Ignite Creation Date:
2024-05-06 @ 8:27 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06394271
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-01
First Post:
2024-04-19
Brief Title:
Early Endovascular Repair Versus Surveillance for Women With Small Abdominal Aortic Aneurysm
Sponsor:
Imperial College London
Organization:
Imperial College London
Study Overview
Official Title:
WARRIORS Trial and Registry
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
WARRIORS
Brief Summary:
Elective Abdominal Aortic Aneurysm AAA repair is offered when the risk of rupture exceeds the risk of surgery Women versus men have a four-fold higher risk of AAA rupture but almost double the operative mortality It is unknown whether the current 55cm diameter AAA repair threshold derived from randomised trials including only 4 women is applicable to women
Therefore should women have their aneurysms repaired electively at smaller diameters than men to improve their AAA-related survival and quality of life WARRIORS is an international randomised controlled trial of early elective endovascular repair versus routine surveillance in women n1112 with small asymptomatic AAA 4-54cm diameter nested within a registry of non-participants The surveillance group will be offered repair for rupture or upon reaching the 55cm threshold Randomisation will be 11 stratified by country age and aneurysm diameter The trial is powered for aneurysm-related mortality or rupture at 5 years Quality-Adjusted-Life-Years is a major secondary outcome Other outcomes include operative mortality and complications anxiety major cardiovascular adverse events and cost-effectiveness Quality-of-life and anxiety questionnaires and standard-of-care using routine data will be collected
The trial aims to progress health equity through provision of evidence for sex-specific clinical guidelines for AAA repair
Therefore should women have their aneurysms repaired electively at smaller diameters than men to improve their AAA-related survival and quality of life WARRIORS is an international randomised controlled trial of early elective endovascular repair versus routine surveillance in women n1112 with small asymptomatic AAA 4-54cm diameter nested within a registry of non-participants The surveillance group will be offered repair for rupture or upon reaching the 55cm threshold Randomisation will be 11 stratified by country age and aneurysm diameter The trial is powered for aneurysm-related mortality or rupture at 5 years Quality-Adjusted-Life-Years is a major secondary outcome Other outcomes include operative mortality and complications anxiety major cardiovascular adverse events and cost-effectiveness Quality-of-life and anxiety questionnaires and standard-of-care using routine data will be collected
The trial aims to progress health equity through provision of evidence for sex-specific clinical guidelines for AAA repair
Detailed Description:
Design
WARRIORS Womens Aneurysm Research Repair Immediately Or Routine Surveillance is an international multicenter open label superiority RCT randomly allocating consenting with small abdominal aortic aneirysm AAA morphologically eligible for endovascular repair EVAR in a 11 ratio to either early AAA repair by EVAR or to routine ultrasonographic surveillance It will have a Vanguard phase with adjudicated endpoints Each participant will be followed up for 5-years
It is planned that the UK will provide135of total target recruitment The remaining patients will be recruited in mainland Europe 325 North America and Australasia 45
The trial will start with an international Vanguard phase of 250 patients to optimise and confirm randomization rates and patient safety operative mortality rate and ensure inclusivity of underserved groups In both the UK and other countries the Vanguard phase is scheduled to start in April 2025 Women will be recruited over 12 months during which period there will be an ongoing programme of qualitative research to optimise recruitment and ensure representation of minority and underserved groups The Vanguard trial will run for a further 6 months to allow completion of interventions and post-operative follow up and analysis of the results The international Vanguard trial is scheduled to run for one year following the opening of 25 of target sites per participating country to assess and feasibility recruitment and safety operative mortality aneurysm exclusion and complications support recruitment rates The Vanguard phase should be completed within the first 30- months of the trial and include a total of 250 women including 50 from the UK and with total accrual of 35 patientsmonth between months 6-12 The qualitative work to optimise recruitment will use the Quintet Recruitment Intervention QRI 12 to identify recruitment obstacles and facilitate improvements to the recruitment process and the SEAR framework 13 to capture ethnic and diversity characteristics and highlight any discrepancies in the recruitment process which may negatively impact underserved groups participating details given below If only 150-249 have been recruited improvement measuresadditional centres will be introduced to achieve the target accrual of 35month with re-evaluation after a further 6 months Remedial measures could include visiting and motivating centers implementation of actions arising from the qualitative work including improving patient-facing material running focus groups with those identifying patients including vascular nurses and sonographers the opening of reserve sites and an incentive programme eg rewards for recruiting every 50th or 1100th woman If 150 patients have been randomised and current monthly recruitment is 35month for months 10-12 the trial should be stopped
The results of the Vanguard trial should enable the Data Monitoring and Ethical Committee DMEC to set stopping rules for the rest of the trial based on operative mortality and major complications In the Vanguard phase we propose that 30-day mortality for early elective EVAR group should not exceed 3 but this will need the agreement of the DMEC
