RESEARCH—HUMAN—CLINICAL STUDIES RESEARCH—HUMAN—CLINICAL STUDIES John D. Nerva, MD* Alessandra Mantovani, MD* Jason Barber, MS* Louis J. Kim, MD*‡ Jason K. Rockhill, MD, PhD*§ Danial K. Hallam, MD*‡ Basavaraj V. Ghodke, MD*‡

Treatment Outcomes of Unruptured Arteriovenous Malformations With a Subgroup Analysis of ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Patients

Laligam N. Sekhar, MD*‡ *Department of Neurological Surgery, ‡Radiology, and §Radiation Oncology, University of Washington, Seattle, Washington Correspondence: Laligam N. Sekhar, MD, FAANS, FACS, Vice Chairman, William Joseph Leedom and Bennett Bigelow Professor, Director, Cerebrovascular Surgery, Director, Skull Base Surgery, Department of Neurological Surgery, University of Washington, Harborview Medical Center, 325 9th Ave, Box 359924, Seattle, WA 98104. E-mail: [email protected] Received, September 4, 2014. Accepted, December 14, 2014. Published Online, January 29, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.

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BACKGROUND: The design and conclusions of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial are controversial, and its structure limits analysis of patients who could potentially benefit from treatment. OBJECTIVE: To analyze the results of a consecutive series of patients with unruptured brain arteriovenous malformations (BAVMs), including a subgroup analysis of ARUBAeligible patients. METHODS: One hundred five patients with unruptured BAVMs were treated over an 8-year period. From this series, 90 adult patients and a subgroup of 61 patients determined to be ARUBA eligible were retrospectively reviewed. A subgroup analysis for Spetzler-Martin grades I/II, III, and IV/V was performed. The modified Rankin Scale was used to assess functional outcome. RESULTS: Persistent deficits, modified Rankin Scale score deterioration, and impaired functional outcome occurred less frequently in ARUBA-eligible grade I/II patients compared with grade III to V patients combined (P = .04, P = .04, P = .03, respectively). Twenty-two of 39 patients (56%) unruptured grade I and II BAVMs were treated with surgery without and with preoperative embolization, and all had a modified Rankin Scale score of 0 to 1 at the last follow-up. All patients treated with surgery without and with preoperative embolization had radiographic cure at the last follow-up. CONCLUSION: The results of ARUBA-eligible and unruptured grade I/II patients overall show that excellent outcomes can be obtained in this subgroup of patients, especially with surgical management. Functional outcomes for ARUBA-eligible patients were similar to those of patients who were randomized to medical management in ARUBA. On the basis of these data, in appropriately selected patients, we recommend treatment for low-grade BAVMs. KEY WORDS: Arteriovenous malformation, Clinical outcome, Endovascular embolization, Microsurgical resection, Stereotactic radiosurgery Neurosurgery 76:563–570, 2015

U

DOI: 10.1227/NEU.0000000000000663

nruptured brain arteriovenous malformations (BAVMs) are lesions that carry a lifelong risk of neurological disability

ABBREVIATIONS: ARUBA, A Randomized Trial of Unruptured Brain Arteriovenous Malformations; BAVM, brain arteriovenous malformation; mRS, modified Rankin Scale; SAIVMs, Scottish Audit of Intracranial Vascular Malformations Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.neurosurgery-online.com).

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and death. The basic tenet behind offering treatment is that the natural history of an unruptured BAVM is worse than a treated BAVM. Treatment in the form of microsurgical resection, endovascular embolization, radiosurgery, or combinations thereof is aimed at eliminating the risk of hemorrhage or improving symptoms such as seizures, headache, or other neurological deficits. Not surprisingly, the treatments pose several risks, including lack of cure, morbidity, and mortality, which are often dependent on the anatomy and treatment modality of the BAVMs. Controversy exists over which unruptured

