Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm

Jonathan Golledge,Bruce Neal,Qiang Li,Greg Jones,Dylan Morris,Clare Arnott,Richard Norman,Justin Roake,Helen Monaghan,Matt Bown,Joseph Moxon

doi:10.1186/s13063-021-05915-0

Abstract

BackgroundMultiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms.MethodsMAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05).DiscussionCurrently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design.Trial registrationAustralian Clinical Trials ACTRN12618001707257. Registered on 16 October 2018

Highlights

Background and rationale {6a} Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults [1]
Protocol for the Metformin Aneurysm Trial (MAT): A placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm
The funders and sponsor had no role in the design of this protocol or the decision to submit it for publication

Summary

Introduction

Background and rationale {6a} Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults [1]. Most AAAs are identified by incidental imaging or screening when they are small, asymptomatic and at low risk of rupture [2]. Up to 70% of small asymptomatic AAAs expand in size over time to ≥55 mm when the risk of rupture increases [2, 3]. The only established way to prevent AAA rupture is elective repair by open or endovascular surgery [4, 5]. Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms

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