The performance and results of the Vanguard trial will be scrutinized by both the Trial Steering Committee and the DMEC
Identification and recruitment of participants
Women with small AAA 40-54 cm based on local measurements by ultrasound being monitored for AAA growth in hospital or community screening and surveillance programmes Women also may be identified from imaging studies for other conditions with referral to vascular surgeons in which case the CT or other imaging measurement 9centre line orthogonal diameter should be the entry criterion
Trial centres will be vascular hubscentres able to deliver both EVAR and surveillance programmes and have an annual EVAR caseload of 20 cases with audited operative mortality of 3 for EVAR via national registry or similar standard monitoring procedures
The trial EVAR procedures will be delivered by vascular surgeons in accredited hospitals for vascular surgery in all participating countries
Qualitative Research to optimize recruitment
The Quintet Recruitment Intervention QRI will be used to identify recruitment obstacles and facilitate improvements to the recruitment process QRI semi-structured interviews with individuals involved in screening and presenting WARRIORS to patients will take place across all sites n3-5 per site Interviews with patients who decline randomisation will also be used to explore the reasons for not taking part in the trial Interviews will be recorded digitally and analysed following the conventions of thematic and the constant comparison approach Summaries of anonymised findings will be presented to WARRIORS principal investigators and to the trial management groups in each country including supporting evidence to describe factors hindering recruitment A potential plan of action to improve recruitment will be proposed to facilitate decision making and define responsibilities for implementation
Screening and pre-randomisation evaluations
Participants will have a known AAA with diameter between 40 cm and 54 cm based on ultrasonography Potential participants for the trial will have a CTA examination of the aorta iliac and femoral arteries to assess inclusion and exclusion criteria morphological eligibility for EVAR and presence of proximal aneurysms unless a CTA has been completed within the previous 6 months The baseline questionnaires for quality f life and anxiety should be administered before the eligibility assessment CTA Women also will be assessed for Rockwood frailty score There is no test required before the participant enters the trial Potential participants will be screened to determine whether they meet all the inclusion criteria and none of the exclusion criteria listed for the trial Sites will be asked to capture patient initials of each identified patient and to record the reasons for ineligibility Women who are ineligible for the trial can opt for follow up in the associated registry
Potential participants will be given information on the trial by local research staff when appropriate They will be given a copy of the patient information sheet PIS and informed consent form ICF Translations in local languages will be available as appropriate Patients will be given at least 24 hours to read the PIS and consider their participation
There will be an infographic or video explanation of the trial and a decision aid which has been developed specifically for this trial
The consent may only take place once all the above procedures are completed
Randomization and Blinding
Randomization 1112 women with small AAA will be randomized 11 Randomization will be carried out using a web-based randomization and Electronic Data Capture EDC system called OpenClinica and women will be allocated to treatment using a variable block randomization schedule stratified by country age 75 75 years and aneurysm diameter 40-49 50 cm This will be generated by computer algorithm and released after checking patient eligibility and written consent
Blinding For ethical and practical reasons patients and clinicians cannot be blinded to treatment allocation However endpoints will be adjudicated by an expert panel PROBE study - Prospective Randomized Open Blinded End-point
Follow-up
Follow up visits will take place at each of the sites in a clinical examination room for interview examination and required questionnaires to be completed Each study visit will be expected to take less than one hour including rest periods for the subject For patients in the early EVAR group follow up visits are likely to be preceded by imaging by Duplex or CT scan to check continuing endograft exclusion of the AAA Follow up for quality of life and anxiety questionnaires may be conducted by telephone or video conferencing which should precede the follow up imaging study at 1 3 and 5 years after randomization Data for aneurysm or other cardiovascular event treatments at hospitals not participating in the study will be collected from routine national health data sets such as MHS Digital for English patients or Medicare in the USA
Data will be collected on electronic case report forms using a study database hosted at Imperial College London
INTERVENTION - Endovascular aneurysm repair EVAR
The purpose of EVAR is to exclude the AAA from the circulation and therefore avoid the risk of future aneurysm rupture Many different endografts are licensed and available Newly approved devices will be added and any advances in technology tracked The sizing of the aorta and planning of the operation should be conducted on a 3D workstation as standard
