrum and flow	158	91 (81 to 96)	93 (91 to 95)	12.94 (9.74 to 17.19)	0.09 (0.04 to 0.23)
Above LoD threshold on admission and Δ20%	Mixed	High risk for patient flow	148	82 (78 to 86)	52 (49 to 55)	1.73 (1.59 to 1.88)	0.34 (0.26 to 0.43)
On presentation and at 3 hours, Δ20%	Mixed	High risk for patient flow	148	77 (72 to 82)	26 (23 to 29)	1.04 (0.97 to 1.12)	0.87 (0.69 to 1.11)
Prediction of MACE
Presentation samples, 99th centile threshold	Mixed	High risk for patient flow for one study	239,63	88 (85 to 91)	93 (91 to 94)	12.57 (8.88 to 15.35)	0.13 (0.06 to 0.28)

FIGURE 10.

Receiver operating characteristic space plot of the Abbott ARCHITECT hs-cTnT assay.

Multiple samples

Two studies48,58 provided data on the performance of a variety of diagnostic strategies involving multiple sampling (see Table 5). None of these strategies appeared to offer a performance advantage over testing based on a single sample. Figure 11 illustrates our proposed optimal testing pathway for the Abbott ARCHITECT hs-cTnI assay; this strategy is included in cost-effectiveness modelling. As with Figure 9, which presents the Roche Elecsys hs-cTnT optimal strategy, Figure 11 shows the application of this two-stage approach to a theoretical cohort of 1000 people presenting with symptoms suggestive of ACS (STEMI excluded), with a prevalence of NSTEMI of 17%; the estimated number of people with AMI and a negative test result who would be erroneously discharged based on this testing strategy is three (zero at the first stage and three at the second stage). It was assumed that the diagnostic performance of hs-TnI using the 99th centile diagnostic threshold on a sample taken 3 hours after presentation is the same for people in whom NSTEMI is not ruled out by the initial test (hs-cTnI > LoD) as for the initial population; this was because no test performance data were available for the combination of initial hs-cTnI test using the LoD diagnostic threshold followed by 3-hour hs-cTnI and using the 99th centile threshold.

FIGURE 11.

Testing pathway for the Abbott ARCHITECT hs-cTnI assay used in cost-effectiveness modelling.

Diagnostic accuracy of the Beckman Coulter Access high-sensitivity cardiac troponin I assay

Study details

Two diagnostic cohort studies,39,73 reported in three publications,39,64,73 provided data on the diagnostic performance of the Beckman Coulter Access hs-cTnI assay. Both studies assessed a precommercial version of the assay and both reported accuracy data for the diagnosis of AMI (any AMI65,73 or NSTEMI39). No study assessed the performance of the Beckman Coulter Access hs-cTnI assay for the prediction of MACE within 30 days of the index admission. The diagnostic performance estimates, for all combinations of diagnostic threshold and test timing assessed by included studies, are summarised in Table 6. Figure 12 shows the diagnostic performance of all testing strategies assessed, plotted in ROC space.

TABLE 6 - Accuracy of the Beckman Coulter Access hs-cTnI assay: summary estimates (95% CIs)

Key results, used in cost-effectiveness modelling, are highlighted in bold text.

Grouping	Population	Risk of bias	n	Sensitivity (%)	Specificity (%)	LR+	LR–
Prediction of AMI
Presentation sample, 9 ng/l and 18 ng/l	All	High risk for patient flow on one study	239,73	92 (88 to 95)	75 (72 to 77)	3.68 (2.46 to 4.48)	0.11 (0.07 to 0.16)
Presentation sample, 99th centile (9 ng/l)	Mixed	High risk for patient flow	1 39	92 (88 to 95)	75 (72 to 78)	3.67 (3.26 to 4.13)	0.11 (0.07 to 0.17)
On presentation and at 1 hour: Δ27%	STEMI excluded	High risk for patient flow	139,63	63 (53 to 71)	66 (63 to 69)	1.85 (1.55 to 2.21)	0.56 (0.44 to 0.72)

FIGURE 12.

Receiver operating characteristic space plot of the Beckman Coulter Access hs-cTnI assay.

Comparative diagnostic accuracy of the Roche Elecsys high-sensitivity troponin T assay, the Abbott ARCHITECT high-sensitivity troponin I assay and the Beckman Coulter Access high-sensitivity troponin I assay

Only one study39 provided data for a direct comparison of the diagnostic performance of all thee hs-cTn assays in the same population. These data were for the use of the 99th centile threshold in a sample taken at presentation. This was also the only time point and threshold assessed for each study by individual included studies. As can be seen from Tables 7 and 8, below, the summary estimates of the performance of each test, derived from all studies reporting data for this threshold, were similar to estimates derived from the direct comparison study alone.

Selection of diagnostic strategies for inclusion in cost-effectiveness modelling

Diagnostic strategies for each hs-cTn assay were selected for inclusion in cost-effectiveness modelling based on optimal diagnostic performance as indicated by data from the systematic review. In addition, wherever possible, data from studies that excluded patients with STEMI (i.e. where the target condition was NSTEMI) were preferentially selected.

Search strategy

Searches were undertaken to identify cost-effectiveness studies of high-sensitivity TnT/I. As with the clinical effectiveness searching, the main EMBASE strategy for each set of searches was independently peer reviewed by a second Information Specialist, using the Canadian Agency for Drugs and Technologies in Health (CADTH) Peer Review Checklist. 28 Search strategies were developed specifically for each database and keywords associated with high-sensitivity TnT/I were adapted according to the configuration of each database. Full search strategies are reported in Appendix 1.

The following databases were searched for relevant studies from 2005 to October 2013:

• MEDLINE (OvidSP): 2005–2013/10/wk1.

• MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP): up to 2013/10/1.

• EMBASE (OvidSP): 2005–2013/10/17.

• NHS Economic Evaluation Database (NHS EED) (Wiley): Cochrane Library Issue 3 2005 to July 2013.

• Health Economic Evaluation Database (HEED) (Wiley): 2005–2013/10/18.

• EconLit (EBSCO): 2005–2013/09/01.

• Science Citation Index (SCI) (Web of Science): 2005–2013/10/21.

• Conference Proceedings Citation Index – Science (CPCI) (Web of Science): 2005–2013/10/21.

• Research Papers in Economics (REPEC) (Internet): up to 2013/10/21 http://repec.org/.

Identified references were downloaded in EndNote X4 software for further assessment and handling.

References in retrieved articles were checked for additional studies.

Inclusion criteria

Studies reporting a full economic analysis, which related explicitly to the cost-effectiveness of hs-cTn or standard cTn (with cTn implying either cTnI or cTnT) testing, with survival and/or quality-adjusted life-years (QALYs) as an outcome measure, were eligible for inclusion. Specifically, one of the strategies had to include cTn testing. Studies that reported only a cost-analysis of cTn testing were not included in the review.

Quality assessment

Full cost-effectiveness studies were appraised using the Drummond checklist. 77

Results

The literature search identified 152 reports. After initial screening of titles and abstracts, five reports7,19,78–80 were considered to be potentially relevant: two full papers79,80 and three HTA reports. 7,19,78 Two additional reports81,82 were provided by a clinical expert: a Canadian optimal use report82 (similar to an HTA report) and an abstract81 that was referred to in this report. All seven identified reports7,19,78–82 fulfilled inclusion criteria based on full-text assessment. The seven publications related to five studies. Figure 13 shows the flow of studies through the review process, Table 9 lists the study details and the results of the quality assessment are shown in Table 10.

FIGURE 13.

Flow of studies through the review process. CA, conference abstract; HTA, Health Technology Assessment; JA, journal article.

Troponin tests considered in the model

The health-economic analysis will estimate the cost-effectiveness of different Tn testing methods for diagnosing or ruling out NSTEMI, in patients presenting at the ED with suspected NSTE-ACS, who have no major comorbidities requiring hospitalisation (e.g. as HF or arrhythmia) and in whom STEMI has been ruled out. Those diagnosed with NSTEMI will then be admitted to the hospital for AMI treatment and those diagnosed as without NSTEMI can be discharged without AMI treatment and further hospital stay. AMI treatment might include aspirin, statins and ACE inhibitors and consideration of coronary revascularisation for high-risk cases. 7 Initiating AMI treatment for NSTEMI will reduce the probability of MACEs, particularly cardiac death and re-infarction.

Standard serial Tn testing, for patients with acute chest pain attributable to possible ACS, does not achieve optimal sensitivity in detecting AMI until 10–12 hours after onset of symptoms. Waiting for 10–12 hours after symptom onset is burdensome for patients and induces additional health-care costs. Therefore, various alternatives have been proposed, using more sensitive Tn tests, for the early rule-out of NSTEMI (within the 4-hour NHS ED target). 89

Two hs-cTn assays (Roche Elecsys hs-cTnT and Abbott ARCHITECT hs-cTnI) are currently used in NHS laboratories in England and Wales. One additional assay (Beckman Coulter hs-cTnI) was listed in the scope for this assessment, pending CE marking. However, each of these tests can be used at different time points and with different diagnostic thresholds, resulting in multiple possible strategies for each test. Whether or not a test strategy was included in the economic model was decided based on optimal diagnostic performance, given the available evidence on accuracy for a population with STEMI ruled out, and on applicability in clinical practice (see Results of the assessment of clinical effectiveness assessment, above). The test strategies evaluated in the model are:

• Standard Tn at presentation and at 10–12 hours (reference standard).

• Roche Elecsys hs-cTnT at presentation: 99th centile threshold.

• Roche Elecsys hs-cTnT (optimal strategy): LoB threshold at presentation followed by 99th centile threshold peak within 3 hours and/or Δ20% (compared with presentation test) at 1–3 hours (see Figure 9).

• Abbott ARCHITECT hs-cTnI at presentation: 99th centile threshold.

• Abbott ARCHITECT hs-cTnI (optimal strategy): LoD threshold at presentation, followed by 99th centile threshold at 3 hours (see Figure 11).

• Beckman Coulter hs-cTnI at presentation: 99th centile threshold.

• No testing, discharge all patients without testing or treatment (only in sensitivity analyses). A Tn test may not be indicated when clinical judgement assesses the probability that a patient is experiencing an AMI as low. Therefore, consistent with the protocol, this hypothetical strategy is included in sensitivity analyses wherein the AMI prevalence is varied.

In the base case, it was assumed that standard Tn had perfect sensitivity and specificity (reference case) for diagnosing AMI. Using this assumption, all patients testing positive on a hs-cTn test but negative on the standard Tn would be classified as FPs. This implies that their risk for adverse events would be the same as for those patients testing negative on both the hs-cTn test and the standard Tn, and that they ought to be discharged home without further immediate treatment. However, recent evidence has shown that patients with a negative standard Tn, but a positive hs-cTn, may be at higher risk for adverse events than patients who test negative on both the standard and the high-sensitive Tn (Goodacre S, Medstar Washington Hospital Center, Washington, DC, USA; Lipinski M, University of Sheffield, Sheffield, UK: 2014, personal communication). A secondary analysis was therefore performed, which attributed a higher risk of adverse events to a proportion of patients testing FP with the hs-cTn test.

