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Trial registered on ANZCTR


Registration number
ACTRN12618000378224
Ethics application status
Approved
Date submitted
1/03/2018
Date registered
14/03/2018
Date last updated
18/10/2019
Date data sharing statement initially provided
18/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Appropriateness of Coronary investigation in myocardial injury and Type 2 myocardial infarction
Scientific title
The Appropriateness of Coronary investigation in myocardial injury and Type 2 myocardial infarction
Secondary ID [1] 293590 0
NHMRC APP: 1145612
Universal Trial Number (UTN)
U1111-1206-5267
Trial acronym
ACT-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Myocardial Infarction (MI) 305841 0
Myocardial injury 305842 0
Condition category
Condition code
Cardiovascular 305051 305051 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Type 2 Myocardial Infarction (T2MI) and myocardial injury patients will be assessed for eligibility, consented appropriately and then randomised to one of two treatment arms.

Arm 1 (intervention arm) -
Those randomly allocated to arm 1 will receive routine invasive angiography within 5 days of randomisation*. The technique of angiography will be as per local practice; radial or femoral access will be permitted and revascularisation will be at the discretion of the treating team. CT angiography may be considered as an alternative to invasive angiography but must be undertaken within 5 days of randomisation*.

*Angiography undertaken outside the 5-day window will be considered a protocol violation however these patients will be retained in analysis.

Adherence will be monitored through review of medical records.
Intervention code [1] 299844 0
Diagnosis / Prognosis
Comparator / control treatment
Arm 2 (control arm)-
Those randomly allocated to arm 2 will receive conservative management as per National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Management of Acute Coronary Syndromes 2016. Functional may be undertaken within the post-randomisation period as per local clinical decision. Functional testing may be with either ECG, stress echocardiography, nuclear perfusion scanning or stress MRI. CT angiography, while not invasive, is not considered functional testing.

Adherence will be monitored through review of medical records.
Control group
Active

Outcomes
Primary outcome [1] 304212 0
All-cause mortality (rather than cardiovascular mortality, as all-cause mortality is more relevant from a clinical decision-making perspective).

All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Births, Deaths and Marriages and the National Death Index will be used to collect mortality and cause of death. data.
Timepoint [1] 304212 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [1] 341269 0
Cardiovascular mortality defined as death from cardiogenic shock, myocardial infarction, heart failure/acute pulmonary oedema, cardiac arrhythmia/sudden cardiac death, or cerebrovascular accident, as documented as an antecedent cause within 1 month of death on the death certificate.

All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Births, Deaths and Marriages and the National Death Index will be used to collect mortality and cause of death.
Timepoint [1] 341269 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [2] 341270 0
Myocardial Infarction defined as a rise and fall in cardiac biomarkers associated with chest pain/discomfort >20min, new ECG changes consistent with myocardial ischaemia or a new myocardial defect on echocardiography or angiographic or autopsy evidence of a thrombotic coronary lesion, consistent with the new Universal Definition.1.


All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems.
Timepoint [2] 341270 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [3] 341271 0
Unstable angina defined as chest pain/discomfort with an accelerated pattern or occurring at rest requiring hospital admission, associated with: dynamic ECG changes consistent with ischaemia; or functional testing indicative of ischaemia; and/or demonstrated coronary stenosis>70% by visual estimation.


All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems.
Timepoint [3] 341271 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [4] 341272 0
Unplanned cardiovascular events: non-elective (and not associated with randomisation to anatomic arm) coronary revascularization; cerebrovascular accidents; atrial or ventricular arrhythmias; heart failure without MI; peripheral revascularization; as documented by a hospital discharge summary or diagnosis-related group (DRG) report.

All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems.
Timepoint [4] 341272 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [5] 341273 0
Significant bleeding using the international clinical trial definitions from BARC, GUSTO, TIMI and ACUITY.

All data will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems.
Timepoint [5] 341273 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [6] 341274 0
Percentage of in-hospital care compliance with current guidelines.
This includes stress testing, echocardiography, coronary angiography and cardiac medications at discharge.

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.
Timepoint [6] 341274 0
Estimated median of 24 months post enrolment.
Secondary outcome [7] 344033 0
Health-related quality of life (EQ-5D).

