Information for clinicians and trialists

Contact the trial team

Trial email: warriors@imperial.ac.uk

Janet Powell: j.powell@imperial.ac.uk

Colin Bicknell: colin.bicknell@imperial.ac.uk

Anna-Louise Pouncey: a.pouncey@imperial.ac.uk

Funders

British Heart Foundation, with additional support from Medtronic, Terumo Aortic and internationally from Finnish Heart Foundation, Swedish Heart & Lung Foundation, Novo Nordisk, Denmarks Frie Forskningfond,  and Vascular Foundation Australia.

Research aim

To assess whether women with small abdominal aortic aneurysm (AAA) currently are treated too late in their clinical course.

Primary aim: For women with small abdominal aortic aneurysm (AAA, 4.0-5.4 cm diameter), to assess whether early endovascular aneurysm repair (EVAR) compared to routine surveillance decreases the composite outcome of AAA rupture and aneurysm-related mortality over five years.

Secondary aim: For women with small abdominal aortic aneurysm (AAA, 4.0-5.4 cm diameter), to assess whether early endovascular aneurysm repair (EVAR) compared to routine surveillance increases quality-adjusted-life-years (QALYs) over five years.

Other aims: to compare operative mortality, major cardiovascular events (MACE), all-cause mortality, costs and cost-effectiveness between the two randomised groups.  Also, in the surveillance group to assess the rate of losing eligibility for EVAR as the AAA expands.

Trial information

Background

Women have smaller arteries and lower AAA population prevalence, but this is disputed and dependent on diagnostic threshold. AAA is ~5 times more common in men if a 3 cm diameter threshold is applied but only ~1.3 times greater when an increase of >1.5 times the normal infrarenal aortic diameter is used. Women were under-represented in the four major randomised trials of small asymptomatic AAA repair, comprising on average only 4.3% of participants. These trials have defined the risk-benefit and intervention threshold for AAA in men, but do not represent women. This is highly pertinent, as women have 4 times greater rupture risk of small AAA. Individual patient meta-analysis (15475 people) demonstrated that in women the rupture risk at 4.2cm diameter was the same as at 5.5cm for men. Increased AAA size is also associated with increased operative complexity and peri-operative mortality. Every 1 cm increase in diameter is associated with an 18% increase in adjusted odd of 30-day mortality for open repair. For endovascular aneurysm repair (EVAR or keyhole surgery), increased size is also significantly associated with a reduction in both 30-day and 5-year survival. Systematic review with meta-analysis demonstrates that women have higher operative mortality and complications rates than men - 30-day mortality following elective open repair is 6% and for EVAR 2.3% (odds ratio versus men 1.49 and 1.86 respectively even after adjustment for co-morbidities). These disparities are consistent worldwide and have not ameliorated with time. With a 30-day mortality of 6% open repair cannot be considered a safe elective procedure for women. EVAR is the preferred treatment modality among most AAA patients. Eligibility for EVAR by anatomical criteria declines at significantly lower AAA diameter for women compared to men. At the 5.5 cm diameter threshold, women are less likely to be selected for endovascular repair than men (34% vs 54%) and more likely to be selected for conservative management (34% vs 19%). Overall, women are 25% less likely to receive elective AAA repair, but increasingly likely to present with AAA rupture, which carries >10-fold increased mortality. Therefore, it is possible that the opportunity for effective AAA treatment in women is being missed. While various retrospective analyses have called for sex-specific criteria for AAA repair, without dedicated prospective research, uncertainty regarding the risk-benefit threshold and sex-specific disparity in AAA repair remain.

Design

Randomised controlled trial with parallel registry for women ineligible for the trial. The intervention is early keyhole surgery. The standard care group is surveillance, with delayed repair when the AAA diameter reaches 5.5 cm.