Based on the available evidence, two analyses were performed:

• Base-case analysis.

• Secondary analysis, assuming that FPs in the hs-cTn testing strategies do not have the same risk for adverse events as TNs. Instead, these patients were assigned a higher risk for (re-)infarction and death, to reflect the idea that when the hs-cTn test gives a positive result, in some cases this must be caused by a disease process, whether or not the strict definition of AMI is met. The risk of adverse events in patients with positive hs-cTn but a negative standard Tn is higher than the patients testing negative on both the hs-cTn test and the standard Tn, but lower than risk of adverse events in patients diagnosed with NSTEMI (i.e. both positive hs-cTn and standard Tn).

Model structure

This assessment uses the HTA report by Goodacre et al. 7 as a starting point for cost-effectiveness modelling. The Goodacre report compared the cost-effectiveness of several diagnostic strategies for ACS. The assessment group received the health-economic model (in SIMUL8 2011, Simul8 Corporation, Boston, MA, USA) that this HTA was based on, and this model was used as a starting point to develop a de novo model (in Microsoft Excel 2003: Microsoft Corporation, Redmond, WA, USA) adapted to better fit the scope of the current assessment. In the health-economic model the mean expected costs and QALYs were calculated for each alternative strategy. These long-term consequences were estimated based on the accuracy of the different testing strategies followed by AMI treatment or discharge from the hospital without AMI treatment for patients presenting at the ED with suspected NSTE-ACS, including patients with NSTEMI and patients without NSTEMI, who are further subdivided into ‘No ACS, no UA’ and ‘Unstable angina’. For this purpose a decision tree and a Markov model were developed. The decision tree was used to model the 30-day outcomes after presentation, based on test results and the accompanying treatment decision. These outcomes consisted of ‘No ACS, no UA’, ‘Unstable angina’, ‘Non-fatal AMI (untreated)’, ‘Non-fatal AMI (treated)’ and ‘Death’. The decision tree is shown in Figure 14.

FIGURE 14.

Decision tree structure.

The long-term consequences in terms of costs and QALYs were estimated using a Markov cohort model (Figure 15) with a lifetime time horizon (60 years). The cycle time was 1 year, except for the first cycle, which was adjusted to 335.25 days (365.25–30) to ensure that the decision tree period (30 days) and the first cycle combined summed to 1 year. The following health states were included:

• ‘No acute coronary syndrome and no unstable angina (no ACS, no UA)’

• ‘Unstable angina’

• ‘Post AMI (treated and untreated)’

• ‘Post AMI with re-infarction’

• ‘Death’.

FIGURE 15.

Markov model structure. a, During the first year post AMI, a distinction is made between treated and untreated AMI.

Model parameters

Estimates for the model input parameters were retrieved from the literature and by consulting experts for unpublished data. Accuracy estimates were derived from the systematic review component of this assessment (see Results of the assessment of clinical effectiveness assessment, above).

Overview of main model assumptions

The main assumptions in the health-economic analyses were:

• Serial Tn testing (comparator) has perfect accuracy (sensitivity = 1.0 and specificity = 1.0).

• For the Roche Elecsys hs-cTnT and Abbott ARCHITECT hs-cTnI optimal strategies it was assumed that the sensitivity and specificity for the subpopulation not discharged after the presentation test is equal to the sensitivity and specificity for the initial group (presenting at the ED).

• The life expectancy, quality of life and costs for FP patients is, in the base-case analysis, equal to the life expectancy, quality of life and costs of TN patients. This assumption was amended in the secondary and sensitivity analyses.

• In contrast with AMIs occurring during the decision tree period, all AMIs (either first or re-infarction) occurring in the Markov trace are diagnosed correctly and thus treated.

• UA is always correctly diagnosed and thus treated.

• The re-infarction probability for the ‘Post-MI with re-infarction’ health state is equal to the re-infarction probability for the ‘Post-MI’ health state.

• The increased ‘Post-MI’ re-infarction and mortality probabilities for untreated AMI were assumed to last 1 year: afterwards a RR of 1.0 was applied (for untreated vs. treated AMI).

• There is no additional benefit of starting treatment early, so treatment effect for high-sensitive strategies is equal to treatment effect for standard Tn strategy.

• All 30-day deaths (after presentation at the ED) are due to fatal AMI events and will receive the associated costs.

Secondary analysis

For the base case, it was assumed that patients who tested negative on standard Tn and positive on hs-cTn tests would experience life expectancy and quality of life equal to TN patients. This assumption is, however, debatable, as unpublished data (Goodacre S, Lipinski M, personal communication) show that patients with a negative standard Tn test and positive hs-cTn test have an increased risk of (re-)infarction and mortality compared with those who test negative on both standard Tn and hs-cTn tests. Although this risk was not as high as in patients with both positive standard Tn and positive hs-cTn tests, it could still be considered prognostically important. Therefore, in this secondary analysis the risk of re-infarction and mortality was adjusted for patients who tested FP (see Table 11). It was assumed that for this proportion of patients, the relative treatment benefit would be equal to that for TP patients. As the prevalence of this ‘higher risk subgroup’ is likely to be the same for all comparators, it was assumed that this proportion was equal to the lowest proportion of FP patients for all hs-cTn tests (see Table 13). This ‘higher risk subgroup’ was assumed to be treated for all hs-cTn tests (as they tested positive with these tests) and untreated for the standard Tn test (as they tested negative with this test), thus affecting the probability of adverse outcomes and treatment costs. In addition, the post-MI utility and health-state costs were used for this ‘higher-risk subgroup’.

Sensitivity analysis

For both the base case and the secondary analysis, the following one-way sensitivity analyses were performed to assess the impact of model assumptions and input parameters on the estimated outcomes:

Model assumptions:

• The assumption that the increased post AMI re-infarction and mortality probabilities for untreated AMI lasts for only 1 year was replaced by the assumption that these probabilities would remain elevated for a lifetime.

• The assumption that a doctor will be available on demand and thus that a decision could be made immediately (as in the base case) was replaced with an assumed delay (1, 2 or 3 hours) before a doctor is available and a decision could be made.

• As for the previous sensitivity analysis, except that the delay (1, 2 or 3 hours) applies only once patients are transferred to the general ward 4 hours after presentation (no delay in the ED).

• A total delay of 1.5 hours is assumed (includes delay from the time at which sampling could be performed to the time at which results became available and delay between arrival at hospital and Tn assessment commencing) rather than assuming a total delay of 3 hours (base case).

• AMI treatment costs are applied for patients who tested FP rather than using no treatment costs, as assumed in the base-case analysis.

• In addition to the health-state costs of UA during the first year, the AMI treatment costs are also applied for patients with UA (during the first year), rather than assuming no additional treatment costs.

Model input parameters (varied to lower and upper boundary of the 95% CI unless stated otherwise):

• test costs [test costs was varied over a wider range (£5–40) than the 95% CI]

• AMI treatment costs (±25%)

• post-MI first-year health-state costs

• utility increment for UA compared with AMI

• post-MI disutility compared with no ACS

• mortality (30 day) treated AMI (decision tree)

• mortality (30 day) untreated AMI (decision tree)

• annual re-infarction (after initial AMI)

• RR re-infarction (untreated vs. treated AMI)

• annual post-MI mortality

• annual post-MI mortality after re-infarction

• HR mortality (UA vs. NSTEMI)

• RR mortality (untreated vs. treated AMI).

Subgroup analysis

For both the base case and the secondary analysis, a number of subgroup analyses were performed. The main subgroup analyses were based on age- and sex-dependent re-infarction probabilities, mortality probabilities (for all health states), AMI incidence and quality of life, and could be applied to all test strategies. Accuracy was thus assumed to be subgroup independent (equal to the base case values). The following subgroups were identified:

• Sex.

• Age (45, 55, 65, 75 and 85 years).

• People with a history of previous NSTEMI. For this purpose, a proportion of 0% UA was assumed and the probabilities for the initial ‘Post-MI’ health state were used for the ‘No ACS, no UA’ health state and the probabilities for ‘Post-MI with re-infarction’ were used for the ‘Post-MI’ and ‘Post-MI with re-infarction’ health states. This subgroup analysis was performed for only the base case, as for the secondary analysis this would lead to lower mortality probabilities for FP patients than TN patients (which seems implausible).

• Subgroups with varying AMI prevalence (1%, 5%, 10%, 20%, 30%). In these analyses the no-testing strategy was included as a comparator, as a Tn test may not be indicated when clinical judgement assesses that the probability that a patient is experiencing an AMI is low. For the no-testing strategy it is assumed that patients will be discharged immediately.

It should be noted that the main subgroup analyses (described above) differ from the subgroups described in the systematic review component of this assessment (see Chapter 3, Presentation samples), for which specific accuracy and prevalence data were available. Additional subgroup analyses were performed based on these subgroup-specific accuracy data. However, these analyses could be performed for only the Roche Elecsys hs-cTnT assay at presentation sample, using the 99th centile diagnostic threshold, compared with standard Tn testing; no subgroup-specific accuracy data were available for the other two hs-cTn assays. The following subgroups were considered:

• age ≤ 70 years and age > 70 years

• patients with pre-existing CAD and patients without pre-existing CAD

• symptom onset at < 3 hours before presentation and symptom onset at ≥ 3 hours before presentation.

The subgroups with high pre-test probability and low-to-moderate pre-test probability were not considered, as the prevalence data for these subgroups were unknown.

Base-case analysis

The base-case analysis includes six test strategies. Tables 17 and 18 show the probabilistic results of this analysis. Standard Tn testing was both most effective (15.101 LYs, 11.730 QALYs) and most expensive (£2697). The Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was least effective (15.076 LYs, 11.712 QALYs) and least expensive (£2253). Compared with standard Tn testing, hs-cTn testing resulted in ICERs ranging between £90,725 and £24,019 savings per QALY lost.

Comparisons based on the next best alternative showed that for willingness-to-pay values of < £6600 per QALY, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, would be cost-effective. For thresholds between £6600 and £30,631 per QALY, the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective; above £30,631 per QALY the Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective. Standard Tn becomes cost-effective at a threshold of £90,725 or higher (see Table 18).

At willingness-to-pay thresholds of £20,000 and £30,000 per QALY, the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, had probabilities of being cost-effective of 47% and 35%, respectively. Although the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective at a willingness-to-pay threshold of £30,000 per QALY, the Abbott ARCHITECT hs-cTnI optimal strategy had the highest probability of being cost-effective (35%) at this threshold (Figures 16 and 17).

