Randomized Controlled Trial

. 2014 Feb 15;383(9917):614-21.

doi: 10.1016/S0140-6736(13)62302-8. Epub 2013 Nov 20.

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

J P Mohr¹, Michael K Parides², Christian Stapf³, Ellen Moquete², Claudia S Moy⁴, Jessica R Overbey², Rustam Al-Shahi Salman⁵, Eric Vicaut⁶, William L Young⁷, Emmanuel Houdart⁸, Charlotte Cordonnier⁹, Marco A Stefani¹⁰, Andreas Hartmann¹¹, Rüdiger von Kummer¹², Alessandra Biondi¹³, Joachim Berkefeld¹⁴, Catharina J M Klijn¹⁵, Kirsty Harkness¹⁶, Richard Libman¹⁷, Xavier Barreau¹⁸, Alan J Moskowitz²; international ARUBA investigators

Collaborators, Affiliations

Collaborators

international ARUBA investigators:
J P Mohr, Alan J Moskowitz, Ellen Moquete, Claudia S Moy, Michael K Parides, Rustam Al-Shahi Salman, Christian Stapf, Eric Vicaut, William L Young, J P Mohr, S Marshall, N Ostapkovich, K Lord, C Stapf, C Buchbinder, A J Moskowitz, M K Parides, E Moquete, K McDonald, A Estevez, S Varghese, J R Overbey, E Kumbarce, J Foo, E Vicaut, A Chamam, M Courrèges-Viaud, C Dert, U Fiedler, V Jouis, S Kabla, S Marchand, A Pena, V Rochaud, Karen Furie, Barry R Davis, Michael D Hill, Charles Jungreis, Renee Martin, Duke Samson, Peter R Gilbert, Anthony Furlan, C S Moy, L S Janis, P R Gilbert, Marie-Germaine Bousser, Louis R Caplan, Charles Strother, Brice A K Weir, Hans-Martin Schneble, Aman Patel, Phil M Meyers, John Pile-Spellman, 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, A S Nedelec, M Nonent, F Nataf, D Calvet, E Touzé, D Trystram, R von Kummer, M Baumann, U Bodechtel, I Dzialowski, H 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 Seifert, 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 Bergmann, 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 Hodgeson, E Richards, U Patel, A D Mendelow, A Gholkar, P Mitchell, B Gregson, H Nahser, M Javadpour, P Enevoldson, R White, J Molloy, D Hughes, C Sherrington, 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, W L Young, M T Lawton, R Higashida, S C Johnston, L Feng, J Chen, Z Ajani, S Potrebic, E Wirkowski, J Pile-Spellman, M Brisman, J Jasen, I Kureshi, G Spiegel, I Silverman, S Koch, R L Sacco, M Chen, V Lee, S Prabhakaran, M Harrigan, J Brockington, 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 The Neurological Institute, Columbia University Medical Center, New York, NY, USA.
² International Center for Health Outcomes and Innovation Research, Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ The Neurological Institute, Columbia University Medical Center, New York, NY, USA; Department of Neurology, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France; DHU NeuroVasc, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France. Electronic address: christian.stapf@lrb.aphp.fr.
⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁵ Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁶ Unité de Recherche Clinique, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France.
⁷ Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
⁸ Department of Neuroradiology, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France.
⁹ Department of Neurology, CHRU Lille, Université Lille Nord de France, Lille, France.
¹⁰ Department of Neurology and Neurosurgery, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
¹¹ Charité-Universitätsmedizin Berlin Berlin, Germany; Department of Neurology, Klinikum Frankfurt/Oder, Frankfurt/Oder Oder, Germany.
¹² Department of Neuroradiology, University Hospital Dresden, Dresden, Germany.
¹³ Department of Neuroradiology and Endovascular Therapy, Jean Minjoz Hospital, University of Franche Comté, Besançon, France.
¹⁴ Department of Neuroradiology, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
¹⁵ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center, Utrecht, Netherlands.
¹⁶ Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.
¹⁷ Department of Neurology, North Shore Long Island Jewish Medical Center, New Hyde Park, NY, USA.
¹⁸ Department of Diagnostic and Interventional Neuroimaging, CHU Pellegrin, Bordeaux, France.

PMID: 24268105
PMCID: PMC4119885
DOI: 10.1016/S0140-6736(13)62302-8

Randomized Controlled Trial

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

J P Mohr et al. Lancet. 2014.

. 2014 Feb 15;383(9917):614-21.

doi: 10.1016/S0140-6736(13)62302-8. Epub 2013 Nov 20.

Authors

Collaborators

international ARUBA investigators:
J P Mohr, Alan J Moskowitz, Ellen Moquete, Claudia S Moy, Michael K Parides, Rustam Al-Shahi Salman, Christian Stapf, Eric Vicaut, William L Young, J P Mohr, S Marshall, N Ostapkovich, K Lord, C Stapf, C Buchbinder, A J Moskowitz, M K Parides, E Moquete, K McDonald, A Estevez, S Varghese, J R Overbey, E Kumbarce, J Foo, E Vicaut, A Chamam, M Courrèges-Viaud, C Dert, U Fiedler, V Jouis, S Kabla, S Marchand, A Pena, V Rochaud, Karen Furie, Barry R Davis, Michael D Hill, Charles Jungreis, Renee Martin, Duke Samson, Peter R Gilbert, Anthony Furlan, C S Moy, L S Janis, P R Gilbert, Marie-Germaine Bousser, Louis R Caplan, Charles Strother, Brice A K Weir, Hans-Martin Schneble, Aman Patel, Phil M Meyers, John Pile-Spellman, 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, A S Nedelec, M Nonent, F Nataf, D Calvet, E Touzé, D Trystram, R von Kummer, M Baumann, U Bodechtel, I Dzialowski, H 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 Seifert, 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 Bergmann, 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 Hodgeson, E Richards, U Patel, A D Mendelow, A Gholkar, P Mitchell, B Gregson, H Nahser, M Javadpour, P Enevoldson, R White, J Molloy, D Hughes, C Sherrington, 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, W L Young, M T Lawton, R Higashida, S C Johnston, L Feng, J Chen, Z Ajani, S Potrebic, E Wirkowski, J Pile-Spellman, M Brisman, J Jasen, I Kureshi, G Spiegel, I Silverman, S Koch, R L Sacco, M Chen, V Lee, S Prabhakaran, M Harrigan, J Brockington, 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 The Neurological Institute, Columbia University Medical Center, New York, NY, USA.
² International Center for Health Outcomes and Innovation Research, Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ The Neurological Institute, Columbia University Medical Center, New York, NY, USA; Department of Neurology, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France; DHU NeuroVasc, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France. Electronic address: christian.stapf@lrb.aphp.fr.
⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁵ Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁶ Unité de Recherche Clinique, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France.
⁷ Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
⁸ Department of Neuroradiology, APHP-Hôpital Lariboisière, Univ Paris Diderot-Sorbonne Paris Cité, Paris, France.
⁹ Department of Neurology, CHRU Lille, Université Lille Nord de France, Lille, France.
¹⁰ Department of Neurology and Neurosurgery, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
¹¹ Charité-Universitätsmedizin Berlin Berlin, Germany; Department of Neurology, Klinikum Frankfurt/Oder, Frankfurt/Oder Oder, Germany.
¹² Department of Neuroradiology, University Hospital Dresden, Dresden, Germany.
¹³ Department of Neuroradiology and Endovascular Therapy, Jean Minjoz Hospital, University of Franche Comté, Besançon, France.
¹⁴ Department of Neuroradiology, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
¹⁵ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center, Utrecht, Netherlands.
¹⁶ Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.
¹⁷ Department of Neurology, North Shore Long Island Jewish Medical Center, New Hyde Park, NY, USA.
¹⁸ Department of Diagnostic and Interventional Neuroimaging, CHU Pellegrin, Bordeaux, France.

PMID: 24268105
PMCID: PMC4119885
DOI: 10.1016/S0140-6736(13)62302-8

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

We declare that we have no conflicts of interest.

Figures

**Figure 2. Kaplan-Meier estimated event rate by (A) as-randomised and (B) as-treated**
Crosses depict censored patients. HR=hazard ratio. (A) Log-rank χ²=16·07; p<0·0001. (B) Log-rank χ²=26·9, p<0·0001. Seven patients in the medical management crossed over to interventional therapy. 20 patients in the interventional therapy group did not receive interventional therapy and are deemed crossovers to medical management. Three additional patients randomised to interventional therapy had a stroke before the initiation of interventional therapy and were placed in the medical management group for the as-treated analysis.

See this image and copyright information in PMC

Comment in

Management of unruptured brain arteriovenous malformations.
Knopman J, Stieg PE. Knopman J, et al. Lancet. 2014 Feb 15;383(9917):581-3. doi: 10.1016/S0140-6736(14)60001-5. Lancet. 2014. PMID: 24529458 No abstract available.
Commentary: The ARUBA trial.
Russin J, Spetzler R. Russin J, et al. Neurosurgery. 2014 Jul;75(1):E96-7. doi: 10.1227/NEU.0000000000000357. Neurosurgery. 2014. PMID: 24670633 No abstract available.
[Cerebral arteriovenous malformations: Results of the ARUBA study].
Weber MA. Weber MA. Radiologe. 2014 May;54(5):422-4. doi: 10.1007/s00117-014-2675-x. Radiologe. 2014. PMID: 24692012 German. No abstract available.
The ARUBA study: what is the evidence?
Grasso G. Grasso G. World Neurosurg. 2014 Sep-Oct;82(3-4):e576. doi: 10.1016/j.wneu.2014.04.057. Epub 2014 Apr 13. World Neurosurg. 2014. PMID: 24727184 No abstract available.
Management of brain arteriovenous malformations.
Warlow C. Warlow C. Lancet. 2014 May 10;383(9929):1632-1633. doi: 10.1016/S0140-6736(14)60781-9. Lancet. 2014. PMID: 24814449 No abstract available.
Management of brain arteriovenous malformations.
Al-Shahi Salman R. Al-Shahi Salman R. Lancet. 2014 May 10;383(9929):1633-1634. doi: 10.1016/S0140-6736(14)60782-0. Lancet. 2014. PMID: 24814450 No abstract available.
Management of brain arteriovenous malformations.
Solomon RA, Connolly ES Jr. Solomon RA, et al. Lancet. 2014 May 10;383(9929):1634. doi: 10.1016/S0140-6736(14)60783-2. Lancet. 2014. PMID: 24814451 No abstract available.
Management of brain arteriovenous malformations.
Lawton MT, Abla AA. Lawton MT, et al. Lancet. 2014 May 10;383(9929):1634-1635. doi: 10.1016/S0140-6736(14)60784-4. Lancet. 2014. PMID: 24814452 No abstract available.
Management of brain arteriovenous malformations.
Gross BA, Scott RM, Smith ER. Gross BA, et al. Lancet. 2014 May 10;383(9929):1635. doi: 10.1016/S0140-6736(14)60785-6. Lancet. 2014. PMID: 24814453 No abstract available.
Management of brain arteriovenous malformations--authors' reply.
Stapf C, Parides MK, Moskowitz AJ, Mohr JP. Stapf C, et al. Lancet. 2014 May 10;383(9929):1635-1636. doi: 10.1016/S0140-6736(14)60786-8. Lancet. 2014. PMID: 24814454 No abstract available.
On apples, oranges, and ARUBA.
Meling TR, Proust F, Gruber A, Niemela M, Regli L, Roche PH, Vajkoczy P. Meling TR, et al. Acta Neurochir (Wien). 2014 Sep;156(9):1775-9. doi: 10.1007/s00701-014-2140-7. Epub 2014 Jun 3. Acta Neurochir (Wien). 2014. PMID: 24890935 No abstract available.
Conservative management or intervention for unruptured brain arteriovenous malformations.
Starke RM, Sheehan JP, Ding D, Liu KC, Kondziolka D, Crowley RW, Lunsford LD, Kassell NF. Starke RM, et al. World Neurosurg. 2014 Nov;82(5):e668-9. doi: 10.1016/j.wneu.2014.07.001. Epub 2014 Jul 15. World Neurosurg. 2014. PMID: 25053376 No abstract available.
Management of Unruptured AVMs: The Pendulum Swings.
Chan MD, Soltys SG, Halasz LM, Laack NN, Minniti G, Kirkpatrick JP. Chan MD, et al. Int J Radiat Oncol Biol Phys. 2019 Nov 15;105(4):687-689. doi: 10.1016/j.ijrobp.2019.08.026. Int J Radiat Oncol Biol Phys. 2019. PMID: 31655651 No abstract available.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous