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

Abstract

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.

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

“…At the conclusion of the trial, outcome data were available for only 223 subjects. 12 Further adding to the complexity of the problem is the heterogeneous nature of the disease. Specifically, there are five different groups of AVMs based on the Spetzler-Martin classification, each with a distinct natural history.…”

“…The ICH risk for untreated AVMs is 2% to 6% per year. 2,[6][7][8] However, the annual hemorrhage risk may be as high as 34% if any additional risk factors are present. 9 History of hemorrhage, high blood pressure, intranidal aneurysm, venous stenosis, and deep venous drainage are the main factors that increase the likelihood of AVM rupture.…”

“…4,10,11 Although there are several therapeutic options to eradicate AVMs, the treatment-related morbidity is significant, especially for large, deep-seated, or eloquently located nidi. 6 The recently published ARUBA trial (A Randomized trial of Unruptured Brain Arteriovenous malformations) 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 AVMs. 12 Thus, there is a pressing need to better understand the pathogenesis of AVMs and the molecular mechanisms that destabilize these lesions to develop novel medical therapies, which may reduce the need for invasive intervention.…”

Management of Intracranial Incidental Findings on Brain MRI

“…The individual risk of hemorrhage depends on a number of factors, including location, drainage via the deep brain veins and the presence of an aneurysm in the feeder vessels [39]. Although a current study has demonstrated the superiority of conservative treatment of asymptomatic AVM [47], individual treatment remains a subject of discussion; therefore an examination in a neurovascular center is recommended (Category II).…”

Role of Embolization for Cerebral Arteriovenous Malformations

“…12,13 In the face of recent reports suggesting that medical management may be superior to interventional therapy for unruptured AVMs, at least in the short term, such analyses become all the more critical. 14,15 Assembling a multidisciplinary team with expertise in the medical, surgical, endovascular, and radiation treatment of AVMs is critical for appropriately managing patients with this complex lesion.…”