FIGURE 16.

Cost-effectiveness acceptability curve and incremental cost-effectiveness plane (incremental costs and QALYs compared with standard Tn) for base-case analysis.

FIGURE 17.

Cost-effectiveness acceptability frontier for base-case analysis.

Secondary analysis

The secondary analysis includes the same six test strategies. This analysis assumed that in a proportion of patients with a FP hs-cTn test (i.e. positive hs-cTn test and a negative standard Tn test), there is prognostic significance [i.e. it is associated with an increased risk of adverse events (mortality and re-infarction)].

Standard Tn testing was least effective (14.785 LYs, 11.464 QALYs) and most expensive (£3058). The Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was the least effective hs-cTn test strategy (14.833 LYs, 11.501 QALYs) and, overall, the least expensive strategy (£2781). The Abbott ARCHITECT hs-cTnI optimal strategy was most effective (14.855 LYs, 11.518 QALYs). Standard Tn testing was dominated by all hs-cTn testing strategies.

Comparisons based on the next best alternative showed that for willingness-to-pay values of < £13,623 per QALY, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective. For thresholds between £13,623 and £14,562 per QALY, the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was cost-effective; above £14,562 per QALY the Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective (Tables 19 and 20).

At willingness-to-pay thresholds of £20,000 and £30,000 per QALY, the Abbott ARCHITECT hs-cTnI optimal strategy had the highest probability of being cost-effective (53% and 67%, respectively; Figures 18 and 19).

FIGURE 18.

Cost-effectiveness acceptability curve and incremental cost-effectiveness plane (incremental costs and QALYs compared with standard Tn) for secondary analysis.

FIGURE 19.

Cost-effectiveness acceptability frontier for secondary analysis.

Sensitivity analysis

The deterministic analysis for the base-case analysis is presented in Appendix 5. When it was assumed that the post-MI re-infarction and mortality probabilities would remain elevated for untreated AMI for a life-time period, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £1642 per QALY, at which point the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, became cost-effective up to a threshold of £7602 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds between £7602 and £26,532 per QALY. Standard Tn testing was cost-effective for thresholds of > £26,532 per QALY. Consistent with the base-case analysis, all ‘no doctor on demand’ sensitivity analyses (1, 2 or 3 hours) showed that the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between approximately £8000 and £40,000 per QALY. Similarly, where the total delay decreased to 1.5 hours (and assuming availability of a doctor on demand), the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between £7778 and £29,653 per QALY, at which point the ARCHITECT hs-cTnI optimal strategy became cost-effective. Adding AMI treatment costs for the patients with a FP test substantially impacted upon the results: standard Tn testing was cost-effective for all threshold values of > £16,050 per QALY. Adding AMI treatment costs to the UA health state for the first year had a negligible impact on the incremental outcomes.

The following input parameters had a noticeable impact on the estimated cost-effectiveness: 30-day mortality for treated and untreated AMI (decision tree) and the mortality RR for treated AMI compared with untreated AMI (Markov trace). Varying the remaining parameters did not have a substantial impact on the results (i.e. the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between approximately £10,000 and £35,000 per QALY).

The deterministic analysis for the secondary analysis is presented in Appendix 6. When assuming that the post-AMI re-infarction and mortality probabilities would remain elevated for untreated AMI for a life-time period, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £1853 per QALY, at which point the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, became cost-effective up to a threshold of £2017 per QALY. The Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between £2017 and £5889 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds of > £5889 per QALY. For all ‘no doctor-on-demand’ sensitivity analyses, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £18,000 per QALY for 1, 2 and 3 hours’ delay. The Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between £18,000 and £19,000, £20,000 and £22,000 per QALY in case of 1, 2 and 3 hours’ delay, respectively. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for higher thresholds. Similarly to the deterministic base case, for which the total delay decreased to 1.5 hours (assuming availability of a doctor on demand), the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of below £14,956, at which point the ARCHITECT hs-cTnI optimal strategy became cost-effective. Adding AMI treatment costs for all patients with a FP test gave similar results to the deterministic analysis: the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for all threshold values of < £15,508 per QALY, at which point the Abbott hs-cTnI optimal strategy became the preferred option. Adding AMI treatment costs to the ‘Unstable angina’ health state for the first year had a negligible impact on the incremental outcomes.

The following input parameters had a noticeable impact on the estimated cost-effectiveness of the secondary analysis: increased test cost (of £40 per test), 30-day mortality for treated and untreated AMI (decision tree), and the re-infarction and mortality RR for treated AMI compared with untreated AMI (Markov trace). Varying the remaining parameters did not have a substantial impact on the results.

Subgroup analysis

Additional analyses were performed for subgroups based on age, sex, people with a history of previous NSTEMI, and AMI prevalence. These deterministic subgroup analyses (for the base case) analysis are presented in Appendix 7. Consistent with the base-case analyses, analyses based on age and sex subgroups indicated that, up to an age of 75 years, the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between approximately £10,000 and £35,000 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for higher thresholds up to £115,000–170,000, at which point standard Tn testing became cost-effective. For females aged > 85 years, the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between £15,793 and £74,597 per QALY; the Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds between £74,597 and £259,592 per QALY, and standard Tn testing was cost-effective for thresholds of £259,592 per QALY and higher. For males aged > 85 years, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £28,711 per QALY; the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds between £28,711 and £143,225 per QALY and the Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds between £143,225 and £503,476 per QALY, at which point standard Tn testing became cost-effective. The results for the subgroup with a history of previous NSTEMI were almost identical to the base-case analysis.

For subgroup analyses considering AMI prevalence, no testing was included as additional comparator. For an AMI prevalence of 1%, the no-testing strategy was cost-effective up to thresholds of £27,409 per QALY, at which point the Beckman Coulter hs-cTnI (99th centile) test became cost-effective up to a threshold of £447,934 per QALY. For an AMI prevalence of 5–20%, the no-testing strategy was cost-effective up to thresholds of £8759–11,703 per QALY, at which point the Beckman Coulter hs-cTnI (99th centile) test became cost-effective up to thresholds of £32,042–97,709 per QALY. For an AMI prevalence of 30%, the no-testing strategy was cost-effective up to a threshold of £8431 per QALY, at which point the Beckman Coulter hs-cTnI (99th centile) test became cost-effective up to a threshold of £24,745 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds between £24,745 and £70,942 per QALY.

In addition, cost-effectiveness estimates for the subgroups, described in Chapter 3 (see Presentation samples), based on subgroup-specific accuracy and prevalence, are reported in Appendix 9 (only comparing the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, and standard Tn testing). The results of these analyses indicated that differences in accuracy and AMI prevalence between subgroups had a substantial impact on the cost-effectiveness of the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, compared with standard Tn testing (ICER range: £22,111–355,571; deterministic base case: £41,233).

The deterministic subgroup analyses for the secondary analysis are presented in Appendix 8. For females aged 45 years and males aged 45 or 55 years, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £16,023–17,836 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy became cost-effective for higher thresholds. For females aged 55 or 65 years and males aged 65 or 75 years, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £13,064–16,994 per QALY. From this threshold up to £18,999–25,149 per QALY, the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was most cost-effective. The Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for higher thresholds. For females aged 75 or 85 years, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective up to thresholds of £12,392£21,140 per QALY, at which point the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, became cost-effective up to thresholds of £16,407–26,911 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy became cost-effective for thresholds of > £24,020–45,709 per QALY. For males aged 85 years, the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was cost-effective for thresholds of < £66,418 per QALY. The Abbott ARCHITECT hs-cTnI optimal strategy became cost-effective for higher thresholds.

For subgroup analyses considering AMI prevalence, no testing was included as additional comparator. For an AMI prevalence of 1%, the no-testing strategy was cost-effective up to a threshold of £4563 per QALY, at which point the Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, became cost-effective up to a threshold of £109,991 per QALY, where the Abbott ARCHITECT hs-cTnI optimal strategy became cost-effective. Similarly, for AMI prevalences of 5% and 10% the thresholds were £5209 and £35,574, and £5820 and £22,684, respectively. For a AMI prevalences of 20% and 30%, the Abbott ARCHITECT hs-cTnI optimal strategy was cost-effective for thresholds of > £16,319 and £15,410, respectively.

In contrast with the base-case analysis (described above), the subgroup-specific accuracy and prevalence (only comparing the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, and standard Tn testing) did not have an important impact on the cost-effectiveness (see Appendix 9). The Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was dominant for all subgroups.

Clinical effectiveness

All 18 studies19,39,40,42,44,46,48,49,51,54,55,57,58,63,64,67,70,73 (37 publications19,39,40–74) included in the systematic review assessed the accuracy of one or more hs-cTn tests for the diagnosis of any AMI or for NSTEMI. There were no controlled trials comparing clinical outcomes in people assessed using hs-cTn tests to those assessed using conventional Tn assays. The majority (15/18) of the included studies reported data for the Roche Elecsys hs-cTnT assay; four studies39,48,58,63 reported data for the Abbott ARCHITECT hs-cTnI assay and two studies39,73 reported data for precommercial versions of the Beckman Coulter Access hs-cTnI assay. Not all of the included studies reported data on accuracy for the diagnosis of NSTEMI (i.e. for a population that excluded people with STEMI), which was the target population for this assessment. However, where data were available for both any AMI (population with symptoms suggestive of ACS) and NSTEMI (population which excluded people with STEMI), estimates of test performance were generally similar (see Tables 4 and 6).

When diagnosis was based on a single sample taken at presentation, using the 99th centile for the general population as the diagnostic threshold, positive LRs derived from summary estimates of sensitivity and specificity indicated that neither the Roche Elecsys hs-cTnT assay nor the Beckman Coulter Access hs-cTnI would be adequate to rule in a diagnosis of NSTEMI. The LR+ for the Roche Elecsys hs-cTnT assay was 5.41 (95% CI 3.40 to 8.63) and the LR+ for the Beckman Coulter Access hs-cTnI was 3.67 (95% CI 3.26 to 4.13). By contrast, the LR+ for the Abbott ARCHITECT hs-cTnI assay, in a population that did not exclude STEMI, was 11.47 (95% CI 9.04 to 16.19), indicating that a positive test using this assay may have some utility in confirming a diagnosis of AMI. The corresponding LR–s indicated that a negative test result on a single sample taken at presentation, using the 99th centile for the general population as the diagnostic threshold, would not be adequate to rule out NSTEMI using any of the three assays assessed. LR– was 0.15 (95% CI 0.08 to 0.26) for the Roche Elecsys hs-cTnT, 0.11 (95% CI 0.07 to 0.17) for the Beckman Coulter Access hs-cTnI, and 0.22 (95% CI 0.16 to 0.27) for the Abbott ARCHITECT hs-cTnI assay. Although these LRs are fairly low, the consequences of missing an AMI are so great that a test needs to be able to rule out an AMI with a very high degree of certainty. It should be noted that the Beckman Coulter hs-cTnI assay evaluated in the APACE study39 was described as ‘an investigational prototype’; the 99th centile (9 ng/l), described as ‘according to the manufacturer’, differs from the 99th centile given in the current product information leaflet (40 ng/l),16 and from values reported in a conference abstract, (41 ng/l for the Access II analyser and 34 ng/l for the DxI analyser). 17 When a hypothetical cohort of 1000 people is considered, assuming a prevalence of NSTEMI of 17% [derived from studies included in our systematic review (see Chapter 3, Presentation samples)] the estimated number of people with AMI and a negative test result who would be erroneously discharged based on this testing protocol is 20 for the Roche Elecsys hs-cTnT assay, 14 for the Beckman Coulter Access hs-cTnI assay, and 34 for the Abbott ARCHITECT hs-cTnI assay.

