High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial

Abstract

Background: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome.

Methods: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123.

Findings: Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620).

Interpretation: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population.

Funding: The British Heart Foundation.

Figure 1

Schematic of the High-STEACS trial design and linkage of electronic patient record data sources (A) Diagram illustrating how screening, enrolment, adjudication, and follow-up were done by use of linked routine health-care data in Scotland. The Community Health Index is a population health-care register that includes all individuals resident in Scotland. The Community Health Index number, date and time of presentation, and study inclusion and exclusion criteria were extracted from the TrakCare software application and linked to the ARCHITECT assay platform to identify eligible patients. This number was also used to link all data sources, which are held securely within the NHS safe haven of each Health Board. Eligible patients were assigned a unique study ID and all identifiable data were removed. Anonymised data were transferred to a national analytical platform in the Farr Institute of Health Informatics Research (Edinburgh Bioquarter) for analysis and reporting. (B) Study design, in which sites were separated into early and late implementation designs. ICD-10=International Classification of Diseases, tenth edition. PIS=Prescribing Information System. SIMD=Scottish Index of Multiple Deprivation.

Figure 2

Incidence of myocardial infarction or death from cardiovascular causes at 1 year, stratified by troponin concentration and phase Data are Kaplan-Meier time-to-event curves. Paired log-rank test results are p=0·047 for no myocardial injury, p=0·131 for those reclassified by the hs-cTnI assay, and p=0·019 for those already identified by the contemporary cTnI assay. hs-cTnI=high-sensitivity cardiac troponin I. cTnI=contemporary cardiac troponin I.

Figure 3

Primary and secondary outcomes in patients reclassified by the high-sensitivity cardiac troponin I assay before and after implementation Data are the number and percentage of patients with each outcome in the validation phase and implementation phase and the odds ratio for implementation versus validation. The intra-cluster correlation coefficient from the generalised linear mixed effects model was 0.