A protocol for pre-operative care will be recommended and include pre-operative cardiac and anaesthetic assessments and prehabilitation advice based on the 2021 guidelines from the British Geriatric Society httpswwwbgsorgukcpocfrailty This includes advice about smoking cessation alcohol medication adherence eg antihypertensives statin as tolerated antiplatelet and exercise 1617 Post-operatively the recommended care will be according to European Society of Vascular Surgery 2024 guidelines All patients early intervention and surveillance also should be on medications to minimise cardiovascular risk assuming them to be in a high-risk category with management of smoking cessation lipid levels etc according to European Society of Cardiology guidelines
The procedure may be performed under general local or regional anesthesia
The purpose of the intervention is to reline the aorta and exclude the aneurysm from the circulation to prevent further expansion and eventual rupture With exclusion of the AAA from the circulation the aneurysm sac should cease growth or decrease in diameter Specifically in this trial the intervention will be performed when the aneurysm is between 40-54cm in size
A strict protocol for the technical aspects of EVAR will not be given since practice around the world differs and patient differences necessitate a range of approaches However compliance with best practice guidelines for endovascular aortic aneurysm repair will be an expectation
Clinical practice guidelines EVAR httpswwwjvirorgarticleS1051-04431000761-Xpdf
Clinical practice guidelines AAA httpswwwesvsorgwp-contentuploads201812Wanhainen-A-et-al-ESVS-AAA-GL-2019-epublished-041218pdf
Clinical practice guidelines AAA httpswwwjvascsurgorgarticleS0741-52141732369-8fulltext
Manufacturers Instructions for Use
The procedure will take place in an operating theatre environment with mobile or fixed X-Ray imaging capabilities as per local standard operating procedures Stent graft follow-up will take place at the institution where the index procedure was performed
There are standards outlined for a dedicated EVAR Facility These will be used as the gold standard in this study and provided to all participating units For specifications please see httpswwwvascularsocietyorguk_userfilespagesfilesDocument20Librarymhra_8pp_leaflet_amended_more_pages_web_versionpdf
Before the procedure pre-operative CT imaging assessment will be performed and assessed for suitability for EVAR and must meet the minimum specifications set by the Cor Laboratory The EVAR procedure will be performed based on local assessment of the pre-operative CT scan these will be sent to the core laboratory for independent adjudication The participant must be suitable for EVAR using any approved device within the manufacturers instructions for use The sizing and planning will take place on a dedicate 3D workstation
Before EVAR patients will be managed according to country-specific criteria and undergo full pre-operative assessment Each participant will be seen in the pre-operative assessment clinic with provision of participant information and supporting materials
Pre-operative cardiac investigations will vary from country to country but at minimum should include an ECG and chest X-ray
Any further investigations will be ordered and treatment of conditions that might cause adverse outcomes during any operative procedure or delay recovery will be undertaken at the discretion of the treating team
Prehabilitation advice will be recommended based on guidelines from the British Geriatric Society
Each patient will be consented for the EVAR procedure to ensure the inclusion of EVAR competent centres with excellent safety records
The procedure may be performed under general regional or local anaesthetic Access to the arterial system will be via the common femoral artery either using a percutaneous approach closed with any of the available closure devices or after surgical cut down and control of the artery
Adjuncts to facilitate delivery of the EVAR device for participants with small iliac arteries may include
Construction of a surgical conduit surgically to facilitate access
Balloon angioplasty and stenting of iliac arteries
Construction of an ilio-femoral bypass
Femoral or iliac endarterectomy - patch plasty
Femoral or iliac patch plasty alone
The stent graft will be selected based on size measurements on the pre-operative CT scan Each centre should only use the endografts with which they are familiar and use these within the manufacturers IFU A suitable oversizing of the graft as suggested by the instructions for use of the graft will be used
Planned adjunct procedures may include
Endoanchor or endosuture placement
Licensed branched iliac device
Licensed fusion imaging software
When considering the landing zone of the stent the clinician will plan to land the stent in the healthy parallel neck of the aorta just below the renal arteries consistent with the necessary landing zone requirements of the chosen endograft Balloon moulding will be considered if appropriate following stent graft implantation
Distally the stent will may be landed in the common iliac artery or into the external iliac artery with management of the internal iliac artery
At the end of the procedure post-stent intra-arterial digital subtraction quality control angiogram images will be obtained Further imaging such as rotational CT analysis will be performed at the discretion of the investigator
Unless expected to resolve by the initial post-operative scan in the presence of any type 1 or 3 endoleak the operating team will undertake further procedures to attempt to rectify the endoleak based on local practice and equipment provision
Any further adjunct procedures to treat endoleak will be placed in accordance with their instructions for use Adjunct procedures may include one or more of but will not be limited to
Repeat balloon moulding
Aortic extension cuff
Placement of a Palmaz Cordis balloon-expandable stent
Iliac extension cuff
Endoanchor placement
Chimney graft placement in the visceralrenal vessels
Post-operative care will conform to European Society of Vascular Surgery 2024 guidelines The Enhanced Recovery After Surgery guidelines approved by the Society for Vascular Surgery will be circulated to all sites