Some limited data were available on the diagnostic performance of the Roche Elecsys hs-cTnT assay in clinical subgroups, using a single sample taken at presentation and the 99th centile diagnostic threshold. These data indicated a lower LR– when the test is used in certain population groups [e.g. people aged > 70 years LR– 0.05 (95% CI 0.02 to 0.18); people without pre-existing CAD LR– 0.07 (95% CI 0.04 to 0.16)] and with a high pre-test probability (determined by clinical judgement based on cardiovascular risk factors, type of chest pain, physical findings and ECG abnormalities; LR– 0.09, 95% CI 0.02 to 0.45). Using the hypothetical cohort of 1000 people described above, the estimated number of people with AMI and a negative test result who would be erroneously discharged if the test were used to rule out AMI in these selected populations is five for people aged > 70 years, 10 for people without pre-existing CAD, and 10 for people with a clinical assessment of high pre-test probability. When the performance of the Roche Elecsys hs-cTnT assay was assessed in a population restricted to people who presented at > 3 hours after the onset of symptoms, a similar fall in the LR– was observed (LR– 0.08, 95% CI 0.05 to 0.11); the estimated number of people with AMI and a negative test result who would be erroneously discharged if the test were used to rule out AMI in this populations is 10.

We constructed optimal testing strategies for the Roche Elecsys hs-cTnT assay (see Figure 9 and Chapter 3, Diagnostic accuracy of the Roche Elecsys hs-cTnT assay, Multiple samples) and for the Abbott ARCHITECT hs-cTnI assay (see Figure 11 and Chapter 3, Diagnostic accuracy of the Abbott ARCHITECT hs-cTnI assay, Multiple samples). Both strategies use a two-step process, which provides two potential opportunities to rule out AMI and hence to discharge patients within the 4-hour window specified in the scope for this assessment. This potential is conditional upon the achievement of short (< 1 hour) turnaround times for hs-cTn testing, as recommended by the joint National Academy of Clinical Biochemistry and IFCC guidelines on Tn testing101 and in line with clinical opinion; a study of 1355 ED physicians in the USA indicated that 75% believed that the results of Tn testing should be available to them within 45 minutes. 102 The initial step for both the Abbott ARCHITECT hs-cTnI optimal strategy and Roche Elecsys hs-cTnT optimal strategy was based on the use of an LoB (3 ng/l) diagnostic threshold in a sample taken at presentation and was selected for optimal rule-out potential (low LR–), regardless of poor rule-in performance. For the Roche Elecsys hs-cTnT optimal strategy, the second step involves an additional sample taken 2– 3 hours after admission and was selected to provide the best possible combination of rule-out and rule-in performance. Using the hypothetical cohort of 1000 people previously described, the initial step of the proposed Roche Elecsys hs-cTnT optimal strategy would result in discharge of 407 people, nine of whom would have been erroneously discharged with AMI. The second step of this strategy involves a combination of testing on admission and after 2 hours, where a negative result is defined as both no sample above the 99th centile AND a change of < 20% over 2 hours and provides the optimum rule-out performance (LR– 0.04, 95% CI 0.02 to 0.10); conversely, a positive result is defined as both a peak value above the 99th centile AND a change of > 20% over 2 hours and provides the optimum rule-in performance (LR+ 8.42, 95% CI 6.11 to 11.60). Application of the rule-out component of the second step would result in discharge of a further 286 people, five of whom would have been erroneously discharged. For the proposed Abbott ARCHITECT hs-cTnI optimal strategy, the initial rule-out step would result in discharge of 291 people, all of whom would have been appropriately discharged. The second step of this strategy involves repeat testing on a sample taken 3 hours after admission, using the 99th centile diagnostic threshold. Application of the rule-out component of the second step would result in discharge of a further 486 people, three of whom would have been erroneously discharged. Available data on the Beckman Coulter hs-TnI assay were insufficient to support construction of an optimal testing strategy.

Cost-effectiveness

The review of economic analyses of hs-cTn (i.e. either hs-cTnI or hs-cTnT) testing for the early rule-out of AMI in people with acute chest pain found four HTA reports, two full papers and one abstract. Based on all of these publications, it can be said that, in general, the question of whether hs-cTn testing is cost-effective cannot yet be answered unequivocally. The majority of papers reported substantial ICERs, with considerable uncertainty. In particular, the accuracy of high-sensitivity tests, as well as the efficiency of decision-making based on test results, were found to be important drivers of cost-effectiveness.

In our health-economic analysis, the cost-effectiveness of different testing strategies – involving hs-cTn for the early rule-out of AMI in people with acute chest pain presenting to the ED with suspected ACS and STEMI ruled out – was assessed. All analyses had the same comparator: standard Tn testing at 10–12 hours, which is considered the reference standard and therefore was assumed to have perfect sensitivity and specificity. In addition to the base-case analysis, given some evidence that FPs compared with this reference standard also have a poor prognosis, a secondary analysis was conducted, which assumed an increased adverse event risk for patients with FP hs-cTn tests. A number of subgroup and sensitivity analyses were also performed.

In the base-case analysis, standard Tn testing was both most effective and most costly. Strategies considered cost-effective depending upon ICER thresholds were Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold (thresholds of < £6597), Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold (thresholds between £6597 and £30,042), Abbott ARCHITECT hs-cTnI optimal strategy (LoD threshold at presentation, followed by 99th centile threshold at 3 hours) (thresholds between £30,042 and £103,194), and the standard Tn test (thresholds of > £103,194). The Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, and the Roche Elecsys hs-cTnT optimal strategy [LoB threshold at presentation followed by 99th centile threshold and/or Δ20% (compared with presentation test) at 1–3 hours] were extendedly dominated in this analysis (one of the more effective strategies was better value in that the ICER was lower).

In the secondary analysis, which assumed that a proportion of FPs in the hs-cTn testing strategies had an increased risk of adverse events, standard Tn was least effective and most costly and, therefore, a dominated strategy. The most effective strategy here was the Abbott ARCHITECT hs-cTnI optimal strategy. The Roche Elecsys hs-cTnT optimal strategy was extendedly dominated (one of the more effective strategies was better value in that the ICER was lower), as was the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, in this analysis. Strategies considered cost-effective were Abbott ARCHITECT hs-cTnI assay at presentation, using the 99th centile diagnostic threshold (thresholds of < £12,217), Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold (thresholds between £12,217 and £14,992), and Abbott ARCHITECT hs-cTnI optimal strategy (thresholds of > £14,992).

Sensitivity analyses showed that, in general, there were no major changes in the relative cost-effectiveness of strategies. That is, dominancy and order of relative cost-effectiveness were comparable, although the ICERs were different. Exceptions included assuming that the increased 30-day mortality for treated MI compared with untreated MI applied to a lifetime (instead of only during the first year after presentation at ED), which meant that standard Tn could be cost-effective from a threshold of ≥ £26,352. The same assumption applied to the secondary analysis meant that the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, was no longer extended dominated but was considered cost-effective at thresholds of between £2017 and £5889. Another sensitivity analysis that resulted in substantial changes was assigning AMI treatment costs to patients who tested FP. In the base case, under this assumption, standard Tn became cost-effective at an ICER threshold of £20,000 (ICER £16,050 compared with the Abbott ARCHITECT hs-cTnI optimal strategy). In the secondary analysis, however, assigning treatment costs to FP patients did not have an impact on the position of standard Tn; it was still dominated by another strategy (i.e. less effective and more costly).

Subgroup analyses (with non-subgroup specific accuracy data) for the base case showed that ICERs compared with the next best strategy were slightly higher for males at all ages. Also, for both females and males, ICERs increased with age. In addition, from ages ≥ 55 years (base case 53 years), the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, became extendedly dominated. In the subgroup with previous NSTEMI, again the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was extendedly dominated, and ICERs are slightly higher than in the whole group. Subgroup analysis based on MI prevalence (including a no-testing strategy) indicated that only when MI prevalence is as low as 1% (base case 17%) was the no-testing strategy considered cost-effective up to an ICER threshold of £27,409, after which the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, strategy takes over. The higher the prevalence, the lower the point at which the Beckman Coulter hs-cTnI assay at presentation, using the 99th centile diagnostic threshold, strategy became cost-effective (i.e. £11,703 for prevalence 5%, £9740 for prevalence 10%, and £6597 for 17%).

For the secondary analysis, again, the ICERS for males were slightly higher than for females. For the various age categories, results were rather diffuse, but, as in the base case, ICERs appeared to increase with age. There did not appear to be a substantial difference between the MI prevalence subgroups [i.e. the no-testing strategy was cost-effective only up to rather modest ICER thresholds (£4563–7109) for all values of prevalence].

The subgroup analyses using subgroup-specific accuracy and prevalence could be performed for only the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, as there were no subgroup data on Beckman Coulter hs-cTnI and Abbott ARCHITECT hs-cTnI assays. The comparator was the standard Tn at 10–12 hours, which was assumed to have perfect sensitivity and specificity. For the base case, the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, was always less costly and less effective, but ICERs were more favourable for the following subgroups compared with their counterparts: age ≤ 70 years, with pre-existing CAD, and symptom onset at < 3 hours. For the secondary analysis, the standard Tn was dominated by the Roche Elecsys hs-cTnT assay at presentation, using the 99th centile diagnostic threshold, overall, as this test was both less costly and more effective. However, the subgroups that rendered the highest savings per QALY gained were consistent with the base-case analysis (i.e. age ≤ 70 years, with pre-existing CAD, and symptom onset at < 3 hours). Although data are lacking, it seems likely that these differences between subgroups can be extrapolated, at least partly, to the other tests considered in the base-case analysis.

Clinical effectiveness

Extensive literature searches were conducted in an attempt to maximise retrieval of relevant studies. These included electronic searches of a variety of bibliographic databases, as well as screening of clinical trials registers and conference abstracts to identify unpublished studies. Because of the known difficulties in identifying test accuracy studies using study design-related search terms,103 search strategies were developed to maximise sensitivity at the expense of reduced specificity. Thus, large numbers of citations were identified and screened, relatively few of which met the inclusion criteria of the review.