This data will be obtained through telephone or mail-out follow up.
Timepoint [7] 344033 0
30 days, 12 months, 24 months post enrollment 12 monthly after 24 months until study cessation.
Secondary outcome [8] 344035 0
Resource utilisation (composite outcome):
This includes Medicare data among consenting patients using Medicare Benefits Schedule (MBS), medication use from Pharmaceutical Benefits Schedule (PBS) and SA Health in-patient admissions from the AN-Diagnosis Related Group (DRG) version 6.0.
Timepoint [8] 344035 0
24 months post enrolment.

Eligibility
Key inclusion criteria
The study will enrol in-hospital patients with at least one elevated (“rule-in”) troponin result using the local laboratory standards (Troponin T or I, with test sensitivity as implemented locally) defined as either:

i. Troponin T (Roche Elecsys): >52ng/L
ii. Troponin I (Abbott Architect, Siemens Dimension Vista, Beckman Coulter Access): equal to or over 5 times the assay-specific upper limit of normal.

In addition, all patients must also fulfill all of the following
1. A clinical presentation consistent with a clear non-coronary alternative diagnosis, N.B.: In all cases medical stabilization of patient prior to angiography will be required.
2. Patient is 18 years of age or older; and
3. Patient is willing to give his/her written informed consent;

For trial eligibility, all patients must have an unequivocal acute intercurrent diagnosis. Specifically:
1. Sepsis: Clinical evidence of a fever and/or a raised white cell count plus an elevation in C-reactive protein above the local laboratories reference limit and:
a. Pneumonia: Cough, shortness of breath or positive sputum culture and radiological changes consistent with pneumonia on chest imaging
b. Urosepsis: frequency, urgency or dysuria, with leukocytes in urinalysis and positive urine microscopy and culture
c. Septicaemia: systemic symptoms of fevers, chills or sweats, and positive blood cultures thought not to be a contaminant.
d. Systemic Inflammatory Response Syndrome (SIRS): With 3 or more of:
i. Temperature, <36 °C (96.8 °F) or >38 °C (100.4 °F)
ii. Heart rate, >90 beats/min
iii. Respiratory rate, >20/min or PaCO2<32 mmHg
iv. While bleed cell count, <4x109/L, >12x109/L, or 10% bands
2. Anaemia: haemoglobin <10mg/dL on at least 2 samples within 48 hours
3. Thyrotoxicosis: TSH below the lower limit of normal
4. Atrial tachycardias: Evidence of sustained narrow complex tachycardia (Atrial fibrillation, atrial flutter, SVT) >120bpm for >20 min, documented on ECG monitoring. (i.e documentation of rate but not total duration of tachycardia)
5. Recent non-cardiac surgery, defined as surgical procedure requiring regional or general anaesthesia within 7 days of enrolment
6. Traumatic fractured neck of femur demonstrated on x-ray, within the prior 7 days
7. Acute kidney injury requiring dialysis or causing severe renal impairment (creatinine >150mmol/L) where dialysis remains a therapeutic consideration.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with clinically-defined T1MI: i.e. a rise and/or fall in troponin with at least 1 result above the 99th percentile of normal, with/without ECG changes consistent with ischaemia, and NO evidence of intercurrent illness.
2. Patients with ST-segment elevation on the presenting ECG
3. Haemodynamic instability including hypotension (Systolic BP<90mmHg, or requiring inotrope support), acute kidney injury where creatinine levels are not stable
4. Patients with a prior angiogram within the last 6 months, regardless of the presence or absence of documented coronary artery disease on that investigation.
5. New York Heart Association Class II-IV heart failure or Killip Class II-IV
6. Symptomatic angina with a Canadian Cardiovascular Society class II or more classification
7. Extensive frailty or co-morbidity in whom the treating physicians are unwilling to undertake a coronary angiogram (e.g. severe renal impairment in a patient unwilling to consider dialysis), or where life-expectancy is expected to be less than 2 years.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All enrolled patients will have their baseline GRACE risk score and APACHE III scores evaluated. Block randomisation will be undertaken within strata, based on predicted risk of in-hospital mortality (APACHE III) of <10%, 10-20% and >20% as well as by troponin pattern and enrolling hospital to account for local clinical preferences for ICA vs CTCA. All other subsequent management including choice of secondary prevention therapies will be left to clinician discretion. The utility of clinical, echocardiographic and biomarkers in identifying patients who may benefit from routine invasive management remains uncertain without previously defined criteria, thus these sub-analyses will remain observational and exploratory.
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
All sample size calculations assume a Type I and II error rates of 5% and 20%, respectively. Given the substantial competing risks among these patients, design assumptions have been expressly chosen to detect a clinically meaningful improvement in survival with the anatomic investigative strategy. Informing the design is the observed all-cause mortality rate of 41% by 12 months (from SA Hospitals 2009-2011). However, our sample size calculations have used a conservative survival rate of 70% by 2-year, to account for the potential of selective inclusion. This study is designed to detect a clinically absolute increase in survival of 7% by 2 years with the anatomic investigation strategy (i.e. a relative increase in survival within the coronary investigation arm of 10% [Hazard ratio: 0.75]) in the patients with T2MI [troponin pattern 1], and an 9% relative increase across the entire population (i.e. pattern 1 and 2 combined) [Hazard ratio; 0.77]), which translates to a number needed to treat (NNT) of between 14-18. Consequently, accounting for lost to follow-up rate of 3%, the study will enrol 1800 patients.
Furthermore, this is an event-driven study and follow-up of all participants will continue until 420 primary endpoint events (i.e. death from any cause) have occurred