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NERVA ET AL

BAVMs to treat, which treatment to use, or whether treatment beyond medical management is warranted at all. A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) showed that medical management alone was superior to interventional therapy for the prevention of the primary outcome, death resulting from any cause, or symptomatic stroke at the 33-month follow-up.1 ARUBA also found significantly lower rates of impaired functional outcome in patients medically managed alone.1 On the surface, the trial and these results call into question the merits of treatment and have sparked a heated debate regarding the management of unruptured BAVMs.2-13 Major criticisms include the randomization in ARUBA of BAVMs regardless of grade, relatively limited follow-up in a lifelong disease process, treatment modalities, and lack of external validity.4-10 The definition of stroke has also been questioned and may limit analysis of the primary end point.9 A recent survey indicates there are considerable differences in opinion regarding which patient or BAVM features warrant treatment, observation, or enrollment in a trial.6 BAVMs are as anatomically and physiologically heterogeneous as the patients who harbor them and the management decisions of clinicians who treat them. The question remains: Given all these factors, which patients could potentially benefit from treatment? The purpose of this retrospective study was to review the clinical and radiographic outcomes from a single-center experience with unruptured BAVMs and ARUBA-eligible patients.

inclusion and exclusion criteria were used to define the ARUBAeligible group.1 Inclusion criteria were presence of an unruptured BAVM and age of at least 18 years. All exclusion criteria were applied to patients without a history of rupture and the breakdown to determine ARUBA-eligible status. Sixty-one of 90 patients were found to be ARUBA eligible. Data from the unruptured BAVM cohort were also analyzed in this study, and results from this comprehensive cohort are summarized with detailed analysis included as Supplemental Digital Content. The patient list was developed from analysis of diagnosis and treatment coding data. The database was constructed from a retrospective review of the electronic medical record. Data were obtained for and organized by clinical presentation, BAVM characteristics, management strategy, complications, clinical outcome, and radiographic obliteration. Data were evaluated and analyzed retrospectively by 2 physicians who were not directly involved in the treatment of patients (J.D.N. and A.M.). The Spetzler-Martin scale and 3-tiered grouping (grades I and II combined, grade III, and grades IV and V combined) were used to grade and analyze BAVMs.14,15 Grades I and II were combined, as were grades IV and V, referred to here as grade I/II and grade IV/V, respectively, for purposes of statistical analysis. Deep location was defined as any involvement of the basal ganglia, insula, or thalamus.

METHODS

Embolization

This retrospective study was approved by the University of Washington Institutional Review Board Human Subjects Division. At our institution, 105 consecutive patients with unruptured brain BAVMs were treated from 2005 to 2012 (Figure); 90 patients were at least 18 years old at presentation and were retrospectively reviewed. ARUBA

BAVM embolization was conducted before surgical resection or stereotactic radiosurgery and not to achieve radiographic cure. Four patients underwent embolization as the only modality of treatment, 3 of those patients for palliative treatment of high-risk features. The goals of BAVM embolization were primarily volume reduction and elimination of high-risk features such as arterial supply difficult to access surgically and intranidal aneurysms. All BAVMs undergoing endovascular embolization were treated with Onyx (ev3 Neurovascular, Irvine, California) using a treatment strategy described previously.16 Coil embolization was performed as indicated for BAVM-associated aneurysms. All procedures were performed under general anesthesia. After embolization, all patients underwent head computed tomographic (CT) imaging and were admitted to the neurosurgical intensive care unit for blood pressure management (,120 mm Hg systolic for 24 hours in most cases) and neurological monitoring. In most patients, the treating neurosurgeon was present during or performed the embolization. Larger BAVMs were embolized in a staged fashion, with at least a 2-week interval between the stages to reduce the risk of normal perfusion pressure breakthrough.

Treatments Management decisions were made by a multidisciplinary team of neurological surgeons with cerebrovascular expertise (L.J.K., L.N.S.), interventional neuroradiologists (D.K.H., B.V.G.), and radiation oncologists (J.K.R.). When there was equipoise between surgical resection and radiosurgery, the treatment decision was made by the primary treating surgeon.

Surgery FIGURE. Breakdown of exclusion criteria for 105 patients with unruptured brain arteriovenous malformations. ARUBA, A Randomized Trial of Unruptured Brain Arteriovenous Malformations; mRS, modified Rankin Scale.

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Microsurgical resection was performed with stereotactic localization, neurophysiological monitoring, and indocyanine green or intraoperative cerebral angiography. The technique of microsurgical resection included adequate exposure of the nidus and vasculature, circumferential occlusion of arterial feeders for isolation of the nidus, use of temporary clips to cease

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TREATMENT OUTCOMES OF ARUBA-ELIGIBLE PATIENTS

flow through perforating arteries before coagulation, and occlusion of the major draining vein only after arterial supply had been removed. After surgery, all patients underwent head CT imaging and were admitted to the neurosurgical intensive care unit for blood pressure management (,120 mm Hg systolic for 24 hours in most cases) and neurological monitoring. Diagnostic cerebral angiography was performed on the same or the following day to confirm obliteration. No patient underwent planned staged surgery; 1 patient underwent additional surgery for residual BAVM identified on postoperative angiography. All patients with followup had cerebral angiography to confirm obliteration at 6 to 12 months after surgery.

