Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001254280
Ethics application status
Approved
Date submitted
20/07/2018
Date registered
25/07/2018
Date last updated
1/07/2022
Date data sharing statement initially provided
11/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Resolution of left ventricular thrombus with different anti coagulation strategies
Scientific title
A Prospective Randomized Open, Blinded End-point controlled study evaluating the resolution and recurrence of left ventricular thrombus with different anti coagulation strategies
Secondary ID [1] 295613 0
Nil
Universal Trial Number (UTN)
U1111-1216-0447
Trial acronym
RELEVENT study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
left ventricular thrombus 308938 0
Condition category
Condition code
Cardiovascular 307839 307839 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised 1:1 to either warfarin or a Direct Oral Anti-Coagulant (DOAC).

Participants randomised to a DOAC can be treated with either a factor Xa inhibitor (apixaban or rivaroxaban) or a direct thrombin inhibitor (dabigatran). The choice of DOAC is made according to local availability and clinical judgment and preference.

The dose of DOAC will be the same as recommended by the manufacturer for stroke prevention in atrial fibrillation, with appropriate adjustment for age, body weight, creatinine clearance and bleeding risk. Recommended doses for DOACs for stroke prevention in atrial fibrillation are:

DOAC
Apixaban: Standard Dose 5 mg twice daily, Reduced Dose 2.5 mg twice daily
Rivaroxaban: Standard Dose 20 mg once daily, Reduced Dose 15 mg once daily
Dabigatran: Standard Dose 150 mg twice daily, Reduced Dose 110 mg twice daily

Treatment will be continued for 3 months.
Intervention code [1] 301919 0
Treatment: Drugs
Comparator / control treatment
Warfarin oral tablets for 3 months. Participants may be heparinized with low molecular weight heparin or unfractionated heparin until therapeutic INR is >2.0. Subsequent dosing of warfarin is determined by the INR which will be maintained in the range of 2.0 - 3.0. Upon discharge from hospital, INRs and warfarin dosing will be managed by general practitioners (GP).
Control group
Active

Outcomes
Primary outcome [1] 306814 0
Composite of presence of LV thrombus, stroke or systemic embolism, at 3 months post randomisation. The imaging modality used to detect LV thrombus can be any of echocardiogram with or without contrast agent, cardiac CT, or cardiac MRI scan.

The primary outcome will be assessed blind to treatment group in the following ways:
• Presence of LV thrombus on imaging will be assessed by a core lab blinded to randomised treatment allocation.
• Occurrence of stroke or systemic embolism events will be adjudicated by blinded review of relevant medical information provided to a clinical outcome adjudication committee.
Timepoint [1] 306814 0
Assessed at 3-month follow-up visit and annually for 3 years post randomisation.
Secondary outcome [1] 349720 0
Clinically significant bleeding as defined by the Bleeding Academic Research Consortium (BARC) standard bleeding definitions for clinical trials. Evidence for the endpoint will be determined by self report and medical record review.
Timepoint [1] 349720 0
Assessed at 3-month follow-up visit and annually for 3 years post randomisation.
Secondary outcome [2] 349835 0
Individual component of primary outcome: Occurrence of stroke or systemic embolism within 3-month treatment period, as determined by self-report, Questionnaire for Verification of Stroke Free Status (QVSFS) and review of medical records.
Timepoint [2] 349835 0
Assessed at 3-month follow-up visit and annually for 3 years post randomisation.
Secondary outcome [3] 349836 0
Days alive and out of hospital from randomisation to end of study as determined through self report and review of medical records.
Timepoint [3] 349836 0
From randomisation to end of study (3 years).
Secondary outcome [4] 411421 0
Individual component of primary outcome: Presence of LV thrombus on imaging at 3-month follow-up timepoint, as determined by blinded cardiac image review.
Timepoint [4] 411421 0
Assessed at 3-month follow-up visit and annually for 3 years post randomisation.
Secondary outcome [5] 411422 0
Quality of Life as determined by the EQ-5D-5L questionnaire.
Timepoint [5] 411422 0
Administered at the 3-month follow-up visit and then annually up to 3 years post randomisation.
Secondary outcome [6] 411423 0
Participant reported health and disability as determined through the WHODAS 2.0 12-scale questionnaire.
Timepoint [6] 411423 0
Administered at the 3-month follow-up visit and then annually up to 3 years post randomisation.
Secondary outcome [7] 411424 0
Change in LV thrombus volume/diameter between imaging performed at baseline and at the 3-month follow-up timepoint as determined by blinded review of images by a core laboratory. The imaging modality used to detect LV thrombus can be any of echocardiogram with or without contrast agent, cardiac CT, or cardiac MRI scan.
Timepoint [7] 411424 0
At baseline and 3-months post randomisation.

Eligibility
Key inclusion criteria
Patients with a new diagnosis of left ventricular (LV) thrombus on any imaging modality within the previous 10 days. Patients can be included if diagnosed with LV mural thrombus after acute MI, with ischemic cardiomyopathy or cardiomyopathy from other causes.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if there is a contraindication to study medication (either warfarin or a DOAC), including but not limited to presence of a mechanical heart valve, severe renal dysfunction (eGRF<30mls/min), severe hepatic dysfunction (Child-Pugh Grade C), clinically significant active bleeding or intra-cranial haemorrhage in the prior 6 months).

In addition, pregnant or lactating women or women of childbearing potential, those with Takotsubo cardiomyopathy or those deemed likely to be non-adherent to the study medication or protocol will be excluded.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Treatment allocation is concealed by randomisation by a computer database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation). Randomisation is stratified by cardiac diagnosis (acute myocardial infarction within past 4 weeks versus no acute MI in past 4 weeks).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Reported rates of thrombus resolution range from approximately 50% to 90% of patients following acute MI, with the majority resolving within the first few weeks. In a meta- analysis of recent studies that have compared echocardiography with CMR, resolution rates at 3-6 months were 88%. For the purposes of estimating the number of patients required in this study it is conservatively assumed that 50% of thrombi will resolve at 3 months in both groups. Embolic events are key indicators of efficacy and important components of the composite primary end-point. They are, however, extremely rare among patients receiving OAC therapy and will likely have minimal impact on the number of patients required. Thus, if there is truly no difference between the efficacy of DOACs and warfarin, 780 patients will be required to be 80% certain that the upper limit of a one sided 97.5% CI (or a 95% two sided CI) will exclude a difference in favour of the warfarin treated patients of more than 10%. Assuming a loss to follow-up of 10% (due to death or inability to undergo 3 month imaging etc), 868 patients will be recruited into the trial. The study will have a statistical power of 82% to 94%, if a higher proportion of thrombi resolve (60-80%).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2018
Actual
25/10/2018
Date of last participant enrolment
Anticipated
28/07/2023
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
100
Accrual to date
55
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Recruitment hospital [1] 22658 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 22659 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 22660 0
Liverpool Hospital - Liverpool
Recruitment hospital [4] 22661 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 37935 0
6000 - Perth
Recruitment postcode(s) [2] 37936 0
2139 - Concord
Recruitment postcode(s) [3] 37937 0
2170 - Liverpool
Recruitment postcode(s) [4] 37938 0
5042 - Bedford Park
Recruitment outside Australia
Country [1] 10673 0
New Zealand
State/province [1] 10673 0
all of new Zealand

Funding & Sponsors
Funding source category [1] 300190 0
Charities/Societies/Foundations
Name [1] 300190 0
Greenlane Research and Education Fund
Country [1] 300190 0
New Zealand
Funding source category [2] 311745 0
Charities/Societies/Foundations
Name [2] 311745 0
Heart Foundation (Australia)
Country [2] 311745 0
Australia
Primary sponsor type
Hospital
Name
Auckland District Health Board
Address
Park Rd,Grafton
Auckland, 1030
Country
New Zealand
Secondary sponsor category [1] 313205 0
University
Name [1] 313205 0
The University of Western Australia
Address [1] 313205 0
35 Stirling Highway,
Crawley WA 6009
Country [1] 313205 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301021 0
Southern health and disability ethics committee
Ethics committee address [1] 301021 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 301021 0
New Zealand
Date submitted for ethics approval [1] 301021 0
03/08/2018
Approval date [1] 301021 0
02/10/2018
Ethics approval number [1] 301021 0
Ethics committee name [2] 311189 0
Sir Charles Gairdner Osborne Park Health Care Group HREC
Ethics committee address [2] 311189 0
Sir Charles Gairdner Hospital
2nd Floor A Block
Hospital Avenue
NEDLANDS Western Australia 6009
Ethics committee country [2] 311189 0
Australia
Date submitted for ethics approval [2] 311189 0
05/04/2021
Approval date [2] 311189 0
07/07/2021
Ethics approval number [2] 311189 0
RGS0000004705

Summary
Brief summary
Left ventricular mural thrombus, which is identified in ~5% of patients after anterior ST elevation myocardial infarction, is a major risk factor for stroke. Anti-coagulation with warfarin is the currently recommended treatment. Direct oral anticoagulants (DOACs) such as factor Xa inhibitors apixaban and rivaroxaban, or the direct thrombin inhibitor, dabigatran, have a number of advantages over warfarin, and are an alternative treatment though not currently approved for this indication. There is currently no randomised evidence to guide management of LV thrombus. This multi-center clinical trial will compare effects of DOACs versus warfarin on LV thrombus resolution and incidence stroke and systemic embolism over a 3-month treatment period. Participants will be followed up annually for a period of 3 years to determine long-term health and participant reported outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85618 0
Prof Ralph Stewart
Address 85618 0
Cardiology Department
Level 3
Auckland City Hospital
Park Rd
Grafton Auckland 1030
Country 85618 0
New Zealand
Phone 85618 0
+64 21 2287458
Fax 85618 0
Email 85618 0
[email protected]
Contact person for public queries
Name 85619 0
Prof Ralph Stewart
Address 85619 0
Cardiology Department
Level 3
Auckland City Hospital
Park Rd
Grafton Auckland 1030
Country 85619 0
New Zealand
Phone 85619 0
+64 21 2287458
Fax 85619 0
Email 85619 0
[email protected]
Contact person for scientific queries
Name 85620 0
Prof Ralph Stewart
Address 85620 0
Cardiology Department
Level 3
Auckland City Hospital
Park Rd
Grafton Auckland 1030
Country 85620 0
New Zealand
Phone 85620 0
+64 21 2287458
Fax 85620 0
Email 85620 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
this is not stipulated in consent form


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.