The possibility of publication bias remains a potential problem for all systematic reviews. Considerations may differ for systematic reviews of test accuracy studies. It is relatively simple to define a positive result for studies of treatment, for example a significant difference between the treatment and control groups that favours treatment. This is not the case for test accuracy studies, which measure agreement between index test and reference standard. It would seem likely that studies finding greater agreement (high estimates of sensitivity and specificity) will be published more often. In addition, test accuracy data are often collected as part of routine clinical practice, or by retrospective review of records; test accuracy studies are not subject to the formal registration procedures applied to RCTs and are therefore more easily discarded when results appear unfavourable. The extent to which publication bias occurs in studies of test accuracy remains unclear; however, simulation studies have indicated that the effect of publication bias on meta-analytic estimates of test accuracy is minimal. 104 Formal assessment of publication bias in systematic reviews of test accuracy studies remains problematic and reliability is limited. 27 We did not undertake a statistical assessment of publication bias in this review. However, our search strategy included a variety of routes to identify unpublished studies and resulted in the inclusion of a number of conference abstracts.

Clear inclusion criteria were specified in the protocol for this review, a copy of which is available on the PROSPERO website (registration number CRD42013005939). The eligibility of studies for inclusion is therefore transparent. In addition, we have provided specific reasons for exclusion for all of the studies which were considered potentially relevant at initial citation screening and were subsequently excluded on assessment of the full publication (see Appendix 4). The review process followed recommended methods to minimise the potential for error and/or bias;25 studies were independently screened for inclusion by two reviewers, and data extraction and quality assessment were done by one reviewer and checked by a second (MW and PW). Any disagreements were resolved by consensus.

Studies included in this review were assessed for risk of bias and applicability using the QUADAS-2 tool developed by the authors33 and recommended by the Cochrane Collaboration. 27 QUADAS-2 is structured into four key domains covering participant selection, index test, reference standard, and the flow of patients through the study (including timing of tests). Each domain is rated for risk of bias (low, high or unclear); the participant selection, index test and reference standard domain are, also, separately rated for concerns regarding the applicability of the study to the review question (low, high or unclear). The results of the QUADAS-2 assessment are reported, in full, for all included studies in Appendix 3 and are summarised in Chapter 3 (see Study quality). The main potential sources of bias in the studies included in this assessment were related to patient spectrum and patient flow (QUADAS domains 1 and 4). Reporting of the participant selection process was frequently unclear; a further study55 was rated as unclear for this domain as a large number of patients were not enrolled as a result of ‘technical reasons’ that were not fully defined and so it was not possible to judge whether or not these comprised inappropriate exclusions. The most common feature of studies rated as ‘high risk of bias’ for patient selection was the inclusion of participants based on staffing or work flow considerations; for example, participants were excluded if they presented at night or during busy periods. 42,46,51 All ratings of ‘high risk of bias’ for patient flow were due to high proportions of withdrawals. There were also concerns regarding the applicability of the patient population and the reference standard in some of the included studies. The main area of concern, with respect to population, was for studies that enrolled mixed populations (i.e. when the target condition was any AMI); because the primary focus of this assessment was the diagnosis of NSTEMI in populations where patients with STEMI were excluded (i.e. target condition NSTEMI), the primary focus was the population of patients with STEMI excluded, mixed population studies that were not restricted to this specific patient group were considered to have high concerns regarding applicability. However, as noted above (see Clinical effectiveness), where data were available for both any AMI (mixed population) and NSTEMI (population which excluded people with STEMI), estimates of test performance were generally similar. In accordance with current NICE guidance,11 our review question specified that an appropriate reference standard had to include a standard Tn measurement at baseline and at 10–12 hours after the onset of symptoms in 80% of the population. Although studies generally included a baseline and a second, later, standard Tn measurement, only five19,39,42,51,63 met the specific timing criterion for the second standard Tn measurement; studies that did not meet this criterion were classified as having high concerns regarding applicability.

We identified one recently published systematic review which included an assessment of the accuracy of hs-cTn assays for the diagnosis of AMI and prediction of MACE. 7 This review, by Goodacre et al. ,7 also evaluated standard cTn assays (alone and in combination with other cardiac biomarkers) and the diagnostic accuracy of other cardiac biomarkers, as well as including prediction modelling studies, all of which were outside the scope of this assessment. Our systematic review represents an advance on Goodacre et al. ,7 as it provides a more up-to-date and comprehensive assessment of the performance of hs-cTn assays. Although the Goodacre review7 was published in 2013, search dates were reported as 1995 to November 2010; hence it included only two studies,57,72 which met the definition of a hs-cTn assay used in our assessment. Both of these studies57,72 assessed the diagnostic performance of the Roche Elecsys hs-cTnT assay when applied to a single sample taken at presentation, using the 99th centile diagnostic threshold, and neither excluded participants with STEMI. Both studies57,72 were also included in our systematic review and one study57 contributed data to our summary estimates (based on a total of 15 studies) of the performance of the Roche Elecsys hs-cTnT assay for the diagnosis of any AMI at this threshold studies; the other72 was an early publication of the APACE study, the most recent publication that contributed data to our main analysis (accuracy for the diagnosis of NSTEMI), which included a total of six studies. 39 The summary estimate of sensitivity derived from our systematic review was lower (88% for both any AMI or NSTEMI analyses) than that reported by the Goodacre review (96% for any AMI),7 and our summary estimate of specificity was higher (82% for any AMI and 84% for NSTEMI) than that reported by the Goodacre review7 (72% for any AMI). A more recent systematic review, published as a conference abstract, reported summary estimates of the sensitivity and specificity of hs-cTn on an admission sample of 88% and 82%, respectively, based on data from 17 studies. 105 This review pooled data from different hs-cTn assays in one analysis and also included data from some studies that assessed assays that do not meet the definition of a hs-cTn assay used in our assessment. Despite these limitations, the summary estimates of sensitivity and specificity matched the summary estimates from our review for the performance of the Roche Elecsys hs-cTnT assay for the diagnosis of any AMI; this is unsurprising, as 13 of the 17 studies included in the analysis assed the Roche Elecsys hs-cTnT assay, using the 99th centile diagnostic threshold. 105 Our assessment represents an advance on both of these systematic reviews in that we provide up-to-date estimates of the diagnostic performance of assays meeting a strict definition for hs-cTn, which are stratified by hs-cTn assay type, diagnostic threshold and timing of the Tn test.

We believe that our assessment provides information of direct relevance to UK clinical practice as we focus on the performance of hs-cTn within the 4-hour time window corresponding to the target for NHS EDs, which specifies that ‘no one should be waiting more than four hours in the ED from arrival to admission, transfer or discharge’. 89 Furthermore, we have used the data from our systematic review to propose strategies for how hs-cTn assays might be applied and interpreted in order to maximise diagnostic performance. These strategies were devised with consideration to test timing, diagnostic threshold and interpretation of combinations of multiple test results. One limitation of this approach is that our estimates of the effectiveness and cost-effectiveness of the proposed two-step strategies require the assumption that the diagnostic performance of the second step is the same when used in people in whom NSTEMI is not ruled out by the first step as it is when used in the whole population (see Chapter 3, Diagnostic accuracy of the Roche Elecsys hs-cTnT assay, Multiple samples, and Diagnostic accuracy of the Abbott ARCHITECT hs-cTnI assay, Multiple samples). This assumption was necessary because no combined test performance data were available for the proposed strategies. However, it can be argued that the assumption is reasonable as the first step in both strategies focuses on rule-out performance and thus has a low LR+. This means that there is a relatively small change in the prevalence of AMI between the first and second steps (17–27% for the Roche Elecsys hs-cTnT optimal strategy and 17–24% for the Abbott ARCHITECT hs-cTnI optimal strategy).

Our assessment was less comprehensive for the Abbott ARCHITECT hs-cTnI assay and the Beckman Coulter hs-cTnI assay than for the Roche Elecsys hs-cTnT, because available data were limited for these two assays.

Cost-effectiveness

Our cost-effectiveness analysis is the most comprehensive to date in terms of the number of relevant hs-cTn test strategies for the early rule-out of AMI in people presenting to the ED with acute chest pain and suspected ACS. Moreover, the de novo probabilistic model was based on one previously developed for a published and peer reviewed HTA. 80 This model was also used in a later assessments on the cost-effectiveness of biomarkers in patients with suspected ACS. 19 For the present analysis, a number of adjustments were made to the model, but most of the assumptions were maintained.

The model was also informed by a comprehensive, high-quality, systematic review of DTA. Additional parameters were either those from the original HTA model, or any of the further assessments, or, where necessary, were based on a pragmatic literature review. Such a review is standard practice in economic modelling given the large number of parameters required and we expect that the review has delivered the most relevant information given that it focused on identifying the most recent large UK-based studies.

As in any economic model, a number of major and minor assumptions had to be made. It is important to understand the impact of these assumptions in order to interpret correctly the results of the model. The impact of most assumptions has been explored in sensitivity and secondary analyses. However, one major assumption that was maintained throughout all analyses was the conservative assumption of no health benefit of early treatment in the hs-cTn strategies compared with ‘late’ treatment in the standard cTn strategy. Although many experts believe that there must be a benefit, at least to some extent, of treating patients early, there is no evidence to support or quantify a timing effect, as yet. In addition, there may well also be adverse effects associated with early treatment also (e.g. the risk of bleeding, unnecessary percutaneous coronary interventions, etc.). The Canadian HTA report82 identified in the economic review (see Chapter 4, Canadian Agency for Drugs and Technologies in Health optimal use report) did include an advantage for early treatment compared with late treatment, based on one study,106 which investigated the effect of a 36-hour treatment delay. The RR found in this study106 was then recalculated, assuming a constant effect of timing on treatment benefit, to a RR of 1.035 of mortality for a treatment delay of 6 hours compared with early treatment, was again adjusted to 1.01 based on expert opinion. Any possible adverse effect of early treatment was not considered in this analysis. A similar approach would have been possible in the present model, but, in our view, this would not be informative, given the level of uncertainty underlying this final estimate. Therefore, it was decided to leave out a possible effect of timing of treatment. This could be considered a conservative approach but even this is uncertain.

