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Trial registered on ANZCTR


Registration number
ACTRN12622001088730p
Ethics application status
Submitted, not yet approved
Date submitted
13/07/2022
Date registered
5/08/2022
Date last updated
5/08/2022
Date data sharing statement initially provided
5/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Re-engineering the clinical approach to suspected cardiac chest pain assessment; extending chest pain research evidence to the pre-hospital setting, enabled by novel point of care high-sensitivity cardiac troponin I (hs-cTnI) and artificial intelligence.
Scientific title
Re-engineering the clinical approach to suspected cardiac chest pain assessment; extending chest pain research evidence to the pre-hospital setting, enabled by novel point of care hs-cTnI and artificial intelligence.
Secondary ID [1] 307545 0
Nil Known
Universal Trial Number (UTN)
U1111-1278-2078
Trial acronym
RAPIDx AI-Prehospital
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Coronary Syndromes 326979 0
Condition category
Condition code
Cardiovascular 324168 324168 0 0
Coronary heart disease
Emergency medicine 324169 324169 0 0
Other emergency care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention proposes a new model of care for initial chest pain assessment, which uses portable heart-related blood tests (high sensitivity troponin I level) and digital algorithms to support decision-making.

The intervention will be administered by paramedics and general practitioners. Point of Care (POC) high sensitivity troponin I will be taken promptly, ideally within the first 10 minutes of the paramedic/GP encounter, however this will not be protocolized as part of the clinical trial.

The POC high sensitivity troponin I level, as well as key clinical characteristics such as age, gender, prior coronary disease, nature and location of symptoms, the presences or absence of clinical finding, coronary risk factors (such as most recent cholesterol level, hypertension, diabetes, smoking status and family history) and baseline ECG will be gathered and assimilated into an algorithm.

The timing of the ECG may occur immediately before or after POC high sensitivity troponin I testing, and ideally within the first 10 minutes of the paramedic/GP encounter, however this will not be protocolized as part of the clinical trial.

The algorithm will produce a predicated likelihood of 48 hour death, myocardial infarction (MI), pulmonary embolism (PE) and aortic dissection. This will be displayed within the mobile clinical interface (i.e. digital application). Access to the clinical interface will either be via phone, tablet, or similar digital device.

Data entry to receive an algorithm output is expected to take no more than 5 minutes at most. This predicted outcome rate information will be presented to the patient. From this, the health care worker and patient will decide whether the patient goes to ED or a Priority Care Centre for further assessment.

The following dispositions will be offered:
• If the algorithm-determined likelihood of adverse event is 1.0% and the high sensitivity troponin result is NOT elevated, and the ECG is NOT considered abnormal:
1. Patients will have the choice between being transported to and assessed further at a priority care centre OR the emergency department.
2. Rapid access cardiac clinic may be considered. Provision of the clinic appointment must occur within 72 hours. Rapid access cardiac clinic appointment bookings will be facilitated by the priority care centre at the end of the encounter.

• If the algorithm-determined likelihood of adverse event is >1.0% OR there is an elevated high sensitivity troponin level, OR an abnormal ECG:
1. Patients will be transported to the emergency department for further assessment

Rapid access cardiac clinic: These clinics will be staffed by dedicated nursing and medical experts with cardiac training and/or expertise. Subsequent testing will be determined by the treating clinicians, but application of the National Institute for Health and Care Excellence (NICE) guidelines recommended. These guidelines make recommendations regarding functional or invasive coronary testing based on characterisation of chest pain and cardiovascular risk factors.

Priority Care Centres provide community-based health care for patients with urgent but non-life-threatening conditions, who would otherwise be seeking a service from an Emergency Department. Priority Care Centres are led by experienced General Practitioners with additional care from specially trained acute care nurses. They are health care facility that can provide prompt, risk-appropriate care for those not requiring emergency care.

A cardiac clinic refers to outpatient clinic led by a cardiologist. Rapid access refers to the ability to obtain an appointment in a short timeframe (e.g. 72 hours). These rapid access cardiac clinical provide opportunity for timely cardiovascular assessment for risk-appropriate cohorts of patients such as those with new chest pain.

Monitoring of uptake and adherence of the intervention during the study will occur via data review of the digital application and comparative investigation within the health system data if needed.

Intervention code [1] 324004 0
Diagnosis / Prognosis
Comparator / control treatment
As recommended by the current guidelines, all standard of care control patients will be referred to the emergency department. The same baseline key clinical characteristics and coronary risk factors will be gathered and entered within the digital application as for the intervention group. No risk prediction estimate will be calculated and provided. However, if the initial ECG demonstrates ST segment elevation, instructions to call an ambulance (if currently located at a GP practice) will be provided. Clinical details of the patient will be stored for study administration purposes and a referral to the ED will be generated.
Control group
Active

Outcomes
Primary outcome [1] 331978 0
The primary outcome will be the composite endpoint comprising of:
-Cardiovascular mortality
-New or recurrent Types 1, 3, 4, 5 MI defined by the current 4th Universal Definition of Myocardial Infarction (or latest iteration if subsequent iteration released).
-Pulmonary Embolus (PE) as defined by pulmonary artery filling defects documented on a CT pulmonary angiogram or mismatched ventilation/perfusion defects on a nuclear VQ scan.
-Aortic dissection as defined by an intimal breach of the aortic within its thoracic or abdominal course as documented on either CT, MRI or transoesophageal echocardiography.