Stereotactic Radiosurgery Radiosurgical treatment was performed on an outpatient basis with the Gamma Knife (Elekta, Stockholm, Sweden). Treatment targets were delineated on CT angiography, magnetic resonance angiography, or diagnostic cerebral angiography obtained on the day of treatment. Followup magnetic resonance angiography was obtained at 6- to 12-month intervals as determined by the treating provider. Radiographic obliteration was diagnosed by CT angiography or magnetic resonance angiography at follow-up, and diagnostic cerebral angiography was used to confirm obliteration as indicated. Prospectively staged radiosurgery was used in 7 patients with larger BAVMs.

RESULTS Patient Characteristics and Treatment Modalities in ARUBA-Eligible Patients The baseline patient characteristics, BAVM characteristics, and treatment modalities of the 61 ARUBA-eligible patients are listed in Table 1. By Spetzler-Martin grade, 51% were grade I/II, 33% were grade III, and 16% were grade IV/V. All ARUBA-eligible patients completed treatment, and treatment modalities are listed in Table 1. Treatment modalities for ARUBA-eligible patients were compared with ARUBA data as published.1 Significantly more patients were treated with multimodality therapy compared with ARUBA as-treated patients (P , .001).

TABLE 1. Baseline Characteristics and Treatment Modalities for ARUBA-Eligible Patientsa Patient Characteristic

Clinical Outcome The modified Rankin Scale (mRS) was used to grade pretreatment and posttreatment clinical outcome. The mRS scores were obtained retrospectively from electronic medical records of clinical appointments with treating providers (neurological surgeons, radiation oncologists), neurologists, and physiatrists. Neurological deficits and clinical outcome were recorded regardless of imaging findings. Follow-up length was determined after the last treatment. A major complication was defined as any posttreatment hemorrhage, return to operating room, transient neurological deficit, persistent neurological deficit, and posttreatment mortality. Clinical documentation and timing of follow-up limited a detailed analysis of seizure and headache outcome. Posttreatment seizures were included as transient neurological deficits. Impaired functional outcome was defined as an mRS score $2 at the last follow-up to be consistent with ARUBA trial criteria. Analysis of impaired functional outcome defined as an mRS score $3 was also performed. Radiographic obliteration was defined as no evidence of residual BAVM on follow-up imaging.

Statistical Analysis IBM SPSS Statistics 19 was used for statistical analysis. Independentsamples t test and the Fisher exact test were used to test significance of association. A subgroup analysis was performed by grade (ie, grades I/II, III, and IV/V) and treatment modality. Grade I/II patients were compared with grade III to V patients. Treatment modalities were categorized by definitive method (ie, surgery with or without embolization; radiosurgery with or without embolization). Spetzler-Martin grades and treatment modalities were compared between ARUBA data (as published1) and ARUBA-eligible patients. Statistical significance was defined as a value of P ,.05, and there were no adjustments for multiple comparisons. For age and length of follow-up, a 2-sided t test was used to compare groups. All other comparisons between groups were performed with a 2-sided Fisher exact test.

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ARUBA Eligible

N Age, mean (SD), y Female, n (%) Clinical presentation, n (%) Seizure Headache Focal deficit Asymptomatic mRS score, n (%) 0 1 Spetzler-Martin grade, n (%) I II III IV V Maximum diameter, mean (SD), cm Eloquent location, n (%) Deep venous drainage, n (%) Location, n (%) Lobar Deep location Only deep location Cerebellum Brainstem Associated aneurysm, n (%) Treatment modality, n (%) Surgery alone Embolization alone Embolization and then surgery Radiosurgery alone Embolization and then radiosurgery All modalities

61 40 (15) 29 (48) 24 27 12 12

(39) (44) (20) (20)

29 (48) 32 (52) 6 (10) 25 (41) 20 (33) 7 (12) 3 (5) 2.9 (1.8) 42 (69) 25 (41) 54 5 3 4

(89) (8) (5) (7) 0 15 (25)

3 (5) 0 (0) 28 (46) 23 (38) 7 (12) 0 (0)

a

ARUBA, A Randomized Trial of Unruptured Brain Arteriovenous Malformations; mRS, modified Rankin Scale.