WARRIORS is an international multicentre, open label, superiority RCT, randomly allocating consenting women with small AAA, morphologically suitable for EVAR in a 1:1 ratio to either early EVAR or routine ultrasonographic surveillance.  This will be an international trial anchored in the UK, where there will be 15-18 recruiting sites, each aiming to randomise 10 patients.   There will be a further ~100 recruiting sites from across the world, including North America, Europe and Australasia. In total the trial plans to randomise 1112 women in 1:1 ratio of either early EVAR or routine surveillance with delayed repair for either AAA rupture or reaching the threshold diameter of >5.4 cm.  There will be a Vanguard phase, enrolling 250 patients internationally, of 250 patients to confirm both the feasibility of recruitment, and that the safety of the policy of early EVAR is within the range reported by observational studies from the USA. The primary composite outcome of aneurysm-related mortality and aneurysm rupture will be assessed at 5 years after randomisation.

Sample size

1112 women with small AAA, identified from trial vascular centres in 8 or more countries.

Setting

Vascular centres across the UK and worldwide. Recruitment is due to start in mid-2025.

Timelines

All patients will be followed up for a minimum of 5 years.

Inclusion/exclusion criteria

Inclusion criteria

  • female sex
  • age ≥50 years
  • infra-renal abdominal aortic aneurysm with a maximum infrarenal aortic anterior-posterior diameter 4.0-5.4 cm, aneurysm, measured on ultrasonography or the centreline orthogonal diameter on Computed Tomography (CT) scan when this is the discovery imaging mode.
  • Local assessment that arterial morphology is suitable for EVAR within manufacturer’s IFU for any licensed infrarenal endograft, including those with concomitant common iliac aneurysm(s), provided the device is landed in the iliac arteries, without coverage of patent internal iliac arteries.
  • Rockwood frailty score <7.

Exclusion criteria

  • Male sex
  • aneurysm of the infrarenal aorta of <4.0 or >5.4cm
  • infrarenal aneurysm not not meeting IFU for any specific licensed endograft for standard EVAR
  • inability to give informed consent
  • previous abdominal aortic surgery
  • age <50 years
  • concomitant thoracic aortic aneurysm of >4.0cm diameter
  • excessive frailty (Rockwood score >7)
  • life expectancy <2 years in the opinion of the investigator
  • severe contrast allergy not amenable to pretreatment with steroids/antihistamines (e.g. anaphylaxis)
  • those considered unlikely to comply with follow-up
  • concomitant common iliac artery aneurysm unless: a) the arterial morphology is within the IFU for standard infrarenal EVAR; or b) the arterial morphology is suitable for a licensed iliac branch device; or c) the internal iliac artery is occluded and the stent limb can be landed in the external iliac artery without embolisation of the internal iliac artery.
  • Target population: N=8608 (Approx 200 participants per site over 24 months)
  • *Examples of procedures from which patients are at highest-risk of VTE and usually require extended duration pharmacological thromboprophylaxis (EDPTP) include, but are not limited to: orthopaedic surgery (total hip replacement, total knee replacement, colorectal surgery (colectomy, splenectomy), upper gastrointestinal surgery (oesophagectomy, gastrectomy), urological surgery (cystectomy, nephrectomy), and gynaecological oncology surgery (radical hysterectomy, radical trachelectomy).

Excluded women with AAAs ≥4.0 cm diameter will still be eligible for inclusion in a parallel registry.

There will be no patient excluded as a result of geographical location, disability, gender, marriage and civil partnership status, ethnicity, religion or belief, sexual orientation, socioeconomic status or access to health or social care. 

Study team
Chief Investigators at Imperial College London
  • Janet Powell
  • Colin Bicknell
  • Anna-Louise Pouncey
Also from Imperial College London
  • Statistician Emanuela Falaschetti
  • Cardiologist Darrel Francis
  • Imperial Clinical Trials Unit
Health Economists
  • Manuel Gomes, University College London
  • Rikke Sorgaard, University of Southern Denmark
Qualitative health research
  • Rachel Evley, University of Leicester.
Patient representative
  • Sara Bosely
UK co-investigators
  • Olivia McBride, Dundee
  • Rachel Bell, Newcastle
  • Matthew Bown, Leicester
  • Ian Loftus, Core Laboratory St George’s Hospital London.
Trial documents
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