Randomized Controlled Trial

. 2017 Oct 3;89(14):1499-1506.

doi: 10.1212/WNL.0000000000004532. Epub 2017 Sep 6.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

J P Mohr¹, Jessica R Overbey², Ruediger von Kummer², Marco A Stefani², Richard Libman², Christian Stapf², Michael K Parides², John Pile-Spellman², Ellen Moquete², Claudia S Moy², Eric Vicaut², Alan J Moskowitz², Kirsty Harkness², Charlotte Cordonnier², Alessandra Biondi², Emmanuel Houdart², Joachim Berkefeld², Catharina J M Klijn², Xavier Barreau², Helen Kim², Andreas Hartmann; International ARUBA Investigators

Collaborators, Affiliations

Collaborators

International ARUBA Investigators:
E Houdart, D Bresson, B George, J P Saint-Maurice, C Stapf, J P Lejeune, P Aguettaz, S Blond, C Cordonnier, X Leclerc, C Rossi, A Biondi, R Billon-Grand, T Moulin, X Barreau, C Marchal, V Michel, A Thévenoux, I Tedeschi, S Timsit, P Dam-Hieu, P Meriot, F M Merrien, M Nonent, F Nataf, D Calvet, E Touzé, D Trystram, R von Kummer, M Baumann, U Bodechtel, I Dzialowski, L Hentschel, J Kepplinger, V Pütz, G Schackert, K Wartenberg, A Hartmann, T Funk, A Schilling, R Wurm, J Berkefeld, H Braun, M W Lorenz, I Santos, V Seifer, R Wolff, J Meisel, E Herrmann, C Hohaus, Y Minkus, M Dichgans, H Brueckmann, A Dörr, G Fesl, A Muacevic, C Schichor, F Wollenweber, B M Wowra, A Zollver, M Schumacher, U Bergmam, C Hader, W D Niesen, C Taschner, V Velthoven-Wurster, I Wanke, S Hagedorn, O Kastrup, I Sandalcioglu, U Sure, H B van der Worp, C J M Klijn, J W Berkelbach van der Sprenkel, T H Lo, J M C van Dijk, O Eshghi, G J Luijckx, M Arnold, A Raabe, G Schroth, M Heldner, M Reinert, R Al-Shahi Salman, B Colam, S Erridge, R Sellar, J Steers, P M White, K Harkness, S Coley, T Hodgson, E Richards, U Patel, A D Mendelow, A Gholkar, P Mitchell, B Gregson, R White, H Nahser, M Javadpour, P Enevoldson, J Molloy, D Hughes, J Holland, C Sherrington, A Ingham, M A Stefani, M L Fagundes Chaves, A Finkelsztejn, D Roy, J Raymond, F Guilbert, T Darsaut, K Butcher, J Silva, P Klurfan, Byung-Woo Yoon, J A Kim, S Jung, Y Kim, C Kim, R Libman, D J Langer, J P Mohr, T Kitago Young, W L, M T Lawton, R Higashida, S C Johnston, L Feng, J Chen, Z Ajani, S Potrebic, E Wirkowski, J Pile-Spellman, M Brisman, J Yasen, I Kureshi, G Spiegel, I Silverman, S Koch, R L Sacco, M Chen, V H Lee, S Prabhakaran, M Harrigan, J Brockington, Nelson L, R M Zweilfer, J I Lopez, J Biller, M Schneck, D Anderson, S Cullen, V Rao, N Moayeri, V Tse, A P Bowles Jr, K Nassr