The participant will stay as an inpatient for standard post-operative monitoring and recovery before being discharged Recovery and discharge arrangements will vary from site to site and should follow standard of care pathways at that site
After discharge from the hospital after EVAR patients will attend for CTMRI scan at between 3 and 12-weeks which is clinically necessary to assess the placement of the stent Participants will attend for subsequent clinical and imaging either with ultrasound or CT scanning for stent graft monitoring as directed by local follow up arrangements and the trial follow up protocol
During the trial period modifications of the procedure and devices will be expected as new technology if developed The proceduraldevice modifications will be tracked to ensure that the results of the outcomes from EVAR are not affected positively or negatively leading to errors in the trial conclusions
STANDARD MANAGEMENT - Surveillance with ultrasound or other imaging surveillance with delayed repair for rupture or aneurysm diameter reaching 55 cm threshold
All women will be monitored for AAA growth Ultrasonographic surveillance is the preferred method since it is non-invasive whilst being highly sensitive and specific although in some countries eg USA CT including non-contrast CT may be used for surveillance For AAA between 40-44 cm diameter annual surveillance can be recommended increasing to every 6 months for AAA of 45 cm diameter or greater or according to current local practice and standard operating procedures For ultrasound surveillance the anterior-posterior diameter should be measured in the longitudinal plane since this is more repeatable than the transverse diameter Calliper placement for measurements should be consistent at each surveillance visit Outer-to-outer diameter measurements are preferred but where sonographers are trained to measure either leading edge to leading edge or inner-to-inner diameters these methods should be used and documented When CT imaging is used for surveillance the centreline orthogonal diameter should be measured When the diameter exceeds 54 cm the participant should have a prompt target within 2 weeks consultation with a vascular surgeon consideration of AAA repair by which ever method is recommended by the local team The operation CRF should be completed and the participant will then enter routine clinical follow up
If there is any suspicion of AAA rupture the patient must be admitted immediately as an emergency preferably to a vascular surgeon the site where the patient has been followed up
If there is a suspicion of impending rupture with symptoms of back or abdominal pain referable to the aneurysm further investigations should be performed and consideration given to early elective repair Thromboembolic evens referable to the aneurysm are also an indication for consideration of early elective urgent repair These conditions are known as symptomatic AAA
All randomized patients will be offered smoking cessation advice and adjunct therapies as well as best medical therapy including statins with a cardiologist-guided protocol European Society of Cardiology guidelines for the high-risk category This protocol will include and exercise blood pressure body weight and LDL-cholesterol targets and good diabetic control where relevant All patients will receive advice about exercise and physical activity These measures will be conducted using patient-facing educational resources and through communication with their GeneralFamily Practitioner
Permanent Discontinuation of Study Intervention and Withdrawal from Study
Permanent discontinuation of study intervention
Participants may discontinue study intervention for the following reasons
At the request of the participant
Adverse event Serious Adverse Event
If the investigator considers that a participants health will be compromised due to adverse events or concomitant illness that develop after entering the study
Withdrawal from Study
Withdrawal from the study refers to discontinuation of study intervention and study procedures and can occur for the following reasons
Participant decision
Loss to follow-up
Procedures for Withdrawal from Study
If a subject withdraws prematurely the reason for withdrawal will be recorded in the CRFeCRF and medical records All study visits up to the point of any planned withdrawal will be completed
SAFETY REPORTING
Adverse Event AE
An AE is any untoward medical occurrence in a SAFETY REPORTING
Adverse Event AE
An AE is any untoward medical occurrence in a patient or clinical trial participant An AE can therefore be any unfavourable and unintended sign including an abnormal laboratory finding symptom whether or not considered related to the trial protocol
Adverse Event recording
Adverse events will be assessed at each study visit The following will be assessed for all adverse events
date of onset
description of event
frequency
severity
causality
outcomes
action taken
For the purposes of the study AEs will be followed up according to local practice until the event has stabilised or resolved or the follow-up visit whichever is the sooner
Adverse events that are not serious adverse events will only be recorded on adverse event forms if the adverse event either occurs within 90 days of the index AAA repair or is aortic related The following will be noted as aortic related events
Any events within 30 days of index repair
Access vessel dissection or rupture
Buttock claudication
Endoleak
Graft kinking clinically significant
Graft migration of 5mm
Graft limb thrombosisstenosisocclusion
Limb ischaemia or toe amputation
New onset claudication
Pseudo-aneurysm at graft insertion site
Surgical site infection
All SAEs will be recorded throughout the study
Severity of Adverse Events
The assessment of severity will conform to the following definitions
Mild Awareness of event but easily tolerated
Moderate Discomfort enough to cause some interference with usual activity
Severe Inability to carry out usual activity
Causality of Adverse Events
The assessment of causality will conform to the following definitions