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Major Complications and Clinical Outcomes of ARUBA-Eligible Patients For ARUBA-eligible patients, there were no mortalities, and major complication rates were 9 of 31 (29%) for surgery, 6 of 35 (17%) for embolization, and 6 of 30 (20%) for radiosurgery. Overall outcomes by grade regardless of treatment modality are listed in Table 2 and detailed below. Persistent neurological deficits after treatment were found in 16% of patients overall, including 7% of grade I/II patients, 20% of grade III patients, and 40% of grade IV/V patients. Transient deficits occurred in 12% of patients (16% of grade I/II, 10% of grade III), and posttreatment hemorrhages without neurological deficit occurred in 5% of patients (all grade I/II). Mean follow-up was 2.1 years and similar across grades. For consistency with ARUBA, impaired functional outcome was defined as an mRS score $2. At the last follow-up, impaired functional outcome occurred in 3% of grade I/II patients, 25% of grade III patients, and 20% of grade IV/V patients. When mRS score of 0 to 2 is used to define good outcome and mRS score $3 as impaired outcome, 7% of patients (0% of grade I/II, 15% of grade III, and 10% of grade IV/V) had impaired outcome. Compared with grade III to V patients, fewer grade I/II patients had persistent neurological deficits (7% vs 27%; P = .04), worse mRS scores after treatment (13% vs 37%; P = .04), and last follow-up mRS score $2 (3% vs 23%; P = .03). Outcomes by treatment modality (ie, surgery without and with preoperative embolization; radiosurgery without and with preoperative embolization) are listed in Table 3 and detailed below. No patient underwent endovascular embolization as stand-alone therapy. Microsurgical Resection Without and With Preoperative Embolization Surgery without and with preoperative embolization was used to treat 31 of 61 patients (51%), including 19 of 31 grade I/II patients (61%), 9 of 20 grade III patients (45%), and 3 of 10 grade IV/V patients (30%; Table 3). Mean age was 38 years and similar across

the grades. Mean follow-up was 1.3 years and also similar across the grades. Major complications were observed in 32% of grade I/II, 56% of grade III, and 100% of grade IV/V patients. Persistent posttreatment neurological deficits were observed in 5% of grade I/II, 33% of grade III, and 100% of grade IV/V patients. At the last follow-up, 0% of grade I/II, 33% of grade III, and 33% of grade IV/V patients had mRS scores $2. All patients achieved radiographic cure. Grade I/II patients had lower rates of persistent deficits (5% vs 50%; P = .007), worse mRS scores after treatment (11% vs 58%; P = .01), and last follow-up mRS score $2 (0% vs 33%; P = .016) compared with grade III to V patients (Table 3). Stereotactic Radiosurgery Without and With Pretreatment Embolization Radiosurgery without and with pretreatment embolization was used to treat 30 of 61 patients (49%), including 12 of 31 grade I/II patients (39%), 11 of 20 grade III patients (55%), and 7 of 10 grade IV/V patients (70%; Table 3). Mean age was 41 years and similar across the groups. Mean follow-up was 2.9 years and similar across grades. Major complications were observed in 33% of grade I/II, 9% of grade III, and 14% of grade IV/V patients. Persistent posttreatment neurological deficits were observed in 8% of grade I/II, 9% of grade III, and 14% of grade IV/V patients. At the last follow-up, 8% of grade I/II, 18% of grade III, and 14% of grade IV/V patients had mRS scores $2. Radiographic cure in patients with at least 2 years of follow-up was achieved in 8 of 10 grade I/II patients (80%), 4 of 6 grade III patients (67%), and 1 of 4 grade IV/V patients (25%). There were no significant differences in clinical outcome in patients undergoing radiosurgery between grades I/II and grades III to V patients. Overall Results of Unruptured BAVMs The baseline patient characteristics, BAVM characteristics, and treatment modalities of all adult unruptured BAVMs (ARUBA eligible and ineligible) are listed in the Table, Supplemental Digital Content 1 (http://links.lww.com/NEU/A713). Ninety

TABLE 2. Major Complications and Clinical Outcome in ARUBA-Eligible Patientsa Overall n (%) Age, y, mean (SD) Major complication, n (%) Persistent deficit Transient deficit Hemorrhage without deficit Follow-up mRS Follow-up, mean (SD), y Worse mRS score after treatment, n (%) Last mRS score $ 2, n (%) Last mRS score $ 3, n (%) a

