Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001277437
Ethics application status
Approved
Date submitted
30/08/2016
Date registered
12/09/2016
Date last updated
22/10/2021
Date data sharing statement initially provided
25/06/2019
Date results information initially provided
22/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of two drug thinning agents (unfractionated heparin and low-molecular weight heparin) for prevention of stroke after brain aneurysm treatment utilizing coils or stents
Scientific title
Enoxaparin for Postoperative Prophylaxis in Intracranial Coiling and Stents (EPPICS): A randomized trial of low molecular weight heparin and unfractionated heparin for prevention of arterial thromboembolic complications after endovascular intracranial aneurysm treatment
Secondary ID [1] 290057 0
None
Universal Trial Number (UTN)
U1111-1187-0444
Trial acronym
EPPICS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intracranial Aneurysm 300110 0
Intracranial Lesions 300111 0
Condition category
Condition code
Stroke 299994 299994 0 0
Ischaemic
Stroke 299995 299995 0 0
Ischaemic
Cardiovascular 300050 300050 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Endovascular treatment of intracranial aneurysm with coils and stents requires procedural anticoagulation, most commonly with unfractionated intravenous heparin (UFH). Where the risk of thromboembolic complications is high (eg post stenting) heparinisation is continued for 24-48hrs post treatment. Post-procedural anticoagulation regimes aim for ‘therapeutic range’ based on repeated laboratory testing of sampled blood. In practice this can be difficult to achieve with consistency using UFH. Low molecular weight heparin (LMWH) offers some theoretical advantages over UFH but there is no published data on its use in neurointervention.

We propose to compare post-procedural anticoagulation using UFH with LMWH (enoxaparin) in patients treated electively for intracranial aneurysms. Patients who meet entry criteria will be randomised to one of three regimes:
a) UFH - continuous IV infusion, titrated by APTT test results (current standard of care)
b) LMWH given as a single dose of 1.5mg/kg by subcutaneous injection at the end of the procedure
c) LMWH given 1.0mg/kg by subcutaneous injection at the end of the procedure and at 12hours.
Intervention code [1] 295779 0
Prevention
Intervention code [2] 295820 0
Treatment: Drugs
Comparator / control treatment
Comparator group:
1) Unfractionated Heparin (UFH)

Comparisons will be made between the above and these additional groups of anticoagulants
2) Low-molecular weight heparin (single dose, 1.5mg/kg)
3) Low-molecular weight heparin (split dose, 1.0mh/kg, BD)
Control group
Active

Outcomes
Primary outcome [1] 299476 0
The primary outcome will be achievement of therapeutic range as assessed by APTT (UFH) or anti Xa (LMWH) testing

Patients will be categorized in a binary fashion – either being within the therapeutic range or being sub/supratherapeutic.
Timepoint [1] 299476 0
Within 24-48h hours of administered medication
Secondary outcome [1] 327291 0
Secondary outcome 1: The frequency of thromboembolic complications (either symptomatic or asymptomatic) in post-operative intracranial aneurysm coiling, including stent or balloon assisted coiling within the first 24-48 hours after cessation of intraoperative heparin, as assessed by neurological examination and pre- / post- procedure MRI
Timepoint [1] 327291 0
Neurological Examination within 24 hours of conclusion of endovascular procedure
MRI brain scan within 48 hours after the conclusion of endovascular procedure
Secondary outcome [2] 327433 0
Secondary Outcome 2: The frequency of hemorrhagic complications in post-operative intracranial aneurysm coiling, including stent or balloon assisted coiling within the first 24-48 hours after cessation of intraoperative heparin, as assessed by neurological examination and pre- / post- procedure MRI
Timepoint [2] 327433 0
Neurological Examination within 24 hours of conclusion of endovascular procedure
MRI brain scan within 48 hours after the conclusion of endovascular procedure

Eligibility
Key inclusion criteria
Patients admitted for elective endovascular treatment of intracranial aneurysm are eligible for inclusion.
Participants should understand the project and provide voluntary consent

Eligible patients will be admitted to the study if at the end of the endovascular procedure the operator determines that a period of post procedural anticoagulation is clinically indicated. The 3 most common reasons for this are:
1) Placement of an indwelling endovascular device, such as a stent
2) Presence of procedural platelet aggregation
3) Perceived increased risk of thromboembolic events due to
(3a) large area of coil exposure at aneurysm neck
(3b) loop protrusion into parent artery
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
< 18 years of age (i.e. paediatric population)
- acute endovascular treatment (eg acute subarachnoid haemorrhage)
- impaired renal function (eGFR < 30)
- MRI contraindications (e.g. pacemakers)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed Opaque envelopes (numbered):
Operator will select the top package from a stack, which they are unaware of the contents of.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This will be done in conjunction with the QIMR Berghofer Statistics Unit.
The primary endpoint will be to compare the proportion of therapeutic anticoagulation across all three arms. We will further determine whether there are differences between arms with respect to symptomatic or asymptomatic arterial thromboembolic events in unruptured intracranial aneurysms and whether there are differences in the immediate post-operative period after intracranial endovascular aneurysm coiling and/or stenting with respect to reduction in cerebral microbleeds. We will test for balance between arms and tabulate the variables listed above using chi-squared tests for factor variables and appropriate tests of means, either parametric or nonparametric tests. The remainder of the analyses will be descriptive, which will motivate the design of a larger randomized trial