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2018
Actual
13/11/2018
Date of last participant enrolment
Anticipated
31/12/2020
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
1800
Accrual to date
40
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 298208 0
Government body
Name [1] 298208 0
National Medical and Health Research Council (NHMRC)
Country [1] 298208 0
Australia
Primary sponsor type
Individual
Name
Prof Derek Chew
Address
1 Flinders Dr, Bedford Park SA 5042
Country
Australia
Secondary sponsor category [1] 297307 0
University
Name [1] 297307 0
Flinders University
Address [1] 297307 0
1 Flinders Dr, Bedford Park SA 5042
Country [1] 297307 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299215 0
Southern Adelaide Clinical Human Research Ethics Committee (SACHREC)
Ethics committee address [1] 299215 0
Ethics committee country [1] 299215 0
Australia
Date submitted for ethics approval [1] 299215 0
13/04/2018
Approval date [1] 299215 0
24/09/2018
Ethics approval number [1] 299215 0
Ethics committee name [2] 304563 0
Population Health NSW
Ethics committee address [2] 304563 0
Ethics committee country [2] 304563 0
Australia
Date submitted for ethics approval [2] 304563 0
21/03/2019
Approval date [2] 304563 0
19/07/2019
Ethics approval number [2] 304563 0

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

Contacts
Principal investigator
Name 79686 0
Prof Derek Chew
Address 79686 0
Flinders Medical centre,
1 Flinders Drive, Bedford Park 5042
South Australia
Country 79686 0
Australia
Phone 79686 0
+61884042001
Fax 79686 0
Email 79686 0
derek.chew@flinders.edu.au
Contact person for public queries
Name 79687 0
Kristina Lambrakis
Address 79687 0
Department of Cardiovascular Medicine, Flinders Medical Centre

1 Flinders Drive, Bedford Park 5042
South Australia
Country 79687 0
Australia
Phone 79687 0
+610882045836
Fax 79687 0
Email 79687 0
Kristina.Lambrakis@sa.gov.au
Contact person for scientific queries
Name 79688 0
Derek Chew
Address 79688 0
Flinders Medical centre,
1 Flinders Drive, Bedford Park 5042
South Australia
Country 79688 0
Australia
Phone 79688 0
+61884042001
Fax 79688 0
Email 79688 0
derek.chew@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
Data may contain individual participant information that will not be readily de-identifiable. IPD sharing will be considered at a later stage.


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocolThe ACT-2 design paper - Lambrakis, K., French, J., Scott, I., Briffa, T., Brieger, D., Farkouh, M., . . . Chew, D. (2019). The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design. American Heart Journal, 208, 11-20. https://doi.org/10.1016/j.ahj.2018.09.016  


Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseType-II myocardial infarction and chronic myocardial injury rates, invasive management, and 4-year mortality among consecutive patients undergoing high-sensitivity troponin T testing in the emergency department.2020https://dx.doi.org/10.1093/ehjqcco/qcz019
EmbaseTroponin elevation pattern and subsequent cardiac and non-cardiac outcomes: Implementing the Fourth Universal Definition of Myocardial Infarction and high-sensitivity troponin at a population level.2021https://dx.doi.org/10.1371/journal.pone.0248289
EmbaseType 2 MI and Myocardial Injury in the Era of High-sensitivity Troponin.2022https://dx.doi.org/10.15420/ecr.2021.42
N.B. These documents automatically identified may not have been verified by the study sponsor.