This data will be obtained by data-linkage of clinical and administrative public and private hospital and health service data, births deaths and marriages and Medicare and PBS data, where applicable.

N.B All MIs PEs and Aortic Dissections diagnosed within 12 hours presentation to either a PCC or ED will be excluded from the primary outcome.
Timepoint [1] 331978 0
30 days post-index presentation
Secondary outcome [1] 411795 0
All-cause mortality

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems and linkage to national databases (e.g. NDI, MBS/PBS).. Where required, paper medical records will be sought.
Timepoint [1] 411795 0
30 days, and 12 months post index presentation.
Secondary outcome [2] 411796 0
Composite endpoint comprising of re-presentation with myocardial infarction (Types 1, 3, 4,5), myocardial injury or unstable angina.

All data for in-hospital care will be obtained by data linkage of public hospital admissions and care through electronic medical records systems and linkage to national databases (e.g. NDI, MBS/PBS). Where required, paper medical records will be sought.
Timepoint [2] 411796 0
30-days and 12 months post-index presentation
Secondary outcome [3] 411797 0
Re-presentation to any emergency department with suspected cardiac chest pain.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems and linkage to national databases (e.g. NDI, MBS/PBS). Where required, paper medical records will be sought.
Timepoint [3] 411797 0
30-days and 12-months post-index presentation
Secondary outcome [4] 411798 0
Cardiac medications at discharge

This outcome will be assessed through linkage of health system data systems.
Timepoint [4] 411798 0
30-days and 12-months post-index presentation
Secondary outcome [5] 411799 0
Health-related quality of life (EQ-5D-5L)

This data will be acquired through surveying of participants at specified timepoints.
Timepoint [5] 411799 0
30-days, 6-and 12-months post-index presentation.
Secondary outcome [6] 411800 0
Resource utilisation over 12 months: Medicare data among consenting patients using Medical Benefits Schedule (MBS), medication use from Pharmaceutical Benefits Schedule (PBS) and inpatient admissions from the AN-Diagnosis Related Group (DRG) version 8.0.

This secondary outcome data will be acquired through the SA Health data infrastructure for all SA residents. This data will be obtained by data linkage of public and private hospital admissions and care through systems and, from Medicare (Medical Benefits Schedule (MBS), Pharmaceutical Benefits Schedule (PBS)), and in-patient admissions from the AN-Diagnosis Related Group (DRG).
Timepoint [6] 411800 0
12 months post-index presentation
Secondary outcome [7] 412539 0
Priority care centre length of stay

This outcome will be assessed through linkage of health system data systems.
Timepoint [7] 412539 0
30-days and 12-months post-index presentation.
Secondary outcome [8] 412540 0
Emergency department length of stay

This outcome will be assessed through linkage of health system data systems.
Timepoint [8] 412540 0
30-days and 12-months post-index presentation.
Secondary outcome [9] 412541 0
Hospital length of stay

This outcome will be assessed through linkage of health system data systems.
Timepoint [9] 412541 0
30-days and 12-months post-index presentation.
Secondary outcome [10] 412542 0
Cardiac investigations

This outcome will be assessed through linkage of health system data systems.
Timepoint [10] 412542 0
30-days and 12-months post-index presentation.
Secondary outcome [11] 412543 0
Cardiac procedures

This outcome will be assessed through linkage of health system data systems.
Timepoint [11] 412543 0
30-days and 12 months post-index presentation
Secondary outcome [12] 412544 0
Re-presentation with myocardial injury

All data for in-hospital care will be obtained by data linkage of public hospital admissions and care through electronic medical records systems and linkage to national databases (e.g. NDI, MBS/PBS). Where required, paper medical records will be sought.
Timepoint [12] 412544 0
30-days and 12 months post-index presentation
Secondary outcome [13] 412545 0
-Re-presentation with unstable angina.

All data for in-hospital care will be obtained by data linkage of public hospital admissions and care through electronic medical records systems and linkage to national databases (e.g. NDI, MBS/PBS). Where required, paper medical records will be sought.
Timepoint [13] 412545 0
30-days and 12 months post-index presentation

