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Indication - Acute myocardial infarction
High-sensitivity troponin T (hs-cTnT)
Facility level:
2. Laboratory
Assay formats
Immunoassay
Status history
First added in 2022
Purpose type
Aid to diagnosis
Purpose
To aid in the diagnosis of acute myocardial infarction Note: When used for emergency or critical care, results are time- sensitive.
Specimen types
Plasma, Serum
WHO prequalified or recommended products
N/A
WHO supporting documents
HEARTS: technical package for cardiovascular disease management in primary health care: risk-based CVD management (2020) https://apps.who.int/iris/handle/10665/333221
Technical specifications for procurements
None
Codes
ICD11 code: BA41

Summary of evidence evaluation

Although the evidence provided in this application is incomplete and/or nonspecific, the existence of very well established guidelines in the European Union (EU), the United Kingdom and the United States with clear underpinnings and recommendations on hs-cTnI makes it clear that there is high value in the hs-cTnI test. International guidelines endorse hs-cTnI. As such, no further evidence is warranted from the applicant. However, to make the application more complete, the following should have been considered: ■ Specify condition(s) of interest. In this application CVD and myocardial infarction are used back and forth. The applicant used multiple interchangeable terms throughout the application (myocardial infarction, acute coronary syndrome, CVD). ■ Provide more insight into the quality-of-life impact of the disease/condition of interest. ■ Provide more insight into the costs and impact on costs of a potential intervention. ■ The systematic review submitted does not mention POC test(s), so performance may differ significantly. ■ Only one commercially available test has been reported in the scientific literature, and the domain of that publication is not the same (healthy vs symptomatic individuals).

Summary of SAGE IVD deliberations

Both hs-cTnT and hs-cTnI assays are essential tools in the management of coronary artery disease and the differential diagnosis of acute myocardial infarction. SAGE IVD raised several concerns related to the confusing nature of this application. The application was ostensibly for a POC test, but the data supporting the POC were limited and referred only to diagnostic performance. Evidence on how to frame the diagnostic algorithm and on the clinical utility of the assay was all based on laboratory testing. The experts know of no studies of POC capillary finger-stick tests outside of the hospital setting. Moreover, in 2020 the European Society of Cardiology (ESC) recommended against POC tests for the management of acute coronary syndromes. The FDA has also not approved any POC troponin test. One SAGE IVD member pointed out that this POC is intended for use in primary health care in remote areas; but if angioplasty or fibrinolysis are not available within 90 minutes, the proposition makes little sense. The experts also raised a methodological question about the predictive value of the test in low-prevalence settings. SAGE IVD noted that Médecins Sans Frontières have made POC tests a priority in general in the interest of faster, more affordable results. Nonetheless, the SAGE IVD group maintained that more data are needed on the clinical validity of the tests and to ensure adequate performance, particularly with regard to false positives and negatives. For these reasons, SAGE IVD agreed to list the submission as a laboratory-based test only but emphasized that the group fully supports further research into the POC version of the test and eventual application to EDL 5 with better evidence. Literature cited in the discussion: HEARTS: technical package for cardiovascular disease management in primary health care: risk-based CVD management. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/333221, accessed 30 July 2023). Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment element. Eur Heart J. 2021:42(5):373–498 (https://academic.oup.com/eurheartj/article/42/5/373/5899003, accessed 14 December 2022).

SAGE IVD recommendation

SAGE IVD recommended adding hs-cTnT to EDL 4 for consistency with the existing entry for a troponin test in EDL 3 and because the hs-cTnI and hs-cTnT are similarly used ■ in Section II.b Cardiovascular health; ■ using the immunoassay format; ■ using serum and plasma as specimen types; ■ to aid in the diagnosis of acute myocardial infarction. The experts further recommended introducing a new section in the EDL to be called II.b: Cardiovascular health. SAGE IVD also recommended linking the EDL entry to the WHO HEARTS technical package for cardiovascular disease management in primary health care.

Details of submission from 2022

Background

Disease condition and impact on patients Cardiovascular disease (CVD) is the number one cause of death globally (1). Only 10% of patients who go to the emergency department with chest pain are actually experiencing a heart attack (2). Every year 17.7 million people die from CVDs, an estimated 31% of all deaths worldwide (2). Over 75% of CVD deaths occur in LMICs (2). About 610 000 people die of heart disease in the United States every year, which amounts to one in every four deaths (3). The hs-cTnI test at POC aims to relieve the burden of care in the emergency department. This is possible because the use of this test in the emergency department decreases turnaround time for diagnostic results (compared to sending samples to the laboratory or utilizing a contemporary POC troponin test), which in turn leads to faster patient throughput in the emergency department. If not utilized, greater emergency department overcrowding can occur, which is deleterious for patient outcomes. For patients with non-ST-segment elevation myocardial infarction (NSTEMI), long emergency department stays were associated with decreased use of guideline-recommended therapies and a higher risk of recurrent myocardial infarction (4). In addition, hospital and emergency department overcrowding is associated with increased mortality. Reducing overcrowding may improve outcomes for patients requiring emergency hospital admission (5). Finally, emergency department crowding is associated with poor quality of care for patients with severe pain, namely, total lack of treatment or delay until treatment (6). Does the test meet a medical need? The new generation of highly sensitive troponin assays allows earlier detection of acute myocardial infarction, reducing the time window for serial measurement to 3 hours. Cardiac troponin (cTn) has become a continuous variable, with accurate measurement below the 99th percentile as well as absolute changes within 1 or 2 hours. This has enabled development of algorithms for reliable rule-out and rule-in of acute myocardial infarction within 2 hours. As a result, high-sensitivity cTn assays are an important aid to clinicians in optimizing management of acute coronary syndrome (ACS) in addition to clinical assessment and electrocardiogram (ECG), and enable definitive diagnosis of acute myocardial infarction. Serial measurements of high-sensitivity cTn are important in differentiating acute from chronic cardiac myocyte damage. Given that symptoms are not specific and ECG is not diagnostic 70% of the time, clinicians need cardiac biomarkers (7). How the test is used Using capillary blood from a finger stick, hs-cTnI results are achievable to aid in the diagnosis of myocardial infarction. This streamlined patient-testing workflow advances care delivery and accelerates clinical decision-making, as recommended by the European Society of Cardiology’s rapid algorithm. This algorithm recommends that clinical decision-making be taken with a high-sensitivity troponin test, signs and symptoms, a 12-lead ECG and a patient history.

