title: Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials.
abstract: OBJECTIVE The ARUBA study (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [AVMs]) on unruptured brain AVMs has been the object of comments and editorials. In the present study the authors aim to systematically review critiques, discuss design issues, and propose a framework for future trials. METHODS The authors performed a systematic review of the French and English literature on the ARUBA study published between January 2006 and February 2015. The electronic search, including the Cochrane Library, MEDLINE (PubMed and Ovid), CINAHL, and EMBASE databases, was complemented by hand searching and cross-referencing. The comments were categorized as items related to the design, the conduct, and the analysis and interpretation of the trial. RESULTS Thirty-one articles or letters were identified. The pragmatic design, with heterogeneity of patients and lack of standardization of the treatment arm, were frequently stated concerns. The choice of outcome measures was repeatedly criticized. During the trial, low enrollment rates, selection bias, and premature interruption of enrollment were frequent comments. The short follow-up period, the lack of subgroup analyses, the lack of details on the results of the various treatments, and a contentious interpretation of results were noted at the analysis stage. A fundamental problem was the primary hypothesis testing conservative management. The authors believe that other trials are needed. Future trials could be pragmatic, test interventions stratified at the time of randomization, and look for long-term, hard clinical outcomes in a large number of patients. CONCLUSIONS In the authors' view, the ARUBA trial is a turning point in the history of brain AVM management; future trials should aim at integrating trial methodology and clinical care in the presence of uncertainty.
authors.affiliation: Department of Surgery, Service of Neurosurgery, Centre Hospitalier de l'Université de Montréal (CHUM), Notre-Dame Hospital.|Service de Neurochirurgie, CHU Cavale Blanche, INSERM UMR 1101 LaTIM, Brest; and.
authors.forename: Elsa
authors.initials: E
authors.lastname: Magro
authors.affiliation: Department of Surgery, Service of Neurosurgery, Centre Hospitalier de l'Université de Montréal (CHUM), Notre-Dame Hospital.|Groupe d'étude de la Thrombose en Bretagne Occidentale, Brest, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Gentric
authors.affiliation: Department of Surgery, Division of Neurosurgery, University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada.
authors.forename: Tim E
authors.initials: TE
authors.lastname: Darsaut
authors.forename: Daniela
authors.initials: D
authors.lastname: Ziegler
authors.affiliation: Direction de l'Enseignement et de l'Académie CHUM|Bibliothèque; and.
authors.lastname: Msi
authors.affiliation: Department of Surgery, Service of Neurosurgery, Centre Hospitalier de l'Université de Montréal (CHUM), Notre-Dame Hospital.
authors.forename: Michel W
authors.initials: MW
authors.lastname: Bojanowski
authors.affiliation: Department of Radiology, Service of Neuroradiology, CHUM, Notre-Dame Hospital, Montreal, Quebec.
authors.forename: Jean
authors.initials: J
authors.lastname: Raymond
mesh_terms: D001164:Arteriovenous Fistula / Q000628:therapy*; D005544:Forecasting; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design
keywords: A Randomized Multicenter Clinical Trial of Unruptured Brain AVMs; ARUBA = A Randomized Trial of Unruptured Brain Arteriovenous Malformations; AVM = arteriovenous malformation; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; brain arteriovenous malformation; care trial; mRS = modified Rankin Scale; randomized trial; vascular disorders