Grades I and II

Grade III

Grades IV and V

Grades III-V

Significance

61 40 (15) 20 (33) 10 (16) 7 (12) 3 (5)

31 39 10 2 5 3

(51) (15) (32) (7) (16) (10)

20 43 6 4 2 0

(33) (15) (30) (20) (10) (0)

10 36 4 4 0 0

(16) (16) (40) (40) (0) (0)

30 41 10 8 2 0

(39) (15) (33) (27) (7) (0)

.62 ..99 .04 .23 .24

2.1 (1.9) 15 (25) 8 (13) 4 (7)

1.9 4 1 0

(1.8) (13) (3) (0)

2.1 7 5 3

(2.2) (35) (25) (15)

2.6 4 2 1

(2.0) (40) (20) (10)

2.3 11 7 4

(2.1) (37) (23) (13)

.48 .04 .03 .05

ARUBA, A Randomized Trial of Unruptured Brain Arteriovenous Malformations; mRS, modified Rankin Scale.

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TREATMENT OUTCOMES OF ARUBA-ELIGIBLE PATIENTS

TABLE 3. Major Complications, Clinical Outcome, and Radiographic Cure by Grade and Treatment Modality in ARUBA-Eligible Patientsa

a

ARUBA Eligible

Overall

Grades I and II

Grade III

Grades IV and V

Grades III-V

Significance

Total patients, n Patients treated with surgery with/without embolization, n (%) Age, mean (SD), y Major complication, n (%) Persistent deficit, n (%) Transient deficit, n (%) Posttreatment hemorrhage, n (%) Worse mRS score after treatment, n (%) Last mRS score $ 2, n (%) Last mRS score $ 3, n (%) Cure, n (%) Follow-up, mean (SD), y Patients treated with radiosurgery with/without embolization, n (%) Age, mean (SD), y Major complication, n (%) Persistent deficit, n (%) Transient deficit, n (%) Worse mRS score after treatment, n (%) Posttreatment hemorrhage, n (%) Last mRS score $ 2, n (%) Last mRS score $ 3, n (%) Cure, n (%) Cure with follow-up . 2 y, n (%) Follow-up, mean (SD), y

61 31 (51)

31 19 (61)

20 9 (45)

10 3 (30)

30 12 (40)

... ...

38 (14) 14 (45) 7 (23) 4 (13) 5 (16) 9 (29) 4 (13) 3 (10) 31 (100) 1.3 (1.4) 30 (49)

40 (15) 6 (32) 1 (5) 2 (11) 3 (16) 2 (11) 0 (0) 0 (0) 19 (100) 1.5 (1.6) 12 (39)

36 (12) 5 (56) 3 (33) 2 (22) 1 (11) 5 (56) 3 (33) 2 (22) 9 (100) 1.0 (1.0) 11 (55)

34 (16) 3 (100) 3 (100) 0 1 (33) 2 (67) 1 (33) 1 (33) 3 (100) 1.0 (1.0) 7 (70)

35 (12) 8 (67) 6 (50) 2 (17) 2 7 (58) 4 (33) 3 (25) 12 (100) 1.0 (1.0) 18 (60)

.35 .08 .007 .63 ..99 .01 .02 .05 ... .40 ...

41 (17) 6 (20) 3 (10) 3 (10) 6 (20) 0 (0) 4 (13) 2 (6) 14 (47) 13/20 (65) 2.9 (2.1)

36 (16) 4 (33) 1 (8) 3 (25) 2 (17) 0 (0) 1 (8) 0 (0) 8 (67) 8/10 (80) 2.6 (1.8)

49 (15) 1 (9) 1 (9) 0 2 (18) 0 (0) 2 (18) 1 (9) 4 (36) 4/6 (67) 3.0 (2.5)

36 (17) 1 (14) 1 (14) 0 2 (29) 0 (0) 1 (14) 0 (0) 2 (29) 1/4 (25) 3.2 (2.0)

44 (17) 2 (11) 2 (11) 0 4 (22) 0 (0) 3 (17) 1 (6) 6 (33) 5/10 (50) 3.1 (2.3)

.21 .18 ..99 .05 ..99 ... .63 ..99 .14 .35 .53

ARUBA, A Randomized Trial of Unruptured Brain Arteriovenous Malformations; mRS, modified Rankin Scale.