Eligibility
Key inclusion criteria
Patients seeking care from out-of-hospital health providers will be considered eligible for analysis if they meet all of the following:
a) Clinical features of chest pain or suspected acute coronary syndrome (ACS) as the principal cause in an out-of-hospital environment (as deemed by health service); and
b) At least one high-sensitivity troponin assay is drawn; and
c) Age of 18 years or older;
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients seeking care from out-of-hospital health providers will be considered ineligible for analysis if they meet any of the following:
a) Have had an in-hospital assessment for suspected cardiac chest pain within 30 days; or
b) Reside interstate or overseas; or
c) Wish to opt-out.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size calculation: The key motivating design feature of the trial is safety (<1% primary endpoint by 30 days) among patients choosing ambulatory care (objective 1). Hence, this component of the study determines the overall size. Assuming a primary endpoint among those choosing ambulatory assessment of 0.3%, 620 patients choosing this option will be required to ensure a confidence bound that does not cross 1% (i.e. level of acceptable safety). Hence, assuming that 50% of patients with a =1% predicted risk choose the ambulatory model of care, and 15% enrolled have a predicted risk >1%, a total sample size per am of 1458 patients will be required (i.e. 620 x 2 (50% choosing ED) x 1.18 (15% with risk > 1%). To allow for loss to follow-up, this study will enrol a total of 3000 patients. The study has > 80% power to demonstrate that for 12-month follow-up the hazard ratio for time to the primary endpoint between the two groups is no worse than 2.

Primary analysis: The primary analysis will employ the intention-to-treat (ITT) population including all eligible randomised patients, but given the non-inferiority design, the per-protocol population will be used in key secondary analyses. The study will be reported according to CONSORT guidelines. The two groups will be compared on baseline characteristics, with Chi-squared tests undertaken for categorical variables, and independent samples t-tests for continuous variables. Non-parametric analyses will be used where necessary. The initial analysis will compare the time to the composite primary outcome within 30-days between the pre-hospital model of care and standard care groups, using Poisson regression with variances adjusted for clustering to account for correlation within clinical teams.

Economic analysis: Patient-level measures of utility derived from the EQ-5D instrument will be integrated with survival curves to estimate quality-adjusted life years in each trial arm using the quality-adjusted survival analysis (QASA) method. Time and resources required for decision-support implementation will be included in the cost-effectiveness analysis. Within-trial incremental costs associated with the decision-support and with standard care will be estimated from patient data on MBS, PBS and hospital use (estimated 30% of cohort). Within-trial cost-effectiveness will then be analysed allowing for bivariate uncertainty with bootstrapping of patient costs and effects to maintain covariance structure. This analysis will include cost-effectiveness, acceptability, net benefit and expected net loss curves to inform decision makers of the optimal strategy at any given threshold, uncertainty around this decision, and the value of further research locally and internationally.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
27/03/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
5000
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 22789 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 22790 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 22791 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [4] 22792 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [5] 22793 0
Modbury Hospital - Modbury
Recruitment hospital [6] 22794 0
Noarlunga Health Service - Noarlunga Centre
Recruitment postcode(s) [1] 38075 0
5042 - Bedford Park
Recruitment postcode(s) [2] 38076 0
5000 - Adelaide
Recruitment postcode(s) [3] 38077 0
5011 - Woodville
Recruitment postcode(s) [4] 38078 0
5112 - Elizabeth Vale
Recruitment postcode(s) [5] 38079 0
5092 - Modbury
Recruitment postcode(s) [6] 38080 0
5168 - Noarlunga Centre

Funding & Sponsors
Funding source category [1] 311818 0
Government body
Name [1] 311818 0
National Health and Medical Research Council (NHMRC)
Country [1] 311818 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
1 Flinders Drive, Bedford Park 5042, South Australia
Country
Australia
Secondary sponsor category [1] 313295 0
None
Name [1] 313295 0
Address [1] 313295 0
Country [1] 313295 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311263 0
Southern Adelaide Clinical Human Research Ethics Committee.
Ethics committee address [1] 311263 0
Ethics committee country [1] 311263 0
Australia
Date submitted for ethics approval [1] 311263 0
06/06/2022
Approval date [1] 311263 0
Ethics approval number [1] 311263 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120494 0
Prof Derek Chew
Address 120494 0
Flinders Medical Centre
GPO Box 2100, Adelaide 5001, South Australia
Country 120494 0
Australia
Phone 120494 0
+61 08 8404 2001
Fax 120494 0
Email 120494 0
derek.chew@flinders.edu.au
Contact person for public queries
Name 120495 0
Kristina Lambrakis
Address 120495 0
College of Medicine & Public Health, Flinders University
Flinders Medical Centre
Cardiology, Level 6, Rm 6R347
1 Flinders Drive
Bedford Park SA 5042
Country 120495 0
Australia
Phone 120495 0
+61 08 8204 5836
Fax 120495 0
Email 120495 0
kristina.lambrakis@flinders.edu.au
Contact person for scientific queries
Name 120496 0
Kristina Lambrakis
Address 120496 0
College of Medicine & Public Health, Flinders University
Flinders Medical Centre
Cardiology, Level 6, Rm 6R347
1 Flinders Drive
Bedford Park SA 5042
Country 120496 0
Australia
Phone 120496 0
+61 08 8204 5836
Fax 120496 0
Email 120496 0
kristina.lambrakis@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This study will report outcomes on collective and de-identified datasets over a course of 12 months from index presentation on a large volume of participants. Thus, providing IPD will be operationally unfeasible.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.