Unrelated No evidence of any causal relationship
Unlikely There is little evidence to suggest there is a causal relationship and there is another reasonable explanation for the event eg the participants clinical condition other concomitant treatment
Possible There is some evidence to suggest a causal relationship However the influence of other factors may have contributed to the event eg the participants clinical condition other concomitant treatments
Probable There is evidence to suggest a causal relationship and the influence of other factors is unlikely
Definite There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out
Serious Adverse Events SAE
Definition of SAE
An SAE is defined as any event that
Results in death
Is life-threatening eg aortic rupture
Requires hospitalisation or prolongation of existing inpatients hospitalisation eg graft infection or conversion to open repair
Results in persistent or significant disability or incapacity eg major limb amputation
Life-threatening in the definition of serious refers to an event in which the participant was at risk of death at the time of the event it does not refer to an event which hypothetically might have caused death if it were more severe
Hospitalisation means any unexpected admission to a hospital department It does not usually apply to scheduled admissions that were planned before study inclusion or visits to casualty without admission
WARRIORS Womens Aneurysm Research Repair Immediately Or Routine Surveillance is an international multicenter open label superiority RCT randomly allocating consenting with small abdominal aortic aneirysm AAA morphologically eligible for endovascular repair EVAR in a 11 ratio to either early AAA repair by EVAR or to routine ultrasonographic surveillance It will have a Vanguard phase with adjudicated endpoints Each participant will be followed up for 5-years
It is planned that the UK will provide135of total target recruitment The remaining patients will be recruited in mainland Europe 325 North America and Australasia 45
The trial will start with an international Vanguard phase of 250 patients to optimise and confirm randomization rates and patient safety operative mortality rate and ensure inclusivity of underserved groups In both the UK and other countries the Vanguard phase is scheduled to start in April 2025 Women will be recruited over 12 months during which period there will be an ongoing programme of qualitative research to optimise recruitment and ensure representation of minority and underserved groups The Vanguard trial will run for a further 6 months to allow completion of interventions and post-operative follow up and analysis of the results The international Vanguard trial is scheduled to run for one year following the opening of 25 of target sites per participating country to assess and feasibility recruitment and safety operative mortality aneurysm exclusion and complications support recruitment rates The Vanguard phase should be completed within the first 30- months of the trial and include a total of 250 women including 50 from the UK and with total accrual of 35 patientsmonth between months 6-12 The qualitative work to optimise recruitment will use the Quintet Recruitment Intervention QRI 12 to identify recruitment obstacles and facilitate improvements to the recruitment process and the SEAR framework 13 to capture ethnic and diversity characteristics and highlight any discrepancies in the recruitment process which may negatively impact underserved groups participating details given below If only 150-249 have been recruited improvement measuresadditional centres will be introduced to achieve the target accrual of 35month with re-evaluation after a further 6 months Remedial measures could include visiting and motivating centers implementation of actions arising from the qualitative work including improving patient-facing material running focus groups with those identifying patients including vascular nurses and sonographers the opening of reserve sites and an incentive programme eg rewards for recruiting every 50th or 1100th woman If 150 patients have been randomised and current monthly recruitment is 35month for months 10-12 the trial should be stopped
The results of the Vanguard trial should enable the Data Monitoring and Ethical Committee DMEC to set stopping rules for the rest of the trial based on operative mortality and major complications In the Vanguard phase we propose that 30-day mortality for early elective EVAR group should not exceed 3 but this will need the agreement of the DMEC
The performance and results of the Vanguard trial will be scrutinized by both the Trial Steering Committee and the DMEC
Identification and recruitment of participants
Women with small AAA 40-54 cm based on local measurements by ultrasound being monitored for AAA growth in hospital or community screening and surveillance programmes Women also may be identified from imaging studies for other conditions with referral to vascular surgeons in which case the CT or other imaging measurement 9centre line orthogonal diameter should be the entry criterion
Trial centres will be vascular hubscentres able to deliver both EVAR and surveillance programmes and have an annual EVAR caseload of 20 cases with audited operative mortality of 3 for EVAR via national registry or similar standard monitoring procedures
The trial EVAR procedures will be delivered by vascular surgeons in accredited hospitals for vascular surgery in all participating countries
Qualitative Research to optimize recruitment