The assumption that standard Tn, as the reference standard, has perfect sensitivity and specificity was also maintained throughout all analyses. Although a simplification, given that the actual reference standard is standard Tn plus clinical information, this approach is consistent with previous modelling and incorporation of the effect of clinical information to the hs-cTn test would be very difficult, given the current lack of data. To some extent, clinical judgement might already be incorporated into the modelling because, for the effect of treatment (RR for re-infarction and mortality), the study performed by Mills et al. 83 was used. In this study,83 not all patients with negative tests results were left untreated; we might therefore speculate that, where patients who tested negative were treated, this was because of clinical judgement. However, we cannot be certain that the observations from this trial reflect the true contribution of clinical judgement. On the other hand, there is recent evidence that the prognostic performance of standard Tn testing may be imperfect. For example, a negative Tn test might assess correctly that a patient is not experiencing a NSTEMI, but some patients with negative test results may still benefit from treatment. To take this possibility into account, a secondary analysis was performed, which resulted in the standard Tn strategy being dominated by the hs-cTn testing strategies. In other words, it seems reasonable to conclude that not only might hs-cTn be cost-effective, it might also be more effective than standard Tn.

Another assumption, which was varied in sensitivity analysis, with a rather substantial impact on results, was how to attribute costs of treatment to patients testing FP in the hs-cTn treatment strategies. In the base-case analysis, FP patients were assigned survival, quality of life, and costs of TN patients (i.e. they were basically assumed not to be treated). However, if hs-cTn assays were incorporated in clinical practice, patients with a positive result would be treated, at least up to the point where it is discovered they were FP. Therefore, in a sensitivity analysis, FP patients were assigned treatment costs as if they were TP, but mortality and quality of life as if they were TN. For the base case, this would change results quite dramatically, as the hs-cTn strategies would become more expensive but not more effective, whereas for the standard Tn nothing would change. For the secondary analysis (some hs-cTn FPs need and get treatment) things are different, as in this case treatment costs would be incurred for a proportion of patients (5%) but these patients would also receive the benefits of treatment. This approach had a very limited effect on results, in terms of strategies that were cost-effective. In our opinion, the secondary analysis, which assigns treatment costs to all FPs, but also assumes that some of these patients benefit treatment, is the most plausible scenario.

Clinical effectiveness

The performance of any test that uses the 99th centile for the general population as the diagnostic threshold will be dependent upon the characteristics of the reference population from which this value was derived. Although the product information leaflet for the Abbott ARCHITECT hs-cTnI assay recommends that ‘each laboratory should verify that the 99th centile is transferable to its population or establish its own 99th centile’,15 test accuracy data included in the assessment are predominantly based on the 99th centiles for the three assays (Roche Elecsys hs-cTnT, Abbott ARCHITECT hs-cTnI, Beckman Coulter hs-cTnI) as reported by their respective manufacturers. 15,16,18 The 99th centile for the Roche Elecsys hs-cTnT was reported as being derived from a study population of 616 apparently healthy volunteers and blood donors, with an age range of 20–71 years and equal proportions of males and females;107 no further details were reported. The 99th centile for the Abbott ARCHITECT hs-cTnI assay was described as being derived from a study of ‘1,531 apparently healthy individuals in a US population with normal levels of BNP, HbA1c, and estimated GFR values’. 15 Although a 2012 ‘in press’ reference for this study was given in the APACE study,39 we were not able to identify any corresponding publication. It should also be noted that the Beckman Coulter hs-cTnI assay evaluated in the APACE study39 was described as ‘an investigational prototype’; the 99th centile (9 ng/l), described as ‘according to the manufacturer’, differs from the 99th centile given in the current product information leaflet (40 ng/l). 16 The product information leaflet describes this value as being derived from general practice samples obtained from London, UK, and the surrounding area; samples were from 1000 people aged > 40 years, with approximately equal numbers of males and females, and samples from people with abnormal urea and electrolytes, liver function tests, glucose or NT-proBNP (N-terminal pro-β-natiuretic peptide), were excluded. 16 Expected values, and hence diagnostic thresholds, derived from groups of healthy volunteers may have limited applicability to the population in whom hs-cTn testing would be applied in practice, for example with respect to age range. Data provided in the product information leaflets for the Roche Elecsys hs-cTnT assay and the Abbott ARCHITECT hs-cTnI assay both indicated that 99th centile values differed between males and females; the Abbott ARCHITECT hs-cTnI assay reported values of 15.6 ng/l and 34.2 ng/l for females and males, respectively,15 and the Roche Elecsys hs-cTnT assay reported values of 10.0 ng/l and 14.2 ng/l for females and males, respectively. 18 Despite this, we were unable to identify any data on whether the diagnostic performance of tests varies according to sex, when a single common diagnostic threshold is used for both males and females; the effectiveness of using sex-specific diagnostic thresholds therefore remains uncertain. Similarly, we were unable to identify any data on the diagnostic performance of hs-cTn assays when used in people with impaired renal function.

Differences in the populations used to derive the 99th centile diagnostic threshold, and hence in the Tn level at which this threshold set, may also affect the ability of an assay to achieve the first point of the accepted definition of a hs-cTn assay (i.e. a CV of ≤ 10% at the 99th centile for the general population). A standardised definition of the required reference population would be useful in ensuring a ‘level playing field’ for classification of assays as ‘high sensitive’ and would aid comparisons between tests.

We identified some data on the diagnostic performance of hs-cTn testing in clinically important subgroups (older people,39,53 and people with and without pre-existing CAD). 39,47 However, these data were very limited and were available only for the Roche Elecsys hs-cTnT assay. Therefore, there remains some uncertainty about how the diagnostic performance of individual hs-cTn assays may vary in clinically relevant subgroups, as well as what may constitute the optimal testing strategy in these groups.

A significant limitation of this assessment follows from the design of the primary studies included in the systematic review. The objective of these studies was to evaluate the diagnostic performance of hs-cTn assays when compared with a reference standard based on the universal definition of AMI endorsed by the ESC, the ACC, the AHA and the World Heart Federation (WHF). 8,21,22 The scope for this assessment did not include studies that evaluated the use of hs-cTn testing in combination with other tests, thus, studies that assessed the combined accuracy of a clinical risk score and a hs-cTn test used together would have been excluded; however, we did not identify any studies that were excluded on this basis. Studies assessing the diagnostic performance of a hs-cTn test alone, in which participants were subgrouped by clinical risk, met our inclusion criteria and were included in the systematic review. We identified only one study of this type,49 which, as described above (see Clinical effectiveness), indicated that the rule-out performance of hs-cTnT testing may be improved if the test is used in a population with high clinically determined pre-test probability. There remains uncertainty around how hs-cTn testing would perform if used, as it would be in clinical practice, in combination with a clinical assessment of pre-test probability (with or without formal risk scoring). Full assessment of the independent predictive value of hs-cTn testing requires multivariable prediction modelling.

A final area of uncertainty exists with respect to the clinical significance of a ‘FP’ hs-cTn result [i.e. does a positive hs-cTn result imply a clinically important change in cardiac risk, when a diagnosis of AMI is not confirmed (based on standard Tns and the universal definition)]? Re-adjudication of the final diagnosis, using later hs-cTn measurements in place of the conventional Tn results, can provide some insight into this issue. The most recent publication from the APACE study39 reported that when hs-cTnT results (including a 6-hour time point) were included in the reference standard diagnosis, this resulted in 131 participants being classified as having had a small AMI, which would have been classified as ‘no AMI’ where adjudication was based on standard Tn results.

Cost-effectiveness

The main uncertainties for the cost-effectiveness analysis lie in the model assumptions, particularly regarding the effect of actual clinical practice in terms of both other diagnostic information and treatment given this information. Although many of these assumptions have been varied in one-way sensitivity analysis, the precise implication of FN test results, where patients are discharged without essential treatment, or of FP test results, where patients stay in hospital and may receive unnecessary interventions, is unknown.

It should also be emphasised that the uncertainty resulting from the abovementioned assumptions was not parameterised in the model and is therefore not reflected in the PSAs or in the CEACs.

MEDLINE (OvidSP): 1946 to 2013/10/Week 1

Searched: 11 October 2013

1. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (229)

2. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (99)

3. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (563)

4. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (349)

5. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (769)

6. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (66)

7. or/1-6 (1215)

8. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (8642)

9. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot. (4,878,300)

10. 8 and 9 (4209)

11. 7 or 10 (4559)

12. chest pain/ (9293)

13. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (28,602)

14. exp myocardial ischemia/ (357,748)

15. (acute adj2 coronary adj2 syndrome$).ti,ab,ot. (16,495)

16. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot. (285)

17. Unstable angina$.ti,ab,ot. (10,718)

18. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot. (194,088)

19. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot. (53,168)

20. or/12-19 (444,673)

21. 11 and 20 (2503)

22. animals/ not (animals/ and humans/) (3,957,888)

23. 21 not 22 (2336)

MEDLINE In-Process & Other Non-Indexed Citations (OvidSP): up to 2013/10/01; MEDLINE Daily Update (OvidSP): up to 2013/10/01

Searched: 11 October 2013

1. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (32)

2. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (9)

3. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (62)

4. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (29)

5. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (99)

6. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (3)

7. or/1-6 (125)

8. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (5)

9. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot. (388,942)

10. 8 and 9 (3)

11. 7 or 10 (127)

12. chest pain/ (13)

13. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (1742)

14. exp myocardial ischemia/ (170)

15. (acute adj2 coronary adj2 syndrome$).ti,ab,ot. (1544)

16. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot. (3)

17. Unstable angina$.ti,ab,ot. (378)

18. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot. (8220)

19. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot. (4224)

20. or/12-19 (12,386)

21. 11 and 20 (76)

22. animals/ not (animals/ and humans/) (1462)

23. 21 not 22 (76)

EMBASE (OvidSP): 1974 to 2013/10/10

Searched: 11 October 2013

1. “high sensitivity cardiac troponin T”/ or high sensitivity troponin t assay/ (12)

2. “high sensitivity cardiac troponin I”/ or high sensitivity troponin i assay/ (3)

3. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (565)

4. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (190)

5. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (1052)

6. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (598)

7. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (1478)

8. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (106)

9. or/1-8 (2142)

10. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (18,661)

11. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot,hw. (6,591,905)

12. 10 and 11 (9505)

13. 9 or 12 (10,097)

14. thorax pain/ (44,504)

15. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (64,208)

16. acute coronary syndrome/ (24,295)

17. (acute adj2 coronary adj2 syndrome$).ti,ab,ot,hw. (34,428)

18. exp heart muscle ischemia/ (73,551)

19. exp heart infarction/ (266,027)

20. exp Unstable-Angina-Pectoris/ (16,552)

21. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot,hw. (374)

22. Unstable angina$.ti,ab,ot. (14,593)

23. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot,hw. (406,203)

24. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot,hw. (85,655)

25. or/14-24 (498,902)

26. 13 and 25 (6007)

27. animal/ (1,890,932)

28. animal experiment/ (1,720,343)

29. (rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5,825,865)

30. or/27-29 (5,825,865)

31. exp human/ (15,014,990)

32. human experiment/ (317,206)

33. or/31-32 (15,016,431)

