The Case Against A Randomized Trial of Unruptured Brain Arteriovenous Malformations

In November 2013, the primary results of the prospective, multicenter National Institutes of Health–funded study, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA), were published in Lancet. 1 This randomized, nonblinded trial compared medical management alone with medical management plus interventional therapy in patients with unruptured brain arteriovenous malformations (BAVM). Patients were enrolled from 39 clinical sites worldwide. Those patients with previous BAVM treatment or hemorrhage were excluded as were those patients with BAVMs deemed untreatable. The primary end points of the study were symptomatic stroke or death, with a secondary outcome of death and disability as measured by the modified Rankin Scale. The initial study design called for an enrollment of 800 patients but was reduced to 400 after slow trial recruitment prompted a reassessment of the design. When after ≈6 years of enrollment, the trial was halted on the recommendation of the trial’s independent Data and Safety Monitoring Board; outcome data were available for only 223 subjects. Among the randomized subjects, the most common presenting symptoms were seizure and headache. Ninety-four patients (42%) were asymptomatic at the time of diagnosis. BAVMs in the study cohorts were relatively well matched for size, location, and venous drainage pattern, as well as for Spetzler–Martin grade.2 The majority of the patients were identified with Spetzler–Martin grade 1, 2, or 3 (approximately equal) with a few with grade 4 (10%), and no patients with grade 5 were enrolled. The average follow-up period was 33 months. Of the 109 patients in the medical group, 11 patients (10.1%) experienced the primary end point of death or symptomatic stroke, whereas 35 of the 114 patients in the interventional arm (30.7%) met the same end point, making the risk of stroke or death significantly lower in the medical group compared with the interventional group (hazard …