Jay P Mohr1, Jessica R Overbey2, Andreas Hartmann3, Rüdiger von Kummer4, Rustam Al-Shahi Salman5, Helen Kim6, H Bart van der Worp7, Michael K Parides8, Marco A Stefani9, Emmanuel Houdart10, Richard Libman11, John Pile-Spellman12, Kirsty Harkness13, Charlotte Cordonnier14, Ellen Moquete2, Alessandra Biondi15, Catharina J M Klijn16, Christian Stapf17, Alan J Moskowitz2. 1. Doris and Stanley Tananbaum Stroke Center, The Neurological Institute, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: jpm10@cumc.columbia.edu. 2. International Center for Health Outcomes and Innovation Research, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Charité-Universitätsmedizin Berlin, Department of Neurology, Klinikum Frankfurt/Oder, Frankfurt/Oder, Germany. 4. Department of Neuroradiology, University Hospital Dresden, Dresden, Germany. 5. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 6. Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA. 7. Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center, Utrecht University, Utrecht, Netherlands. 8. Department of Cardiovascular and Thoracic Surgery, Albert Einstein Medical Center, Bronx, NY, USA. 9. Department of Neurology and Neurosurgery, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. 10. Department of Neuroradiology, APHP-Hôpital Lariboisière, Université Paris Diderot-Sorbonne Paris Cité, Paris, France. 11. Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. 12. Department of Neuroradiology, NYU-Winthrop Medical Center, Mineola, NY, USA. 13. Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK. 14. Université Lille, Inserm, CHU Lille, U1172, LilNCog, Lille Neuroscience and Cognition, Lille, France. 15. Department of Interventional Neuroradiology, Jean Minjoz Hospital, University of Franche Comté, Besançon, France. 16. Department of Neurology and Neurosurgery, University Medical Center Utrecht, Brain Center, Utrecht University, Utrecht, Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands. 17. Neuroscience Axis, Neurovascular Group, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Division of Neurology, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada; Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
Abstract
BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.
BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.
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