Affiliations

¹ From Columbia University Medical Center (J.P.M.); Icahn School of Medicine at Mount Sinai (J.R.O., M.K.P., E.M., A.J.M.), New York, NY; University Hospital Dresden (R.v.K.), Germany; Federal University of Rio Grande do Sul (M.A.S.), Porto Alegre, Brazil; North Shore-Long Island Jewish Medical Center (R.L.), New York, NY; University of Montreal (C.S.), Quebec, Canada; Winthrop University Hospital (J.P.-S.), Mineola, NY; National Institute of Neurological Disorders and Stroke (C.S.M.), NIH, Bethesda, MD; Hôpital Lariboisière (E.V., E.H.), Paris, France; Royal Hallamshire Hospital (K.H.), Sheffield, UK; Université Lille Nord de France (C.C.); University of Franche Comté (A.B), Besançon, France; Universitätsklinikum Frankfurt am Main (J.B.), Germany; Department of Neurology (C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Radboud University Medical Center, Nijmegen, and Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center, Utrecht, the Netherlands; CHU Pellegrin (X.B.), Bordeaux, France; University of California (H.K.), San Francisco; and Department of Neurology (A.H.), Klinikum Frankfurt (Oder), Germany. jpm10@columbia.edu.
² From Columbia University Medical Center (J.P.M.); Icahn School of Medicine at Mount Sinai (J.R.O., M.K.P., E.M., A.J.M.), New York, NY; University Hospital Dresden (R.v.K.), Germany; Federal University of Rio Grande do Sul (M.A.S.), Porto Alegre, Brazil; North Shore-Long Island Jewish Medical Center (R.L.), New York, NY; University of Montreal (C.S.), Quebec, Canada; Winthrop University Hospital (J.P.-S.), Mineola, NY; National Institute of Neurological Disorders and Stroke (C.S.M.), NIH, Bethesda, MD; Hôpital Lariboisière (E.V., E.H.), Paris, France; Royal Hallamshire Hospital (K.H.), Sheffield, UK; Université Lille Nord de France (C.C.); University of Franche Comté (A.B), Besançon, France; Universitätsklinikum Frankfurt am Main (J.B.), Germany; Department of Neurology (C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Radboud University Medical Center, Nijmegen, and Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center, Utrecht, the Netherlands; CHU Pellegrin (X.B.), Bordeaux, France; University of California (H.K.), San Francisco; and Department of Neurology (A.H.), Klinikum Frankfurt (Oder), Germany.

PMID: 28878048
PMCID: PMC5631171
DOI: 10.1212/WNL.0000000000004532

Randomized Controlled Trial

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

J P Mohr et al. Neurology. 2017.

. 2017 Oct 3;89(14):1499-1506.

doi: 10.1212/WNL.0000000000004532. Epub 2017 Sep 6.

Authors

Collaborators

International ARUBA Investigators:
E Houdart, D Bresson, B George, J P Saint-Maurice, C Stapf, J P Lejeune, P Aguettaz, S Blond, C Cordonnier, X Leclerc, C Rossi, A Biondi, R Billon-Grand, T Moulin, X Barreau, C Marchal, V Michel, A Thévenoux, I Tedeschi, S Timsit, P Dam-Hieu, P Meriot, F M Merrien, M Nonent, F Nataf, D Calvet, E Touzé, D Trystram, R von Kummer, M Baumann, U Bodechtel, I Dzialowski, L Hentschel, J Kepplinger, V Pütz, G Schackert, K Wartenberg, A Hartmann, T Funk, A Schilling, R Wurm, J Berkefeld, H Braun, M W Lorenz, I Santos, V Seifer, R Wolff, J Meisel, E Herrmann, C Hohaus, Y Minkus, M Dichgans, H Brueckmann, A Dörr, G Fesl, A Muacevic, C Schichor, F Wollenweber, B M Wowra, A Zollver, M Schumacher, U Bergmam, C Hader, W D Niesen, C Taschner, V Velthoven-Wurster, I Wanke, S Hagedorn, O Kastrup, I Sandalcioglu, U Sure, H B van der Worp, C J M Klijn, J W Berkelbach van der Sprenkel, T H Lo, J M C van Dijk, O Eshghi, G J Luijckx, M Arnold, A Raabe, G Schroth, M Heldner, M Reinert, R Al-Shahi Salman, B Colam, S Erridge, R Sellar, J Steers, P M White, K Harkness, S Coley, T Hodgson, E Richards, U Patel, A D Mendelow, A Gholkar, P Mitchell, B Gregson, R White, H Nahser, M Javadpour, P Enevoldson, J Molloy, D Hughes, J Holland, C Sherrington, A Ingham, M A Stefani, M L Fagundes Chaves, A Finkelsztejn, D Roy, J Raymond, F Guilbert, T Darsaut, K Butcher, J Silva, P Klurfan, Byung-Woo Yoon, J A Kim, S Jung, Y Kim, C Kim, R Libman, D J Langer, J P Mohr, T Kitago Young, W L, M T Lawton, R Higashida, S C Johnston, L Feng, J Chen, Z Ajani, S Potrebic, E Wirkowski, J Pile-Spellman, M Brisman, J Yasen, I Kureshi, G Spiegel, I Silverman, S Koch, R L Sacco, M Chen, V H Lee, S Prabhakaran, M Harrigan, J Brockington, Nelson L, R M Zweilfer, J I Lopez, J Biller, M Schneck, D Anderson, S Cullen, V Rao, N Moayeri, V Tse, A P Bowles Jr, K Nassr