34. 30 not (30 and 33) (4,642,837)

35. 26 not 34 (5642)

36. limit 35 to yr=“2005 -Current” (4374)

37. remove duplicates from 36 (4282)

Cochrane Database of Systematic Reviews (CDSR) (Wiley), Issue 10/October, up to 2013/10/11; Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley), Issue 9/September, 2013; Database of Abstracts of Reviews of Effects (DARE) (Wiley), Issue 3/July, 2013; Health Technology Assessment Database (HTA) (Wiley), Issue 3/July:2013; NHS Economic Evaluation Database (NHS EED) (Wiley), Issue 3/July, 2013

Searched: 11 October 2013

1. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs):ti,ab,kw (5)

2. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni):ti,ab,kw (5)

3. ((troponin t or tnt or ctnt or tropt or trop t) near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (12)

4. ((troponin I or tni or ctni or tropI or trop I) near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (10)

5. (troponin* near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (27)

6. (troponin* near/5 (architect or elecsys or accutni or accu-tni or access or unicel)):ti,ab,kw (2)

7. #1 or #2 or #3 or #4 or #5 or #6 (42)

8. MeSH descriptor: [Troponin T] this term only (265)

9. MeSH descriptor: [Troponin I] this term only (309)

10. #8 or #9 (543)

11. (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive):ti,ab,kw (170,016)

12. #10 and #11 (236)

13. #7 or #12 (249)

14. MeSH descriptor: [Chest Pain] this term only (335)

15. ((chest or thorax or thoracic) near/2 (pain* or discomfort or tight* or pressure)):ti,ab,kw (1793)

16. (acute near/2 coronary near/2 syndrome*):ti,ab,kw (1678)

17. MeSH descriptor: [Myocardial Ischemia] explode all trees (20,427)

18. (preinfarc* Angina* or pre infarc* Angina*):ti,ab,kw (90)

19. (Unstable angina*):ti,ab,kw (1818)

20. ((heart* or myocardi* or cardiac or coronary) near/2 (preinfarc* or infarc* or attack* or arrest* or occlusion* or isch?emia*)):ti,ab,kw (16,156)

21. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI):ti,ab,kw (4740)

22. #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 (28,923)

23. #13 and #22 from 2005 to 2013 (114)

CDSR search retrieved 0 references; CENTRAL search retrieved 108 references; DARE search retrieved 2 references; HTA search retrieved 1 references; NHS EED search retrieved 3 references.

Science Citation Index – Expanded (SCI) (Web of Science): 1970–2013/10/14; Conference Proceedings Citation Index (CPCI-S) (Web of Science): 1990–2013/10/14

Searched: 14 October 2013

Databases = SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC Timespan = 2005–13

1. 228 TS=(Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs)

2. 90 TS=(Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni)

3. 1438 TS=((troponin* or tnt or ctnt or tropt or tni or ctni or tropI or “trop t” or “trop I”) NEAR/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or “high performance” or ultrasensitive))

4. 1470 #3 OR #2 OR #1

5. 13,963 TS=((chest or thorax or thoracic) NEAR (pain* or discomfort or tight* or pressure))

6. 19,298 TS=(acute NEAR/2 coronary NEAR/2 syndrome*)

7. 393 TS=(preinfarc* angina* or pre infarc* angina)

8. 5481 TS=unstable angina*

9. 115,395 TS=((heart* or myocard* or cardiac or coronary) NEAR/2 (preinfarc* or infarc* or attack* or arrest* or occlusion* or isch?emia*))

10. 40,133 TS=(MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI)

11. 155,342 #10 OR #9 OR #8 OR #7 OR #6 OR #5

12. 835 #11 AND #4

Latin American and Caribbean Health Sciences (LILACS): 1982–2013/09/24 (http://regional.bvsalud.org/php/index.php?lang=en)

Searched: 14 October 2013

International Network of Agencies for Health Technology Assessment (INAHTA): up to 2013/10/15 (www.inahta.org/Search2/?pub=1)

Searched: 15 October 2013

BIOSIS Previews (Web of Knowledge): 1956–2013/10/11

Searched: 14 October 2013

1. Databases=BIOSIS Previews Timespan=2005-2013

2. 266 TS=(Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs)

3. 114 TS=(Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni)

4. 1055 TS=((troponin* or tnt or ctnt or tropt or tni or ctni or tropI or “trop t” or “trop I”) NEAR/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or “high performance” or ultrasensitive))

5. 1095 #3 OR #2 OR #1

6. 7468 TS=((chest or thorax or thoracic) NEAR (pain* or discomfort or tight* or pressure))

7. 11,149 TS=(acute NEAR/2 coronary NEAR/2 syndrome*)

8. 196 TS=(preinfarc* angina* or pre infarc* angina)

9. 3025 TS=unstable angina*

10. 62,717 TS=((heart* or myocard* or cardiac or coronary) NEAR/2 (preinfarc* or infarc* or attack* or arrest* or occlusion* or isch?emia*))

11. 28,931 TS=(MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI)

12. 83,999 #10 OR #9 OR #8 OR #7 OR #6 OR #5

13. 628 #11 AND #4

National Institute for Health Research Health technology Assessment (Internet) (www.hta.ac.uk/) up to 2013/10/14

Searched: 14 October 2013

Browsed with Troponin terms – six results.

Aggressive Research Intelligence Facility (Internet): 1996–2013/10/16 (www.birmingham.ac.uk/research/activity/mds/projects/HaPS/PHEB/ARIF/databases/index.aspx)

Searched: 16 October 2013

Medion database: up to 2013/10/16 (www.mediondatabase.nl/)

Searched: 16 October 2013

Searched: in ‘Whole Database’

PROSPERO (International Prospective Register of Systematic Reviews) (Internet): up to 2013/10/10 (www.crd.york.ac.uk/prospero/)

Searched: 10 October 2013

Searched: in ‘All fields’

Clinicaltrials.gov (Internet) (http://clinicaltrials.gov/ct2/search/advanced)

Searched: 14 October 2013

Advanced search option – search terms box.

metaRegister of Controlled Trials (mRCT) (Internet) (www.controlled-trials.com/)

Searched: 10 October 2013

WHO International Clinical Trials Registry Platform (ICTRP) (Internet) (www.who.int/ictrp/en/)

Searched: 10 October 2013

Advanced search option

Date of registration limited to 01/01/2005 to 10/10/2013

American Heart Association: Scientific Sessions (http://my.americanheart.org/professional/Sessions/ScientificSessions/Archive/Archive-Scientific-Sessions_UCM_316935_SubHomePage.jsp)

Searched: 29 October 2013

2013: Conference not yet taken place at time of searching

2012: http://circ.ahajournals.org/content/vol126/21_MeetingAbstracts

2011: http://circ.ahajournals.org/content/vol124/21_MeetingAbstracts

2010: http://circ.ahajournals.org/content/vol122/21_MeetingAbstracts

2009: http://circ.ahajournals.org/content/120/21/2152.full.pdf

American Association for Clinical Chemistry (www.aacc.org/resourcecenters/meet_abstracts_archive/abstracts_archive/annual_meeting/Pages/default.aspx#)

Searched: 29 October 2013

2013 Abstracts from: Clinical Chemistry, 59(S10):A1–295

www.aacc.org/events/Annual_Meeting/abstracts/Documents/AACC_13_AbstractBook_Complete.pdf

2012 Abstracts from: Clinical Chemistry, 58(S10):a1–A264

www.aacc.org/events/annualmtgdirectory/Documents/AACC_12_AbstractBook-Final-Complete.pdf

2011 Abstracts from: Clinical Chemistry, 57 (S10): A1–A235

www.aacc.org/events/annualmtgdirectory/documents/AACC_11_FullAbstract.pdf

2010 Abstracts from: Clinical Chemistry, 57 (6 Suppl): A1–276

www.aacc.org/events/annualmtgdirectory/Pages/2010PosterAbstracts.aspx#

2009 19–23 July, Chicago, IL, www.abstractsonline.com/viewer/searchAdvanced.asp?MKey={CA6D749E-BE20-4F85-899B-8A84E2268F72}&AKey={B08F832C-9D23-4F0B-96C3-3FA22F3D94A1}

European Society of Cardiology (http://spo.escardio.org/abstract-book/search.aspx)

Searched: 29 October 2013

Results sorted by Link Ranking (www.ncbi.nlm.nih.gov/pubmed/)

Searched: 10 December 2013

Nine of the included publications were not indexed on PubMed. Indexed publications were checked for errata and comments. For each reference, the first 20 references were retrieved by carrying out a Related Citations search using PubMed’s similarity matching algorithm. These records were downloaded for screening. All related citations were checked against the EndNote Library to remove duplicates, and only new unique references were imported and screened = 58 records.

MEDLINE (OvidSP): 1946 to 2013/10/Week 1

Searched: 18 October 2013

1. economics/ (27,116)

2. exp “costs and cost analysis”/ (182,544)

3. economics, dental/ (1866)

4. exp “economics, hospital”/ (19,403)

5. economics, medical/ (8578)

6. economics, nursing/ (3879)

7. economics, pharmaceutical/ (2605)

8. (economic$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab. (427,344)

9. (expenditure$ not energy).ti,ab. (17,552)

10. (value adj1 money).ti,ab. (22)

11. budget$.ti,ab. (17,208)

12. or/1-11 (551,693)

13. ((energy or oxygen) adj cost).ti,ab. (2752)

14. (metabolic adj cost).ti,ab. (798)

15. ((energy or oxygen) adj expenditure).ti,ab. (16,662)

16. or/13-15 (19,503)

17. 12 not 16 (547,348)

18. letter.pt. (803,396)

19. editorial.pt. (334,975)

20. historical article.pt. (299,710)

21. or/18-20 (1,423,597)

22. 17 not 21 (519,320)

23. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (229)

24. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (99)

25. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (563)

26. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (349)

27. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (769)

28. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (66)

29. or/23-28 (1215)

30. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (8642)

31. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot. (4,878,300)

32. 30 and 31 (4209)

33. 29 or 32 (4559)

34. chest pain/ (9293)

35. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (28,602)

36. exp myocardial ischemia/ (357,748)

37. (acute adj2 coronary adj2 syndrome$).ti,ab,ot. (16,495)

38. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot. (285)

39. Unstable angina$.ti,ab,ot. (10,718)

40. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot. (194,088)

41. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot. (53,168)

42. or/34-41 (444,673)

43. 33 and 42 (2503)

44. animals/ not (animals/ and humans/) (3,957,888)

45. 43 not 44 (2336)

46. limit 45 to yr=“2005 -Current” (1457)

47. 22 and 46 (43)

Costs filter: Centre for Reviews and Dissemination. NHS EED Economics Filter: MEDLINE (Ovid) monthly search York: Centre for Reviews and Dissemination; 2010.

