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

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

The struggle is real: dealing with real world data in clinical trials

Background The recently published High-STEACS trial (ClinicalTrials.gov Identifier: NCT01852123) was a randomised controlled trial, enrolling 48,282 patients between June 2013 and June 2016. The trial’s objective was to determine if implementation of a new high-sensitivity troponin assay would improve outcomes in patients presenting with suspected acute coronary syndrome to hospital emergency departments across Scotland. The trial was unusual in that it made use of routine electronic health care data in unconsented patients. This presented a number of data management and governance challenges in the reporting of the trial. Methods The High-STEACS trial accessed routine electronic health care data sources from ten hospitals in two NHS health boards and national datasets in Scotland. Participant data were linked across twelve distinct data sources using the participant CHI (Community Health Index) number as a unique identifier. The study had ethical and local management approval in addition to approval from the Patient Benefit and Privacy Panel approval for record linkage. Data extraction was supported by the NHS Safe Haven of each health board and all eligible patients were assigned a unique study ID prior to the removal of identifiable participant data. De-identified data from each health board were transferred to the NHS Lothian Safe Haven’s secure analysis platform, hosted by the Farr Institute of Health Informatics Research. Data were combined into a single database for statistical analyses. The combined, linked study dataset was accessible only to approved individuals. Results The reporting of the High-STEACS trial presented a number of challenges not encountered in the reporting of a conventional randomised controlled trial. The use of data from electronic health records without individual patient consent allows the research question to be addressed in the whole patient population but requires rigorous data governance processes. The data linkage process was complex – collection of the correct data during the correct timeframe from multiple data sources within a single health board was challenging. This was compounded by then needing the variables in both health boards to map directly to the final combined dataset. As well as the challenges of mapping variables across health boards, a process had to be set up to ensure that patients who may have been seen at different times in both health boards were not included in the combined dataset twice. Conclusions The High-STEACS trial is one of the first of its kind to include this number of patients via routinely collected healthcare data. The strength of this approach was the ability to identify all patients with suspected acute coronary syndrome, rather than limiting findings to a selected, possibly unrepresentative, group as would be the case for a conventional randomised controlled trial. Access to routine healthcare data enabled the creation of a ‘meta database’ by drawing on a number of raw NHS data sources and linking them in a secure manner. It is important to recognise the challenges in processing and ensuring accuracy of these large datasets while meeting governance and privacy standards required for unconsented data

The Amborella genome and the evolution of flowering plants

Amborella trichopoda is strongly supported as the single living species of the sister lineage to all other extant flowering plants, providing a unique reference for inferring the genome content and structure of the most recent common ancestor (MRCA) of living angiosperms. Sequencing the Amborella genome, we identified an ancient genome duplication predating angiosperm diversification, without evidence of subsequent, lineage-specific genome duplications. Comparisons between Amborella and other angiosperms facilitated reconstruction of the ancestral angiosperm gene content and gene order in the MRCA of core eudicots. We identify new gene families, gene duplications, and floral protein-protein interactions that first appeared in the ancestral angiosperm. Transposable elements in Amborella are ancient and highly divergent, with no recent transposon radiations. Population genomic analysis across Amborella's native range in New Caledonia reveals a recent genetic bottleneck and geographic structure with conservation implications

The <em>Amborella</em> Genome and the Evolution of Flowering Plants

Amborella trichopoda is strongly supported as the single living species of the sister lineage to all other extant flowering plants, providing a unique reference for inferring the genome content and structure of the most recent common ancestor (MRCA) of living angiosperms. Sequencing the Amborella genome, we identified an ancient genome duplication predating angiosperm diversification, without evidence of subsequent, lineage-specific genome duplications. Comparisons between Amborella and other angiosperms facilitated reconstruction of the ancestral angiosperm gene content and gene order in the MRCA of core eudicots. We identify new gene families, gene duplications, and floral protein-protein interactions that first appeared in the ancestral angiosperm. Transposable elements in Amborella are ancient and highly divergent, with no recent transposon radiations. Population genomic analysis across Amborella's native range in New Caledonia reveals a recent genetic bottleneck and geographic structure with conservation implications

The Amborella Genome and the Evolution of Flowering Plants

Amborella trichopoda is strongly supported as the single living species of the sister lineage to all other extant flowering plants, providing a unique reference for inferring the genome content and structure of the most recent common ancestor (MRCA) of living angiosperms. Sequencing the Amborella genome, we identified an ancient genome duplication predating angiosperm diversification, without evidence of subsequent, lineage-specific genome duplications. Comparisons between Amborella and other angiosperms facilitated reconstruction of the ancestral angiosperm gene content and gene order in the MRCA of core eudicots. We identify new gene families, gene duplications, and floral protein-protein interactions that first appeared in the ancestral angiosperm. Transposable elements in Amborella are ancient and highly divergent, with no recent transposon radiations. Population genomic analysis across Amborella's native range in New Caledonia reveals a recent genetic bottleneck and geographic structure with conservation implications