The Quintet Recruitment Intervention QRI will be used to identify recruitment obstacles and facilitate improvements to the recruitment process QRI semi-structured interviews with individuals involved in screening and presenting WARRIORS to patients will take place across all sites n3-5 per site Interviews with patients who decline randomisation will also be used to explore the reasons for not taking part in the trial Interviews will be recorded digitally and analysed following the conventions of thematic and the constant comparison approach Summaries of anonymised findings will be presented to WARRIORS principal investigators and to the trial management groups in each country including supporting evidence to describe factors hindering recruitment A potential plan of action to improve recruitment will be proposed to facilitate decision making and define responsibilities for implementation
Screening and pre-randomisation evaluations
Participants will have a known AAA with diameter between 40 cm and 54 cm based on ultrasonography Potential participants for the trial will have a CTA examination of the aorta iliac and femoral arteries to assess inclusion and exclusion criteria morphological eligibility for EVAR and presence of proximal aneurysms unless a CTA has been completed within the previous 6 months The baseline questionnaires for quality f life and anxiety should be administered before the eligibility assessment CTA Women also will be assessed for Rockwood frailty score There is no test required before the participant enters the trial Potential participants will be screened to determine whether they meet all the inclusion criteria and none of the exclusion criteria listed for the trial Sites will be asked to capture patient initials of each identified patient and to record the reasons for ineligibility Women who are ineligible for the trial can opt for follow up in the associated registry
Potential participants will be given information on the trial by local research staff when appropriate They will be given a copy of the patient information sheet PIS and informed consent form ICF Translations in local languages will be available as appropriate Patients will be given at least 24 hours to read the PIS and consider their participation
There will be an infographic or video explanation of the trial and a decision aid which has been developed specifically for this trial
The consent may only take place once all the above procedures are completed
Randomization and Blinding
Randomization 1112 women with small AAA will be randomized 11 Randomization will be carried out using a web-based randomization and Electronic Data Capture EDC system called OpenClinica and women will be allocated to treatment using a variable block randomization schedule stratified by country age 75 75 years and aneurysm diameter 40-49 50 cm This will be generated by computer algorithm and released after checking patient eligibility and written consent
Blinding For ethical and practical reasons patients and clinicians cannot be blinded to treatment allocation However endpoints will be adjudicated by an expert panel PROBE study - Prospective Randomized Open Blinded End-point
Follow-up
Follow up visits will take place at each of the sites in a clinical examination room for interview examination and required questionnaires to be completed Each study visit will be expected to take less than one hour including rest periods for the subject For patients in the early EVAR group follow up visits are likely to be preceded by imaging by Duplex or CT scan to check continuing endograft exclusion of the AAA Follow up for quality of life and anxiety questionnaires may be conducted by telephone or video conferencing which should precede the follow up imaging study at 1 3 and 5 years after randomization Data for aneurysm or other cardiovascular event treatments at hospitals not participating in the study will be collected from routine national health data sets such as MHS Digital for English patients or Medicare in the USA
Data will be collected on electronic case report forms using a study database hosted at Imperial College London
INTERVENTION - Endovascular aneurysm repair EVAR
The purpose of EVAR is to exclude the AAA from the circulation and therefore avoid the risk of future aneurysm rupture Many different endografts are licensed and available Newly approved devices will be added and any advances in technology tracked The sizing of the aorta and planning of the operation should be conducted on a 3D workstation as standard
A protocol for pre-operative care will be recommended and include pre-operative cardiac and anaesthetic assessments and prehabilitation advice based on the 2021 guidelines from the British Geriatric Society httpswwwbgsorgukcpocfrailty This includes advice about smoking cessation alcohol medication adherence eg antihypertensives statin as tolerated antiplatelet and exercise 1617 Post-operatively the recommended care will be according to European Society of Vascular Surgery 2024 guidelines All patients early intervention and surveillance also should be on medications to minimise cardiovascular risk assuming them to be in a high-risk category with management of smoking cessation lipid levels etc according to European Society of Cardiology guidelines
The procedure may be performed under general local or regional anesthesia
The purpose of the intervention is to reline the aorta and exclude the aneurysm from the circulation to prevent further expansion and eventual rupture With exclusion of the AAA from the circulation the aneurysm sac should cease growth or decrease in diameter Specifically in this trial the intervention will be performed when the aneurysm is between 40-54cm in size
A strict protocol for the technical aspects of EVAR will not be given since practice around the world differs and patient differences necessitate a range of approaches However compliance with best practice guidelines for endovascular aortic aneurysm repair will be an expectation
Clinical practice guidelines EVAR httpswwwjvirorgarticleS1051-04431000761-Xpdf
Clinical practice guidelines AAA httpswwwesvsorgwp-contentuploads201812Wanhainen-A-et-al-ESVS-AAA-GL-2019-epublished-041218pdf
Clinical practice guidelines AAA httpswwwjvascsurgorgarticleS0741-52141732369-8fulltext
Manufacturers Instructions for Use