MEDLINE In-Process & Other Non-Indexed Citations (OvidSP): up to 2013/10/01, MEDLINE daily update: up to 2013/10/01

Searched: 18 October 2013

1. economics/ (2)

2. exp “costs and cost analysis”/ (87)

3. economics, dental/ (0)

4. exp “economics, hospital”/ (8)

5. economics, medical/ (0)

6. economics, nursing/ (0)

7. economics, pharmaceutical/ (1)

8. (economic$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab. (39,821)

9. (expenditure$ not energy).ti,ab. (1172)

10. (value adj1 money).ti,ab. (4)

11. budget$.ti,ab. (1822)

12. or/1-11 (41,689)

13. ((energy or oxygen) adj cost).ti,ab. (218)

14. (metabolic adj cost).ti,ab. (67)

15. ((energy or oxygen) adj expenditure).ti,ab. (911)

16. or/13-15 (1160)

17. 12 not 16 (41,354)

18. letter.pt. (24,293)

19. editorial.pt. (14,525)

20. historical article.pt. (68)

21. or/18-20 (38,878)

22. 17 not 21 (40,906)

23. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (32)

24. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (9)

25. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (62)

26. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (29)

27. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot. (99)

28. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (3)

29. or/23-28 (125)

30. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (5)

31. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot. (388,942)

32. 30 and 31 (3)

33. 29 or 32 (127)

34. chest pain/ (13)

35. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (1742)

36. exp myocardial ischemia/ (170)

37. (acute adj2 coronary adj2 syndrome$).ti,ab,ot. (1544)

38. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot. (3)

39. Unstable angina$.ti,ab,ot. (378)

40. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot. (8220)

41. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot. (4224)

42. or/34-41 (12,386)

43. 33 and 42 (76)

44. animals/ not (animals/ and humans/) (1462)

45. 43 not 44 (76)

46. limit 45 to yr=“2005 -Current” (75)

47. 22 and 46 (4)

Costs filter: Centre for Reviews and Dissemination. NHS EED Economics Filter: MEDLINE (Ovid) monthly search. York: Centre for Reviews and Dissemination; 2010.

EMBASE (OvidSP): 1974 to 2013/10/17

Searched: 18 October 2013

1. health-economics/ (33,273)

2. exp economic-evaluation/ (205,882)

3. exp health-care-cost/ (197,503)

4. exp pharmacoeconomics/ (169,588)

5. or/1-4 (471,813)

6. (econom$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab. (590,127)

7. (expenditure$ not energy).ti,ab. (23,360)

8. (value adj2 money).ti,ab. (1320)

9. budget$.ti,ab. (23,595)

10. or/6-9 (613,918)

11. 5 or 10 (885,833)

12. letter.pt. (844,056)

13. editorial.pt. (449,323)

14. note.pt. (587,506)

15. or/12-14 (1,880,885)

16. 11 not 15 (799,169)

17. (metabolic adj cost).ti,ab. (876)

18. ((energy or oxygen) adj cost).ti,ab. (3163)

19. ((energy or oxygen) adj expenditure).ti,ab. (19,981)

20. or/17-19 (23,208)

21. 16 not 20 (794,101)

22. “high sensitivity cardiac troponin T”/ or high sensitivity troponin t assay/ (12)

23. “high sensitivity cardiac troponin I”/ or high sensitivity troponin i assay/ (3)

24. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs).ti,ab,ot. (571)

25. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni).ti,ab,ot. (193)

26. ((troponin t or tnt or ctnt or tropt or trop t) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (1059)

27. ((troponin I or tni or ctni or tropI or trop I) adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (602)

28. (troponin$ adj2 (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive)).ti,ab,ot,hw. (1489)

29. (troponin$ adj5 (architect or elecsys or accutni or accu-tni or access or unicel)).ti,ab,hw,ot. (106)

30. or/22-29 (2155)

31. troponin t/ or troponin I/ or (60304-72-5 or 77108-40-8).rn. (18,726)

32. (sensitiv$ or hs or early or initial or rapid or present$ or ultra or high performance or ultrasensitive).ti,ab,ot,hw. (6,601,404)

33. 31 and 32 (9548)

34. 30 or 33 (10,144)

35. thorax pain/ (44,662)

36. ((chest or thorax or thoracic) adj2 (pain$ or discomfort or tight$ or pressure)).ti,ab,ot,hw. (64,388)

37. acute coronary syndrome/ (24,412)

38. (acute adj2 coronary adj2 syndrome$).ti,ab,ot,hw. (34,558)

39. exp heart muscle ischemia/ (73,666)

40. exp heart infarction/ (266,475)

41. exp Unstable-Angina-Pectoris/ (16,570)

42. (preinfarc$ Angina$ or pre infarc$ Angina$).ti,ab,ot,hw. (374)

43. Unstable angina$.ti,ab,ot. (14,604)

44. ((heart$ or myocardi$ or cardiac or coronary) adj2 (preinfarc$ or infarc$ or attack$ or arrest$ or occlusion$ or isch?emia$)).ti,ab,ot,hw. (406,847)

45. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI).ti,ab,ot,hw. (85,913)

46. or/35-45 (499,787)

47. 34 and 46 (6035)

48. animal/ (1,890,937)

49. animal experiment/ (1,721,607)

50. (rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5,828,979)

51. or/48-50 (5,828,979)

52. exp human/ (15,032,575)

53. human experiment/ (317,393)

54. or/52-53 (15,034,016)

55. 51 not (51 and 54) (4,644,866)

56. 47 not 55 (5669)

57. limit 56 to yr=“2005 -Current” (4401)

58. remove duplicates from 57 (4309)

59. 21 and 58 (129)

Costs filter: Centre for Reviews and Dissemination. NHS EED Economics Filter: EMBASE (Ovid) weekly search. York: Centre for Reviews and Dissemination; 2010.

NHS Economic Evaluation Database (NHS EED) (Wiley) Issue 3/July:2013

Searched: 11 October 2013

1. (Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs):ti,ab,kw (5)

2. (Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or) accutni or accu-tni):ti,ab,kw (5)

3. ((troponin t or tnt or ctnt or tropt or trop t) near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (12)

4. ((troponin I or tni or ctni or tropI or trop I) near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (10)

5. (troponin* near/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive)):ti,ab,kw (27)

6. (troponin* near/5 (architect or elecsys or accutni or accu-tni or access or unicel)):ti,ab,kw (2)

7. #1 or #2 or #3 or #4 or #5 or #6 (42)

8. MeSH descriptor: [Troponin T] this term only (265)

9. MeSH descriptor: [Troponin I] this term only (309)

10. #8 or #9 (543)

11. (sensitiv* or hs or early or initial or rapid or present* or ultra or high performance or ultrasensitive):ti,ab,kw (170,016)

12. #10 and #11 (236)

13. #7 or #12 (249)

14. MeSH descriptor: [Chest Pain] this term only (335)

15. ((chest or thorax or thoracic) near/2 (pain* or discomfort or tight* or pressure)):ti,ab,kw (1793)

16. (acute near/2 coronary near/2 syndrome*):ti,ab,kw (1678)

17. MeSH descriptor: [Myocardial Ischemia] explode all trees (20,427)

18. (preinfarc* Angina* or pre infarc* Angina*):ti,ab,kw (90

19. (Unstable angina*):ti,ab,kw (1818)

20. ((heart* or myocardi* or cardiac or coronary) near/2 (preinfarc* or infarc* or attack* or arrest* or occlusion* or isch?emia*)):ti,ab,kw (16,156)

21. (MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI):ti,ab,kw (4740)

22. #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 (28,923)

23. #13 and #22 from 2005 to 2013 (114)

NHS EED search retrieved three references.

Health Economic Evaluation Database (HEED) (Internet): up to 2013/10/18 (http://onlinelibrary.wiley.com/book/10.1002/9780470510933)

Searched: 18 October 2013

Compound search, (all data), unable to limit by date

Troponin*

AND

sensitiv* OR hs OR early OR initial OR rapid OR present OR ultra OR high performance OR ultrasensitive OR elecsys OR architect OR accutni OR access OR unicel

N=20

Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs or Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra

N=0

Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni

N=0

EconLit (EBSCO) 1990–2013/09/01

Searched: 18 October 2013

Search modes – Boolean/Phrase

S1 TX Troponin* (0)

S2 TX Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs (0)

S3 TX Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni (0)

Science Citation Index Expanded (SCI) (Web of Science): 1970–2013/10/21, Conference Proceedings Citation Index (CPCI-S) (Web of Science): 1990–2013/10/21

Searched: 21 October 2013

1. 622,444 TS=(economic* or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic* or budget*)

2. 10,144 TS=(expenditure* not energy)

3. 952 TS=(value NEAR money)

4. 626,873 #3 OR #2 OR #1

5. 22,383 TS=((energy or oxygen) NEAR cost)

6. 1804 TS=(metabolic NEAR cost)

7. 12,974 TS=((energy or oxygen) NEAR expenditure)

8. 35,684 #7 OR #6 OR #5

9. 602,398 #4 NOT #8

10. 230 TS=(Hstnt or hs-tnt or hsctnt or hs-ctnt or tnt-hs or tnths or ctnths or ctnt-hs)

11. 91 TS=(Hstni or hs-tni or hsctni or hs-ctni or tni-hs or tnihs or ctnihs or ctni-hs or ctni-ultra or accutni or accu-tni)

12. 1442 TS=((troponin* or tnt or ctnt or tropt or tni or ctni or tropI or “trop t” or “trop I”) NEAR/2 (sensitiv* or hs or early or initial or rapid or present* or ultra or “high performance” or ultrasensitive))

13. 1474 #12 OR #11 OR #10

14. 14,001 TS=((chest or thorax or thoracic) NEAR (pain* or discomfort or tight* or pressure))

15. 19,324 TS=(acute NEAR/2 coronary NEAR/2 syndrome*)

16. 393 TS=(preinfarc* angina* or pre infarc* angina)

17. 5486 TS=unstable angina*

18. 115,562 TS=((heart* or myocard* or cardiac or coronary) NEAR/2 (preinfarc* or infarc* or attack* or arrest* or occlusion* or isch?emia*))

19. 40,195 TS=(MI or ACS or STEMI or NSTE-ACS or NSTEACS or nonSTEMI or NSTEMI or AMI or UAP or OMI)

20. 155,582 #19 OR #18 OR #17 OR #16 OR #15 OR #14

21. 839 #20 AND #13

22. 32 #21 AND #9

Databases = SCI-EXPANDED, CPCI-S, CCR-EXPANDED, IC Timespan = 2005–2013.

Research Papers in Economics (REPEC) up to 2013/10/21 (http://econpapers.repec.org/scripts/search/search.asp?pg=-1)

Searched: 21 October 2013

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