Hull Down on the Horizon
2012; Lippincott Williams & Wilkins; Volume: 43; Issue: 7 Linguagem: Inglês
10.1161/strokeaha.112.653584
ISSN1524-4628
AutoresJ.P. Mohr, Alan J. Moskowitz, Michael K. Parides, Christian Stapf, William L. Young,
Tópico(s)Moyamoya disease diagnosis and treatment
ResumoHomeStrokeVol. 43, No. 7Hull Down on the Horizon Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessEditorialPDF/EPUBHull Down on the HorizonA Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) Trial J.P. Mohr, MD, MS, Alan J. Moskowitz, MD, Michael Parides, PhD, Christian Stapf, MD and William L. Young, MD J.P. MohrJ.P. Mohr From the Doris & Stanley Tananbaum Stroke Center (J.P.M.), New York Neurological Institute, Columbia University Medical Center, New York, NY; the International Center for Health Outcomes and Innovation Research (InCHOIR; A.J.M., M.P.), Mt Sinai Medical Center, New York, NY; the Department of Neurology (C.S.), Hôpital Lariboisière, Paris France; and the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology (W.L.Y.), University of California, San Francisco, San Francisco, CA. , Alan J. MoskowitzAlan J. Moskowitz From the Doris & Stanley Tananbaum Stroke Center (J.P.M.), New York Neurological Institute, Columbia University Medical Center, New York, NY; the International Center for Health Outcomes and Innovation Research (InCHOIR; A.J.M., M.P.), Mt Sinai Medical Center, New York, NY; the Department of Neurology (C.S.), Hôpital Lariboisière, Paris France; and the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology (W.L.Y.), University of California, San Francisco, San Francisco, CA. , Michael ParidesMichael Parides From the Doris & Stanley Tananbaum Stroke Center (J.P.M.), New York Neurological Institute, Columbia University Medical Center, New York, NY; the International Center for Health Outcomes and Innovation Research (InCHOIR; A.J.M., M.P.), Mt Sinai Medical Center, New York, NY; the Department of Neurology (C.S.), Hôpital Lariboisière, Paris France; and the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology (W.L.Y.), University of California, San Francisco, San Francisco, CA. , Christian StapfChristian Stapf From the Doris & Stanley Tananbaum Stroke Center (J.P.M.), New York Neurological Institute, Columbia University Medical Center, New York, NY; the International Center for Health Outcomes and Innovation Research (InCHOIR; A.J.M., M.P.), Mt Sinai Medical Center, New York, NY; the Department of Neurology (C.S.), Hôpital Lariboisière, Paris France; and the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology (W.L.Y.), University of California, San Francisco, San Francisco, CA. and William L. YoungWilliam L. Young From the Doris & Stanley Tananbaum Stroke Center (J.P.M.), New York Neurological Institute, Columbia University Medical Center, New York, NY; the International Center for Health Outcomes and Innovation Research (InCHOIR; A.J.M., M.P.), Mt Sinai Medical Center, New York, NY; the Department of Neurology (C.S.), Hôpital Lariboisière, Paris France; and the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology (W.L.Y.), University of California, San Francisco, San Francisco, CA. Originally published5 Jun 2012https://doi.org/10.1161/STROKEAHA.112.653584Stroke. 2012;43:1744–1745Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 See related article, pages 1979.We welcome this opportunity to clarify puzzling misunderstandings concerning our study, A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA).Readers unfamiliar with the trial, seeking a status report, or wishing clarification of points made by Cockroft et al1 are referred to www.Clinicaltrials.gov, www.ARUBAstudy.org, and updated publications,2 editorial page limits preventing many references being cited. ARUBA is the first objective comparison of outcomes for immediate intervention against those of natural history for brain arteriovenous malformations (bAVMs) discovered unbled and deemed suitable for attempted eradication.3 The major outcomes include the rates of death, hemorrhage, and clinical status (measured by the modified Rankin Scale and EuroQol quality-of-life scales). Documentation of each case involves >20 forms for demographics, clinical status, imaging, medical and surgical risk factors, and quality-of-life estimates. Patients randomized to intervention may be treated by surgery, endovascular embolization, and/or radiosurgery as elected by the treating physician and patient; those in the natural history arm are followed without intervention but once a stroke or hemorrhage occurs may receive intervention(s) chosen by the treating team. All patients will be followed for a minimum of 5 years (see subsequently). Outcomes are adjudicated by an independent panel of 4 distinguished academic community members (neurology, interventional neuroradiology, neurosurgery, and radiosurgery). An independent safety officer monitors the trial and reports any concerns to the National Institute of Neurological Disorders and Stroke-appointed independent Data and Safety Monitoring Board. The protocol, which was developed with contributions from neurologists/surgeons/radiologists/interventionalists, was approved by 2 separate National Institute of Neurological Disorders and Stroke study sections as well as a second level of review by National Institute of Neurological Disorders and Stroke council; ARUBA was funded January 2006 and began randomizations in April 2007. National Institutes of Health trials being funded in maximum 5-year segments, ARUBA will seek continuation funding through a submission planned for July 2012.Current publications reflect the remarkable range of options for attempted lesion eradication. Intervention appears thoroughly justified for those having bled given the early hemorrhage recurrence rate. Because bAVMs are embedded in the brain, efforts at eradication need to be balanced against knowledge of the natural history for those unbled. The literature still has limited information for the severity of hemorrhage,4 and for outcomes from intervention. Multispecialty publications offer no formalized intervention plan based on broad consensus.5We wish to correct the misunderstandings promulgated by Cockroft et al.Center qualifications were established during protocol formulation. Polled multispecialty team members agreed that participating investigators must manage at least 10 bAVMs per year. The application includes individual curriculum vitae, including related publications.Noninvasive imaging for identification of the unbled bAVMs was allowed to avoid requiring diagnostic procedures with potential harm. However, eligibility was established by formal angiography in all but 3 of the 193 randomized through March 2012.Center size varies for all prospective, randomized controlled trials, ARUBA included. Despite claims by Cockroft et al, outcome quality has not uniformly been influenced by center size in other large trials.6 ARUBA started with participation agreements from 17 local New York area centers, 37 other US, 5 Australian, 6 Canadian, 1 Brazilian, and 39 European. Many American centers began randomizations and then withdrew, none citing issues with the protocol. Some applicants, from the United States, Europe, and elsewhere, have failed to qualify. Sixty-five centers are currently in contract on 5 continents and an additional 33 centers are enmeshed in application paperwork. As an example, the University of California, San Francisco randomized 4 patients early in the trial and has reported 91 ARUBA-eligibles since the study began in 2007. (The 50 per year cited by Cockroft et al is incorrect and likely represents an estimate of their average annual cohort, bled or not, suitable for intervention or not; ie, many not eligible for randomization in ARUBA.) Contrary to the prediction by Cockroft et al favoring randomization of contentious cases, ARUBA's published demographics2 show a balanced distribution of Spetzler-Martin grades: I, 29.7%; II, 29.7%; III, 29.7%; IV, 10.8%; and V, 0%. Natural history outcomes are not related to center size or inferred interventional management skills.The decision to fund the trial was based in part on evidence by peer review of "community equipoise." "Individual equipoise" reflects the voluntary participation by the patient and treating team, which influences the rate of randomizations. No trial demands or is likely ever to randomize all potentially eligible patients. A consistent offer of the trial is expected, and ideally, the recording of the outcomes for those eligible but not randomized. Few trials attempt a registry arm; for ARUBA, such calls—to ensure complete case outcome data—yielded 1 available since the start of the trial; no cases have been reported. Some ARUBA participants excepted,4,7 registry data before and since ARUBA began have not distinguished outcomes for those bled from unbled nor those ARUBA-eligible. No data are cited by Cockroft et al. Screening reports (logs) for eligibility are voluntarily filed by many ARUBA centers. Accordingly, we do not understand claims by Cockroft et al of "… a lack of screening logs …," this especially when they cite 124 randomized among "… over 900 screened." As of April 2012, 193 patients have been randomized of 1294 reported screened. Only 389 of those reported were actually ARUBA-eligible.Speculations from Cockroft et al for the reasons for changes in sample size are completely unfounded. The study design model is based on an occurrence of a certain number of events overall. Typical of any surgical trial, any procedure-related morbidity and mortality occurs early. The slow enrollment in ARUBA, evident by 2010, necessarily extended the planned time for follow-up, including that for more natural history events. The expected outcomes prompted the Data and Safety Monitoring Board to conclude that an adequate number of events could be achieved with half the originally planned sample size with minimal effect on study power.2 This decision did not involve the clinical investigators, who are completely blinded to all outcome data. We believe that it is critical that both cohorts be followed for a period of time for a sufficient number of outcome events to occur—necessitating additional funding cycles—and for whatever degree of postintervention clinical disturbances to undergo improvements.8 Proposals for a trial of ≥20 years9 must assume both the low pretrial annual estimates for unbled bAVMs of 0.9%10 to 1.2711 and that no medical therapy would develop. The former "natural history" 4.2% annual hemorrhage rates12 applied to a population the majority of whom had already bled and were not treated.13 Should anything like these higher rates apply to ARUBA, the trial should end soon in favor of intervention, this assuming the low morbidity for intervention inferred by Cockroft et al, albeit nowhere published. Meanwhile, medical therapy has had proof of principal for arteriovenous malformations in other organs14; might trials for bAVMs unsuitable for current intervention be in our future?Although we agree that "[P]RCT(s) … cannot answer all the questions in clinical medicine," ARUBA was developed specifically to address the problem of selection bias, an issue that has plagued interpretation of the many natural history and cohort studies.15 In contrast to the situation in the United States, there has been little controversy and higher participation rates from investigators in other countries, thus assuring appropriate representativeness of the cohort. Participation by more centers, including those of the authors, should they qualify, would ensure an ever-larger and more representative database. Effective medical decision-making—and reimbursement policies—increasingly depends on "evidence-based" rather than "eminence-based" guidelines.16,17Sebastian Junger's "Perfect Storm" describes the unhappy fate of a Gloucester, MA, fishing crew willfully ignoring the warnings of a major storm. If we in the practice of medicine and health services impede rational, systematic inquiry, and open, critical discourse—even if unintentionally—then we are indeed headed for the worst sort of storm.We welcome continued dialogue on the trial.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to J.P. Mohr, MD, MS, Director of Doris & Stanley Tananbaum Stroke Center, New York Neurological Institute, 710 W 168th Street, New York, NY 10032-2603. E-mail [email protected]cumc.columbia.eduReferences1. Cockroft KM. Perfect storm. Stroke. 2012; 43: 1979– 1981.LinkGoogle Scholar2. Mohr JP, Moskowitz AJ, Stapf C, Hartmann A, Lord K, Marshall SM , et al. The ARUBA trial: current status, future hopes. Stroke. 2010; 41: e537– e540.LinkGoogle Scholar3. Ross J, Al-Shahi Salman R. Interventions for treating brain arteriovenous malformations in adults. Cochrane Database Syst Rev. 2010; 7: CD003436.Google Scholar4. Choi JH, Mast H, Sciacca RR, Hartmann A, Khaw AV, Mohr JP , et al. Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation. Stroke. 2006; 37: 1243– 1247.LinkGoogle Scholar5. Ogilvy CS, Stieg PE, Awad I, Brown RD, Kondziolka D, Rosenwasser R , et al. AHA scientific statement: recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke. 2001; 32: 1458– 1471.LinkGoogle Scholar6. Barnett HJ, Peerless SJ, McCormick CW. In answer to the question: 'as compared to what?' A progress report on the EC/IC bypass study. Stroke. 1980; 11: 137– 140.LinkGoogle Scholar7. Wedderburn CJ, van Beijnum J, Bhattacharya JJ, Counsell CE, Papanastassiou V, Ritchie V , et al. Outcome after interventional or conservative management of unruptured brain arteriovenous malformations: a prospective, population-based cohort study. Lancet Neurol. 2008; 7: 223– 230.CrossrefMedlineGoogle Scholar8. Marshall RS, Zarahn E, Alon L, Minzer B, Lazar RM, Krakauer JW. Early imaging correlates of subsequent motor recovery after stroke. Ann Neurol. 2009; 65: 596– 602.CrossrefMedlineGoogle Scholar9. Cockroft KM. Unruptured brain arteriovenous malformations should be treated conservatively: no. Stroke. 2007; 38: 3310– 3311.LinkGoogle Scholar10. Stapf C, Mast H, Sciacca RR, Choi JH, Khaw AV, Connolly ES , et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006; 66: 1350– 1355.CrossrefMedlineGoogle Scholar11. Kim H, McCulloch CE, Johnston SC, Lawton MT, Sidney S, Young WL. Comparison of 2 approaches for determining the natural history risk of brain arteriovenous malformation rupture. Am J Epidemiol. 2010; 171: 1317– 1322.CrossrefMedlineGoogle Scholar12. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg. 1990; 73: 387– 391.CrossrefMedlineGoogle Scholar13. Hernesniemi JA, Dashti R, Juvela S, Vaart K, Niemela M, Laakso A. Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery. 2008; 63: 823– 829; discussion 829–831.CrossrefMedlineGoogle Scholar14. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E , et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012; 307: 948– 955.CrossrefMedlineGoogle Scholar15. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000; 342: 1887– 1892.CrossrefMedlineGoogle Scholar16. Berman MF, Hartmann A, Mast H, Sciacca RR, Mohr JP, Pile-Spellman J , et al. Determinants of resource utilization in the treatment of brain arteriovenous malformations. AJNR Am J Neuroradiol. 1999; 20: 2004– 2008.MedlineGoogle Scholar17. Fiehler J, Stapf C. ARUBA—beating natural history in unruptured brain AVMs by intervention. Neuroradiology. 2008; 50: 465– 467.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByVolovici V, Schouten J, Vajkoczy P, Dammers R and Meling T (2021) Unruptured Arteriovenous Malformations, Stroke, 52:3, (1143-1146), Online publication date: 1-Mar-2021. Pan P, Shaligram S, Do Prado L, He L and Su H (2021) The role of mural cells in hemorrhage of brain arteriovenous malformation, Brain Hemorrhages, 10.1016/j.hest.2020.10.005, 2:1, (49-56), Online publication date: 1-Mar-2021. Sai Kiran N, Vidyasagar K, Raj V, Sivaraju L, Srinivasa R, Mohan D and Hegde A (2020) Microsurgery for Spetzler-Martin Grade I–III Arteriovenous Malformations: Analysis of Surgical Results and Correlation of Lawton-Young Supplementary Grade and Supplemented Spetzler-Martin Score with Functional Outcome, World Neurosurgery, 10.1016/j.wneu.2020.08.101, 144, (e227-e236), Online publication date: 1-Dec-2020. de Castro-Afonso L, Vanzim J, Trivelato F, Rezende M, Ulhôa A, Chodraui-Filho S, de Abreu Mattos L, Mounayer C, Nakiri G, Colli B and Abud D (2020) Association between draining vein diameters and intracranial arteriovenous malformation hemorrhage: a multicentric retrospective study, Neuroradiology, 10.1007/s00234-020-02484-y, 62:11, (1497-1505), Online publication date: 1-Nov-2020. Cheng P, Ma L, Shaligram S, Walker E, Yang S, Tang C, Zhu W, Zhan L, Li Q, Zhu X, Lawton M and Su H Effect of elevation of vascular endothelial growth factor level on exacerbation of hemorrhage in mouse brain arteriovenous malformation, Journal of Neurosurgery, 10.3171/2019.1.JNS183112, 132:5, (1566-1573) Qureshi A, Saeed O, Sahito S, Lobanova I, Liaqat J, Siddiq F and Gomez C (2020) Treatment Outcomes of Endovascular Embolization Only in Patients with Unruptured Brain Arteriovenous Malformations: A Subgroup Analysis of ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations), American Journal of Neuroradiology, 10.3174/ajnr.A6443, 41:4, (676-680), Online publication date: 1-Apr-2020. 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Mohr J, Kejda-Scharler J and Pile-Spellman J (2013) Diagnosis and Treatment of Arteriovenous Malformations, Current Neurology and Neuroscience Reports, 10.1007/s11910-012-0324-1, 13:2, Online publication date: 1-Feb-2013. Fountain N (2013) Obliterating the Seizure Focus in AVMs is Effective: More Clinical Data Confirming Common Sense, Epilepsy Currents, 10.5698/1535-7511-13.1.9, 13:1, (9-10), Online publication date: 1-Jan-2013. July 2012Vol 43, Issue 7 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.112.653584PMID: 22669405 Originally publishedJune 5, 2012 KeywordsAVMtreatmentarteriovenous malformationsclinical trialsPDF download Advertisement
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