The procedure will take place in an operating theatre environment with mobile or fixed X-Ray imaging capabilities as per local standard operating procedures Stent graft follow-up will take place at the institution where the index procedure was performed
There are standards outlined for a dedicated EVAR Facility These will be used as the gold standard in this study and provided to all participating units For specifications please see httpswwwvascularsocietyorguk_userfilespagesfilesDocument20Librarymhra_8pp_leaflet_amended_more_pages_web_versionpdf
Before the procedure pre-operative CT imaging assessment will be performed and assessed for suitability for EVAR and must meet the minimum specifications set by the Cor Laboratory The EVAR procedure will be performed based on local assessment of the pre-operative CT scan these will be sent to the core laboratory for independent adjudication The participant must be suitable for EVAR using any approved device within the manufacturers instructions for use The sizing and planning will take place on a dedicate 3D workstation
Before EVAR patients will be managed according to country-specific criteria and undergo full pre-operative assessment Each participant will be seen in the pre-operative assessment clinic with provision of participant information and supporting materials
Pre-operative cardiac investigations will vary from country to country but at minimum should include an ECG and chest X-ray
Any further investigations will be ordered and treatment of conditions that might cause adverse outcomes during any operative procedure or delay recovery will be undertaken at the discretion of the treating team
Prehabilitation advice will be recommended based on guidelines from the British Geriatric Society
Each patient will be consented for the EVAR procedure to ensure the inclusion of EVAR competent centres with excellent safety records
The procedure may be performed under general regional or local anaesthetic Access to the arterial system will be via the common femoral artery either using a percutaneous approach closed with any of the available closure devices or after surgical cut down and control of the artery
Adjuncts to facilitate delivery of the EVAR device for participants with small iliac arteries may include
Construction of a surgical conduit surgically to facilitate access
Balloon angioplasty and stenting of iliac arteries
Construction of an ilio-femoral bypass
Femoral or iliac endarterectomy - patch plasty
Femoral or iliac patch plasty alone
The stent graft will be selected based on size measurements on the pre-operative CT scan Each centre should only use the endografts with which they are familiar and use these within the manufacturers IFU A suitable oversizing of the graft as suggested by the instructions for use of the graft will be used
Planned adjunct procedures may include
Endoanchor or endosuture placement
Licensed branched iliac device
Licensed fusion imaging software
When considering the landing zone of the stent the clinician will plan to land the stent in the healthy parallel neck of the aorta just below the renal arteries consistent with the necessary landing zone requirements of the chosen endograft Balloon moulding will be considered if appropriate following stent graft implantation
Distally the stent will may be landed in the common iliac artery or into the external iliac artery with management of the internal iliac artery
At the end of the procedure post-stent intra-arterial digital subtraction quality control angiogram images will be obtained Further imaging such as rotational CT analysis will be performed at the discretion of the investigator
Unless expected to resolve by the initial post-operative scan in the presence of any type 1 or 3 endoleak the operating team will undertake further procedures to attempt to rectify the endoleak based on local practice and equipment provision
Any further adjunct procedures to treat endoleak will be placed in accordance with their instructions for use Adjunct procedures may include one or more of but will not be limited to
Repeat balloon moulding
Aortic extension cuff
Placement of a Palmaz Cordis balloon-expandable stent
Iliac extension cuff
Endoanchor placement
Chimney graft placement in the visceralrenal vessels
Post-operative care will conform to European Society of Vascular Surgery 2024 guidelines The Enhanced Recovery After Surgery guidelines approved by the Society for Vascular Surgery will be circulated to all sites
The participant will stay as an inpatient for standard post-operative monitoring and recovery before being discharged Recovery and discharge arrangements will vary from site to site and should follow standard of care pathways at that site
After discharge from the hospital after EVAR patients will attend for CTMRI scan at between 3 and 12-weeks which is clinically necessary to assess the placement of the stent Participants will attend for subsequent clinical and imaging either with ultrasound or CT scanning for stent graft monitoring as directed by local follow up arrangements and the trial follow up protocol
During the trial period modifications of the procedure and devices will be expected as new technology if developed The proceduraldevice modifications will be tracked to ensure that the results of the outcomes from EVAR are not affected positively or negatively leading to errors in the trial conclusions
STANDARD MANAGEMENT - Surveillance with ultrasound or other imaging surveillance with delayed repair for rupture or aneurysm diameter reaching 55 cm threshold