Results from 2016 suggest between 50-100 patients per year adhering to the criteria
The initial patient aim will be 75 patients, 25 per arm. This is partially a sample size of convenience, This study will have limited utility in detecting non-inferiority between the two experimental arms and unfractionated heparin with respect to the proportion of patients achieving therapeutic anticoagulation, but it is intended that the cohort will be expanded if this initial pilot study is successful. With N = 25 per arm and assuming a 25% non-inferiority bound around the difference between the proportion of patients on two equally-allocated treatment arms, achieving 90% therapeutic anticoagulation each, we will have 80% power to conclude non-inferiority at an alpha of 0.05.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/09/2016
Actual
22/11/2016
Date of last participant enrolment
Anticipated
Actual
2/07/2020
Date of last data collection
Anticipated
Actual
2/07/2020
Sample size
Target
75
Accrual to date
Final
154
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 6573 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 14179 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 294422 0
Charities/Societies/Foundations
Name [1] 294422 0
Royal Australian and New Zealand College of Radiologists
Country [1] 294422 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane and Women's Hospital
Address
Butterfield Street
Herston, QLD
4029
Country
Australia
Secondary sponsor category [1] 293272 0
Individual
Name [1] 293272 0
Professor Alan Coulthard
Address [1] 293272 0
L3 Ned Hanlon Building
Butterfield Street
Royal Brisbane and Women's Hospital
Herston, 4029
QLD
Australia
Country [1] 293272 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295847 0
Royal Brisbane & Women’s Hospital Human Research Ethics Committee
Ethics committee address [1] 295847 0
Human Research Ethics Committee
Block 7, Floor 7
Butterfield Street
Royal Brisbane and Women's Hospital
Herston
QLD, 4029
Ethics committee country [1] 295847 0
Australia
Date submitted for ethics approval [1] 295847 0
01/07/2016
Approval date [1] 295847 0
01/08/2016
Ethics approval number [1] 295847 0
HREC/16/QRBW/326

Summary
Brief summary
Endovascular treatment of intracranial aneurysm with coils and stents requires procedural anticoagulation, most commonly with unfractionated intravenous heparin (UFH). Where the risk of thromboembolic complications is high (eg post stenting) heparinisation is continued for 24-48hrs post treatment. Post-procedural anticoagulation regimes aim for ‘therapeutic range’ based on repeated laboratory testing of sampled blood. In practice this can be difficult to achieve with consistency using UFH. Low molecular weight heparin (LMWH) offers some theoretical advantages over UFH but there is no published data on its use in neurointervention.

We propose to compare post-procedural anticoagulation using UFH with LMWH (enoxaparin) in patients treated electively for intracranial aneurysms. Patients who meet entry criteria will be randomised to one of three regimes:
a) UFH - continuous IV infusion, titrated by APTT test results (current standard of care)
b) LMWH given as a single dose of 1.5mg/kg by subcutaneous injection at the end of the procedure
c) LMWH given 1.0mg/kg by subcutaneous injection at the end of the procedure and at 12hours.

The primary outcome will be achievement of therapeutic range as assessed by APTT (UFH) or anti Xa (LMWH) testing.
The secondary outcome will be development of a clinically evident thromboembolic event (CETE) or a clinically silent lesion, either ischaemic (CSIL) or hemorrhagic (CSHL), assessed by neurological examination at 24 hours and MRI at 48hrs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68702 0
Prof Alan Coulthard
Address 68702 0
L3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD
4029
Country 68702 0
Australia
Phone 68702 0
+61 7 3646 8599
Fax 68702 0
Email 68702 0
a.coulthard@uq.edu.au
Contact person for public queries
Name 68703 0
Jeffrey Hocking
Address 68703 0
L3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD
4029
Country 68703 0
Australia
Phone 68703 0
+61 7 3646 7225
Fax 68703 0
Email 68703 0
dmi.research.rbwh@gmail.com
Contact person for scientific queries
Name 68704 0
Jeffrey Hocking
Address 68704 0
L3 Ned Hanlon Building
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD
4029
Country 68704 0
Australia
Phone 68704 0
+61 7 3646 7225
Fax 68704 0
Email 68704 0
dmi.research.rbwh@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.