A Randomised Trial of Unruptured Brain Arteriovenous Malformations

SUMMARY

The first WORLDWIDE RANDOMISED CONTROLLED TRIAL for adults with brain AVMs is underway. So far, no-one has ever done a randomised controlled trial (which is the ‘acid test’ for any treatment) to demonstrate that it is beneficial to treat brain AVMs that have never bled (known as ‘unruptured brain AVMs’). Whilst some doctors believe that unruptured brain AVMs should be treated if possible, others do not.

ARUBA will study adults with an unruptured brain AVM. If specialists decide that it is technically possible to treat the brain AVM, anyone who agrees to participate in ARUBA would be randomly allocated to one of two groups: (1) a policy of interventional treatment of the brain AVM, or (2) no immediate interventional treatment of the brain AVM. By interventional treatment, ARUBA is referring to neurosurgery, endovascular embolisation, stereotactic radiotherapy. The intention is to compare the long-term outcome for these 2 groups of people, over at least 5 years.

ARUBA is funded by the National Institute of Neurological Disorders and Stroke (NINDS) in the USA, but it is taking place in Europe and Australia as well.

ARUBA is not funded by a pharmaceutical company, and therefore it is not a commercial trial.

The study’s Principal Investigator is Dr JP Mohr (Columbia-Presbyterian Medical Center, New York, USA), its European Co-Principal Investigator is Dr Christian Stapf (Lariboisiere Hospital, Paris, France), and the UK Co-ordinator for ARUBA is Dr Rustam Al-Shahi (Western General Hospital, Edinburgh, UK).

To date, 102 centres worldwide have indicated a willingness to participate, and 7 of these are in the UK:

• Western General Hospital, Edinburgh

• Walton Centre for Neurology and Neurosurgery, Liverpool

• Radcliffe Infirmary, Oxford

• Frenchay Hospital, Bristol

• Queens Medical Centre, Nottingham

• National Hospital for Neurology and Neurosurgery, London

• Addenbrooke’s Hospital, Cambridge

Background

With advances in modern imaging technologies, many incidental unruptured brain AVMs are being discovered. People are being diagnosed with only minor symptoms from their brain AVM, or perhaps none at all. A population study in Scotland (http://www.sivms.org) has found that for 1 in every 5 people newly-diagnosed with a brain AVM, its discovery will have been incidental and nothing to do with their symptoms.

No currently available data can confirm the need for intervention in unruptured brain AVMs, and little information exists on their natural history to compare the short and long term outcome of intervention of any form as opposed to medical management.

Despite the potential risks and enormous costs of AVM treatment, no studies have directly compared the effects of interventional treatments against each other, or compared interventional treatment with the natural history of the condition.

Haemorrhage rates from unruptured brain AVMs are thought to be low (less than 1% per year), making some specialists uncertain about the merits of treating unruptured brain AVMs, but the risk of haemorrhage is assumed to compound over time. People with a brain AVM that has bled when it is first diagnosed have a higher risk of further bleeding, making specialists less uncertain about the need for interventional treatment.

 Aims of the ARUBA study

1.      To determine whether medical management is superior to invasive treatment of unruptured brain AVMs.

2.      If medical management is not superior to invasive treatment, to determine if medical management is not inferior to invasive therapies for preventing death or stroke in the treatment of unruptured brain AVMs.

3.      To determine whether medical management of brain AVMs decreases the risk of death or disability compared to invasive treatments.

A number of secondary aims will look at differences in quality of life, death, quality-adjusted survival, adverse effects, and costs. The study will also look into the relative benefits of invasive treatments as opposed to medical management depending on size, location, venous drainage pattern or age.

 ARUBA Selection Criteria

The trial will only consider adults with unruptured brain AVMs, that are potentially treatable. Anyone who meets the selection criteria, regardless of sex, race or ethnicity, may be included in the study.

Inclusion Criteria

Participant must:

1.   Have unruptured brain AVM diagnosed by MRI/MRA and/or angiogram.

2.   Be 18 years of age, or older.

3.   Have signed Informed Consent.

Exclusion Criteria

Paricipant must not:

1.     Present with evidence of a recent or prior bleed

2.     Have received prior treatment

3.     Be deemed untreatable by local team or have another vascular or brain condition which precludes invasive therapies

4.      Have a baseline Rankin scale of 2 or more

5.      Have a further condition reducing life expectancy to less than 10yrs
 
6.      Have a reduced platelet count (less than 100 million per ml) 

7.      Have coagulopathy

8.      Be pregnant, lactating or planning on pregnancy

 9.     Be allergic to iodine contrast agents
 
10.    Have multiple brain AVMs

11.    Have any form of arteriovenous or spinal fistulas

12.    Have a diagnosed Vein of Galen type malformation
 
13.    Have a diagnosed cavernous malformation
 
14.    Have a diagnosed dural arteriovenous fistula
 
15.    Have a diagnosed venous malformation
 
16.    Have a diagnosed neurocutaneous syndrome such as von Hippel-Lindau, Sturge-Weber or Wyburn-Mason syndrome
 
17.    Have a brain AVM in the context of moya-moya type changes
 
18.    Have diagnosed HHT (Rendu-Osler-Weber syndrome)