Affiliations

¹ From Columbia University Medical Center (J.P.M.); Icahn School of Medicine at Mount Sinai (J.R.O., M.K.P., E.M., A.J.M.), New York, NY; University Hospital Dresden (R.v.K.), Germany; Federal University of Rio Grande do Sul (M.A.S.), Porto Alegre, Brazil; North Shore-Long Island Jewish Medical Center (R.L.), New York, NY; University of Montreal (C.S.), Quebec, Canada; Winthrop University Hospital (J.P.-S.), Mineola, NY; National Institute of Neurological Disorders and Stroke (C.S.M.), NIH, Bethesda, MD; Hôpital Lariboisière (E.V., E.H.), Paris, France; Royal Hallamshire Hospital (K.H.), Sheffield, UK; Université Lille Nord de France (C.C.); University of Franche Comté (A.B), Besançon, France; Universitätsklinikum Frankfurt am Main (J.B.), Germany; Department of Neurology (C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Radboud University Medical Center, Nijmegen, and Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center, Utrecht, the Netherlands; CHU Pellegrin (X.B.), Bordeaux, France; University of California (H.K.), San Francisco; and Department of Neurology (A.H.), Klinikum Frankfurt (Oder), Germany. jpm10@columbia.edu.
² From Columbia University Medical Center (J.P.M.); Icahn School of Medicine at Mount Sinai (J.R.O., M.K.P., E.M., A.J.M.), New York, NY; University Hospital Dresden (R.v.K.), Germany; Federal University of Rio Grande do Sul (M.A.S.), Porto Alegre, Brazil; North Shore-Long Island Jewish Medical Center (R.L.), New York, NY; University of Montreal (C.S.), Quebec, Canada; Winthrop University Hospital (J.P.-S.), Mineola, NY; National Institute of Neurological Disorders and Stroke (C.S.M.), NIH, Bethesda, MD; Hôpital Lariboisière (E.V., E.H.), Paris, France; Royal Hallamshire Hospital (K.H.), Sheffield, UK; Université Lille Nord de France (C.C.); University of Franche Comté (A.B), Besançon, France; Universitätsklinikum Frankfurt am Main (J.B.), Germany; Department of Neurology (C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Radboud University Medical Center, Nijmegen, and Department of Neurology and Neurosurgery (C.J.M.K.), Brain Center Rudolf Magnus, University Medical Center, Utrecht, the Netherlands; CHU Pellegrin (X.B.), Bordeaux, France; University of California (H.K.), San Francisco; and Department of Neurology (A.H.), Klinikum Frankfurt (Oder), Germany.

PMID: 28878048
PMCID: PMC5631171
DOI: 10.1212/WNL.0000000000004532

Abstract

Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA).

Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013.

Results: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001).

Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades.

Clinicaltrialsgov identifier: NCT00389181.

Classification of evidence: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

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Figures

**Figure 1. Kaplan-Meier curves for time to a primary outcome with initial mRS score ≥2**
(A) As-randomized outcomes for medical only (MM; red) vs medical plus intervention (IT; blue). (B) As-treated outcomes for MM only (red) vs IT (blue). mRS = modified Rankin Scale. Reprinted from Mohr JP, Parides MK, Stapf C, et al., for the International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014;383:614–621. Copyright © 2013, reprinted with permission from Elsevier.

**Figure 2. Three-dimensional plot of modified Rankin Scale scores and counts of patients by Spetzler-Martin grade**
(A) Medical management (MM) as randomized, (B) interventional therapy (IT) as randomized, (C) MM as treated, and (D) IT as treated.

See this image and copyright information in PMC

References

1. Mohr JP, Parides MK, Stapf C, et al. ; for the International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014;383:614–621. - PMC - PubMed
1. Gross RA, Johnston KC. Levels of evidence: taking neurology to the next level. Neurology 2009;72:8–10. - PubMed
1. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–607. - PubMed
1. St Pierre J, Cadieux M, Guerault A, Quevillon M. Statistical tables to detect significance between frequencies in two small samples, with particular reference to biological assays. Rev Can Biol 1976;35:17–23. - PubMed
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Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

Collaborators

Affiliations

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous