A Randomized Trial of Unruptured Brain Arteriovenous Malformations
Starke, Robert M.; Komotar, Ricardo J.; Connolly, E. Sander
Although brain arteriovenous malformations (AVM) are relatively unknown with an incidence of 1.12 to 1.34 per 100,000 person years, AVMs are the primary cause of intracerebral hemorrhage (ICH) in young adults.1 Hemorrhage is the most common presentation occurring in 50% of patients, but seizure and focal neurological deficits are not uncommon.1,6 With the increases in routine imaging and improvements in non-invasive diagnostic studies, there has been an increase in the diagnosis of incidental AVMs.
Surgical therapy may be necessary in patients with intracerebral hemorrhage resulting in significant mass effect, but in patients with unruptured AVMs the best treatment is unclear. Prospective assessment of all AVM patients has found that unruptured AVMs are more frequent, occurring twice as frequently as ruptured AVMs.12 In patients with incidental AVMs, the benefits of treatment, the best therapeutic modality, the risk of hemorrhage, and the overall long-term outcome following both treatment and hemorrhage are controversial. Many potential biases can confound these outcome studies including selection bias, treatment bias, and incomplete follow-up.
Assessment of AVMs as a homogenous group reveals an annual risk of hemorrhage of approximately 2 to 4% per year with a lifetime risk between 17 to 90%.10 Despite these general calculations, AVMs are not homogenous lesions and the annual risk of hemorrhage may vary significantly based on patient and AVM characteristics.13 Additionally, prior studies found that hemorrhage was associated with a 10 to 30% risk of mortality and 30 to 50% morbidity rate,10 but other studies have argued that these rates may be overestimated.3 A number of prospective population studies including the New York Islands Project, Olmsted County Minnesota Study, and the Scottish Intracranial Vascular Malformation Study (SIVMS) have attempted to clarify these outcomes, but large, long-term studies are lacking.
The functional outcomes and obliteration rates following treatment of AVMs also vary significantly between reported studies and according to specific AVM characteristics. Generally, surgical mortality of approximately 3% and a permanent morbidity of 9%,5 embolization related complications of roughly 10%,4 and morbidity after radiosurgery of approximately 10%11 have been reported. Until recently there have been no randomized controlled trials of observation vs therapy for AVMs.
Recently, the results of A Randomized Trial of Unruptured Brain AVMs (ARUBA) were announced at the American Heart Association annual European meeting.14 This study sought to assess the outcomes of patients with AVMs following best medical therapy vs any of the above therapeutic modalities. The original plan was to randomize 800 patients with unruptured brain AVMs that were deemed suitable for attempted eradication to medical therapy or intervention in a 1:1 fashion, and this was subsequently revised to 400 after interim analysis. The primary outcome was the composite measure of death from any cause or stroke and secondary analysis included overall functional outcome and quality of life. Possible treatment options were dictated locally and included endovascular, surgical, and/or radiation therapy. The study was dampened by difficulty with patient enrollment with each site enrolling 1 to 2 patients per year and only 20 to 40 new patients added each year.8
Patient demographics were similar across those receiving medical therapy and intervention with a mean age of 44 years and 41% were female. Seizure occurred in 43%, focal neurological deficit in 14%, and 42% were asymptomatic. Smaller AVMs were more likely in the interventional arm, but deep venous drainage and eloquent location were similar between groups. Randomization assignment and treatment received were similar; 51% of patients were randomized to interventional therapy and 46.5% received interventional therapy.
The study was stopped prematurely by the data safety monitoring board with a mean follow up of approximately 33 months after enrollment of 223 patients. The primary outcome was observed in 11 patients randomized to medical management (10%) and 33 patients randomized to interventional therapy (29%). Mortality was similar between groups occurring in 2 patients randomized to medical management and 3 patients randomized to interventional therapy. Breakdown of AVMs by Spetzler Martin grade demonstrates roughly similar outcomes in Spetzler Martin grade I and II lesions, but significantly worse outcomes in grade III and IV lesions undergoing intervention. Intention to treat analysis demonstrates worse overall functional outcomes in those receiving interventional treatment.
Although the trial provides some information regarding the natural history of observation for AVMs and the risks of intervention, the study is limited by the short follow up period. Additionally, the study is not powered to evaluate the treatment effect by an individual modality. The precise risk according to patient and AVM characteristics is also impossible to quantify given the sample size. We also have very limited information from trial sites on the results of concurrently managed patients who were not randomized.
Over the past 15 years, there has been a movement away from treatment of Spetzler Martin grade 4 and 5 AVMs as treatment of these lesions is widely recognized as being associated with significant risk. As the outcomes of treated patients with Spetzler Martin grade III and IV AVMs appears to have had a major effect on the initial outcome measures in the ARUBA trial, long term follow up is especially needed in this group to demonstrate whether the significant upfront risk following intervention was worth it. That said, high-grade lesions are a heterogeneous group and risks associated with treatment have historically varied significantly. In grade III AVMs surgical morbidity rates can vary from less than 5% in patients with large size to greater than 25% in patients with medium sized AVMs with eloquent or deep location.2,7,9 Similar variability has been reported with regard to the risks of embolization and gamma knife depending on a variety of lesion and patient specific parameters.15,17 To complicate matters further, expertise with one or all of these treatment modalities may vary considerably from center to center making interpretation of results from even multi-centered trials a tricky business at best. Finally, a significant number of deficits that occur following either hemorrhage or intervention will resolve either partially or completely.15-17 The ARUBA study has plans to follow the current cohort for an additional 5 years, but it will be important to pay attention to not only the rate of stroke, but also to the functional significance of the various strokes. It may be that 5 years is long enough follow-up for some AVM patients to ascertain utility, but not long enough for others. Whatever the case the ARUBA data underscores the fact that the question moving forward is not whether patients with unruptured AVMs should receive intervention, but rather which patients should receive treatment. Current literature and the ARUBA trial unfortunately cannot answer this latter question definitively, but will hopefully establish a platform for further studies and discussion of current equipoise.
1. Brown RD Jr, Wiebers DO, Torner JC, O'Fallon WM. Incidence and prevalence of intracranial vascular malformations in Olmsted County, Minnesota, 1965 to 1992. Neurology. 1996;46(4):949–952.
2. de Oliveira E, Tedeschi H, Raso J. Comprehensive management of arteriovenous malformations. Neurol Res. 1998;20(8):673–683.
3. Hartmann A, Mast H, Mohr JP, et al.. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke. 1998;29(5):931–934.
4. Hartmann A, Mast H, Mohr JP, et al.. Determinants of staged endovascular and surgical treatment outcome of brain arteriovenous malformations. Stroke. 2005;36(11):2431–2435.
5. Hartmann A, Stapf C, Hofmeister C, et al.. Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke. 2000;31(10):2361–2364.
6. Hofmeister C, Stapf C, Hartmann A, et al.. Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformation. Stroke. 2000;31(6):1307–1310.
7. Lawton MT. Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery. 2003;52(4):740–749.
8. Mohr JP, Moskowitz AJ, Parides M, Stapf C, Young WL. Hull down on the horizon: a Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial. Stroke. 2007;43(7):1744–1745.
9. Morgan MK, Drummond KJ, Grinnell V, Sorby W. Surgery for cerebral arteriovenous malformation: risks related to lenticulostriate arterial supply. J Neurosurg. 1997;86(5):801–805.
10. Ogilvy CS, Stieg PE, Awad I, 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.
11. Pollock BE, Brown RDJ. Use of the Modified Rankin Scale to assess outcome after arteriovenous malformation radiosurgery. Neurology. 2006;67(9):1630–1634.
12. Stapf C, Mast H, Sciacca RR, et al.. The New York Islands AVM Study: design, study progress, and initial results. Stroke. 2003;34(5):e29–33.
13. Stapf C, Mast H, Sciacca RR, et al.. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):1350–1355.
14. Stapf C, Moskowitz AJ, Parides MK, et al.. Abstract 189: ARUBA—a Randomised trial of Untruptured brains AVMs. Stroke. 2013;44:A189.
15. Starke RM, Ding D, Yen CP, Sheehan JP. A practical scale to predict radiosurgery outcome in arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg. in press 2013.
16. Starke RM, Komotar RJ, Hwang BY, et al.. Treatment guidelines for cerebral arteriovenous malformation microsurgery. Br J Neurosurg. 2009;23(4):376–386.
17. Starke RM, Komotar RJ, Otten ML, et al.. Adjuvant embolization with N-butyl Cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. stroke. 2009;40:2783–2790.
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