All women will be monitored for AAA growth Ultrasonographic surveillance is the preferred method since it is non-invasive whilst being highly sensitive and specific although in some countries eg USA CT including non-contrast CT may be used for surveillance For AAA between 40-44 cm diameter annual surveillance can be recommended increasing to every 6 months for AAA of 45 cm diameter or greater or according to current local practice and standard operating procedures For ultrasound surveillance the anterior-posterior diameter should be measured in the longitudinal plane since this is more repeatable than the transverse diameter Calliper placement for measurements should be consistent at each surveillance visit Outer-to-outer diameter measurements are preferred but where sonographers are trained to measure either leading edge to leading edge or inner-to-inner diameters these methods should be used and documented When CT imaging is used for surveillance the centreline orthogonal diameter should be measured When the diameter exceeds 54 cm the participant should have a prompt target within 2 weeks consultation with a vascular surgeon consideration of AAA repair by which ever method is recommended by the local team The operation CRF should be completed and the participant will then enter routine clinical follow up
If there is any suspicion of AAA rupture the patient must be admitted immediately as an emergency preferably to a vascular surgeon the site where the patient has been followed up
If there is a suspicion of impending rupture with symptoms of back or abdominal pain referable to the aneurysm further investigations should be performed and consideration given to early elective repair Thromboembolic evens referable to the aneurysm are also an indication for consideration of early elective urgent repair These conditions are known as symptomatic AAA
All randomized patients will be offered smoking cessation advice and adjunct therapies as well as best medical therapy including statins with a cardiologist-guided protocol European Society of Cardiology guidelines for the high-risk category This protocol will include and exercise blood pressure body weight and LDL-cholesterol targets and good diabetic control where relevant All patients will receive advice about exercise and physical activity These measures will be conducted using patient-facing educational resources and through communication with their GeneralFamily Practitioner
Permanent Discontinuation of Study Intervention and Withdrawal from Study
Permanent discontinuation of study intervention
Participants may discontinue study intervention for the following reasons
At the request of the participant
Adverse event Serious Adverse Event
If the investigator considers that a participants health will be compromised due to adverse events or concomitant illness that develop after entering the study
Withdrawal from Study
Withdrawal from the study refers to discontinuation of study intervention and study procedures and can occur for the following reasons
Participant decision
Loss to follow-up
Procedures for Withdrawal from Study
If a subject withdraws prematurely the reason for withdrawal will be recorded in the CRFeCRF and medical records All study visits up to the point of any planned withdrawal will be completed
SAFETY REPORTING
Adverse Event AE
An AE is any untoward medical occurrence in a SAFETY REPORTING
Adverse Event AE
An AE is any untoward medical occurrence in a patient or clinical trial participant An AE can therefore be any unfavourable and unintended sign including an abnormal laboratory finding symptom whether or not considered related to the trial protocol
Adverse Event recording
Adverse events will be assessed at each study visit The following will be assessed for all adverse events
date of onset
description of event
frequency
severity
causality
outcomes
action taken
For the purposes of the study AEs will be followed up according to local practice until the event has stabilised or resolved or the follow-up visit whichever is the sooner
Adverse events that are not serious adverse events will only be recorded on adverse event forms if the adverse event either occurs within 90 days of the index AAA repair or is aortic related The following will be noted as aortic related events
Any events within 30 days of index repair
Access vessel dissection or rupture
Buttock claudication
Endoleak
Graft kinking clinically significant
Graft migration of 5mm
Graft limb thrombosisstenosisocclusion
Limb ischaemia or toe amputation
New onset claudication
Pseudo-aneurysm at graft insertion site
Surgical site infection
All SAEs will be recorded throughout the study
Severity of Adverse Events
The assessment of severity will conform to the following definitions
Mild Awareness of event but easily tolerated
Moderate Discomfort enough to cause some interference with usual activity
Severe Inability to carry out usual activity
Causality of Adverse Events
The assessment of causality will conform to the following definitions
Unrelated No evidence of any causal relationship
Unlikely There is little evidence to suggest there is a causal relationship and there is another reasonable explanation for the event eg the participants clinical condition other concomitant treatment
Possible There is some evidence to suggest a causal relationship However the influence of other factors may have contributed to the event eg the participants clinical condition other concomitant treatments
Probable There is evidence to suggest a causal relationship and the influence of other factors is unlikely
Definite There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out
Serious Adverse Events SAE
Definition of SAE
An SAE is defined as any event that
Results in death
Is life-threatening eg aortic rupture
Requires hospitalisation or prolongation of existing inpatients hospitalisation eg graft infection or conversion to open repair
Results in persistent or significant disability or incapacity eg major limb amputation
Life-threatening in the definition of serious refers to an event in which the participant was at risk of death at the time of the event it does not refer to an event which hypothetically might have caused death if it were more severe
Hospitalisation means any unexpected admission to a hospital department It does not usually apply to scheduled admissions that were planned before study inclusion or visits to casualty without admission
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None