Public health relevance

Prevalence Not provided. Socioeconomic impact Not provided.

WHO or other clinical guidelines relevant to the test

■ ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (8): pages 1299–1304 (3.3.2–3.3.4) for recommendation on the use of hs-cTn. Page 1306 (second table on the page) provides the level of evidence, including references to studies. ■ National Institute for Health and Care Excellence: High-sensitivity troponin tests for the early rule-out of NSTEMI. Diagnostic guidance (9): pages 4–5 for recommendations on the use of hs-cTn; pages 14–24 for evidence. ■ 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR1 guideline for the evaluation and diagnosis of chest pain (10).

Evidence for diagnostic accuracy

A systematic review and meta-analysis of diagnostic test accuracy studies were conducted to compare the diagnostic performance of various accelerated diagnostic algorithms of hs-cTn assays for patients with symptoms of acute myocardial infarction. A random-effects bivariate meta-analysis was conducted to estimate the summary sensitivity, specificity, likelihood ratios and area under the receiver operating characteristic curve. Both hs-cTnI- and hs-cTnT-based accelerated diagnostic algorithms were shown to have high sensitivities but moderate specificities for early diagnosis of acute myocardial infarction. Overall, hs-cTnI-based algorithms have slightly higher specificities in early diagnosis of acute myocardial infarction. For patients presenting to the emergency department with typical symptoms, the use of hs-cTnT or hs-cTnI assays at the 99th percentile may help identify patients at low risk for myocardial infarction and promote early discharge from the emergency department (11). Using serial sampling at 0 and 2 hours relative to the 99th percentile upper reference limit (URL), the whole blood POC Atellica VTLi assay showed comparable diagnostic performance for myocardial infarction to the central laboratory Abbott ARCHITECT and Siemens Atellica hs-cTnI assays. Specifically, the POC assay showed clinical sensitivities and NPVs demonstrating comparable diagnostic accuracy for ruling out myocardial infarction using both an overall 99th percentile URL, as well male and female sex-specific URLs. Similarly, the VTLi POC assay showed clinical specificities and PPVs demonstrating comparable rule-in performance to the central laboratory assays. The POC diagnostic data are novel and very timely. The Atellica VTLi POC hs‑cTnI assay addresses the need for both busy, urban, medical centre emergency departments and rural hospital and clinic settings to be able to have the alternative of utilizing a rapid, whole blood POC hs-cTnI assay 24/7 for patient triage and management (12).

Evidence for clinical usefulness and impact

The primary clinical utility impact is the decreased length of stay (LOS) and more patients discharged from emergency departments, due to implementation of high-sensitivity troponin testing. Implementation of an early rule-out pathway for myocardial infarction reduced LOS and hospital admissions. Although noninferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and health care providers (13). For patients with NSTEMI, long emergency department stays were associated with decreased use of guideline-recommended therapies and a higher risk of recurrent myocardial infarction (4).

Evidence for economic impact and/or cost–effectiveness

The analysis shows that the use of a 1-hour algorithm is associated with reduction in overall acute myocardial infarction diagnostic costs, provided it is carefully implemented in clinical practice. These results need to be prospectively validated in the future (14). Section 4.13 of the NICE guidelines states: “All early rule-out test strategies in the model are cost effective compared with standard troponin testing at 0 hours and 12 hours. … Compared with standard troponin testing, high-sensitivity troponin test strategies resulted in incremental cost-effectiveness ratios (ICERs) of less than £7,000 per quality-adjusted life-year (QALY) gained. These ICERs are below £20,000 per QALY gained, which NICE would typically consider to be cost effective” (9). Section 3.35 of the NICE guidelines also states: “The most recent study (Ambavane et al. 2017) reported that a 1-hour strategy using high-sensitivity troponin testing had higher sensitivity (87% compared with 69%) but lower specificity (96% compared with 97%) than standard care. The reference standard used to calculate diagnostic accuracy was determination of final diagnosis based on a comprehensive review of medical records. Total costs were less for the 1-hour strategy compared with standard care (£2,480 compared with £4,561). This was mainly because of a shorter length of stay in the emergency department” (9).

Ethical issues, equity and human rights issues

In areas where patients may not be able to access an established laboratory, POC high-sensitivity troponin improves access and reduces inequities due to cost, mobility/portability, size/weight, etc. Prior to this, these communities may have had no access or extremely delayed access due to long distances or commute times to medical centres (especially relevant for rural areas or areas that lack medical funding). Delayed diagnosis can lead to poor quality of care or nonadherence to guideline-recommended care. Emergency department crowding is associated with poor quality of care for patients with severe pain, namely, total lack of treatment and delay until treatment (6). For patients with NSTEMI, long emergency department stays were associated with decreased use of guideline recommended therapies and a higher risk of recurrent myocardial infarction (4).
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