Elsevier

The Lancet

Volume 383, Issue 9917, 15–21 February 2014, Pages 614-621
The Lancet

Articles
Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial

https://doi.org/10.1016/S0140-6736(13)62302-8Get rights and content

Summary

Background

The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy.

Methods

Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181.

Findings

Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14–0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management.

Interpretation

The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up.

Funding

National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Introduction

Brain arteriovenous malformations are diagnosed most often in adults aged about 40 years. Haemorrhage was the usual means of discovery before non-invasive imaging, but in the past three decades such imaging has helped with the detection of brain arteriovenous malformations and the proportion being diagnosed unruptured has almost doubled.1, 2

An earlier retrospective series3 estimated a 4% crude annual rupture rate for brain arteriovenous malformations, but this risk was derived from combined outcomes, including those already having bled. More recent prospective studies4, 5 report bleeding rates as low as 1% per year for those discovered unruptured. Furthermore, first haemorrhage syndromes are often mild, with bleeding often mainly confined to the brain arteriovenous malformation itself or originating from the venous side of the malformation.6, 7 Approaches to eradicate a brain arteriovenous malformation, bled or not, include various treatment techniques (neurosurgery, endovascular embolisation, and stereotactic radiotherapy) used alone or in combination with varying degrees of treatment-associated morbidity and mortality.8, 9

In the past decade, debates have addressed whether preventive lesion eradication offers a clinical benefit for patients diagnosed with an unruptured brain arteriovenous malformation.10, 11 A Randomised trial of Unruptured Brain AVMs (ARUBA) was organised to address this clinically compelling question.

Section snippets

Study design and participants

ARUBA is a prospective, multicentre, parallel design, non-blinded, randomised controlled trial involving 39 active clinical sites in nine countries (appendix). Site selection was based on centre experience with management of at least ten brain arteriovenous malformations per year, presence of a multidisciplinary arteriovenous malformations treatment team, and documented academic interest in clinical brain arteriovenous malformation research.

We compare the risk of death and symptomatic stroke in

Results

We randomised 226 patients during the period from April 4, 2007, to April 15, 2013, at a mean rate of 3·2 patients per month (appendix). Figure 1 shows the trial profile. We had screened a further 1514 patients for eligibility, of whom 1014 were ineligible for enrolment, largely because of evidence of previous haemorrhage or a history of previous treatment. Of the 500 patients deemed eligible, 323 refused participation in the trial, and 42 were managed by centres that randomised no patients.

Discussion

In this study of 223 patients with unruptured brain arteriovenous malformations, the risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group after a mean follow-up of about 33 months. Patients followed up without intervention also had a significantly lower risk of death and neurological disability (modified Rankin scale ≥2) than those in the interventional group. No unexpected harms were identified, other than a higher proportion

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    *

    Contributed equally

    Prof Young died in August, 2013

    Members listed in appendix

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