patients with BAVMs were reviewed, including the 61 patients in the ARUBA-eligible cohort. Overall, 12 patients (13%) had prior BAVM therapy, which was an exclusion criteria for ARUBA. Endovascular embolization as palliative treatment for risk reduction therapy was used in 4 patients, and 1 patient underwent all treatment modalities. Major complication rates were 12 of 37 (32%) for surgery, 7 of 45 (16%) for embolization, and 12 of 48 (25%) for radiosurgery. There were 2 posttreatment mortalities (1 postembolization, 1 postradiosurgery mortality). For all unruptured patients, fewer grade I/II patients had persistent neurological deficits (5% vs 24%; P = .02), worse mRS score after treatment (13% vs 41%; P = .004), and last follow-up mRS $2 (10% vs 41%; P = .002) compared with grade III to V patients (see Table, Supplemental Digital Content 2, http://links.lww.com/NEU/ A714). In patients treated with surgery without and with preoperative embolization, fewer grade I/II patients had major complications (27% vs 73%; P = .008), persistent deficits (5% vs 47%; P = .004), worse mRS score after treatment (9% vs 53%; P = .006), and last follow-up mRS score $2 (0% vs 33%; P = .007) compared with grade III to V patients (see Table, Supplemental Digital Content 3, http://links.lww.com/NEU/A715). All surgical patients obtained a radiographic cure. In patients treated with

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radiosurgery without and with pretreatment embolization, there were similar rates of major complication, worse mRS score after treatment, last follow-up mRS $2, and radiographic cure for grade I/II patients compared with grade III to V patients. Radiographic cure in patients with at least 2 years of follow-up was obtained in 6 of 8 grade I/II patients (75%), 4 of 7 grade III patients (57%), and 5 of 8 grade IV/V patients (63%; Table, Supplemental Digital Content 3, http://links.lww.com/NEU/A715).

DISCUSSION This retrospective review of a consecutive series of adult unruptured BAVMs including a subgroup of ARUBA-eligible patients has identified a group of patients with excellent clinical and radiographic outcomes after treatment. For both ARUBAeligible and unruptured patients overall, grade I/II patients had better mRS scores with lower rates of persistent neurological deficits and impaired functional outcome compared with grade III to V patients combined. All grade I/II patients treated with surgery without and with preoperative embolization obtained radiographic cure, and none had impaired functional outcome (ie, mRS score $2) at the last follow-up.

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NERVA ET AL

Comparison With ARUBA Trial Data The outcomes of ARUBA-eligible patients in this study compared favorably with published functional outcomes for medical management in the ARUBA trial. Importantly, significantly more ARUBA-eligible patients were treated with multimodality therapy compared with ARUBA interventional therapy. In ARUBA, 15.1% and 14.0% of medical management patients at 30 and 36 months had mRS scores $2, respectively.1 For interventional therapy patients, the rates were 46.2% and 38.6%, respectively.1 In this study, 13% of ARUBA-eligible patients had mRS scores $2 at the last follow-up (mean, 2.1 years). The rates by grouping were as follows: 3% of grade I/II patients, 25% of grade III patients, and 23% of grade IV/V patients. Importantly, the functional outcomes reported in this study are at the last clinical follow-up, which differs from how ARUBA reported functional outcome. However, despite this limitation and methodological differences, the outcomes of ARUBA-eligible patients, in particular grade I/II patients, highlight that treatment may be justified in this subset of patients. The finding that grade I/II patients, regardless of ARUBA eligibility, have better clinical and radiographic outcomes compared with patients with higher-grade BAVMs is not a new finding. Surgical resection, preoperative embolization, curative embolization, and stereotactic radiosurgery have all yielded better outcomes in this subset of patients.15,17-22 However, these results do call into question the claim of clinical equipoise for randomizing these patients and the generalizability of ARUBA data. Furthermore, the results also highlight the need for prospective, multicenter data to better identify patients who may benefit most from treatment compared with medical management. One of the main questions behind ARUBA is if BAVMs should be treated in the first place, given a 1% to 2% annual risk of hemorrhage in unruptured BAVMs, relatively low morbidity from hemorrhage, and potentially higher morbidity from treatment than from the natural history.1,12,13,23 In the decision to offer treatment, the cumulative risk of hemorrhage based on patient age is important, which Cockroft11 found to be 44% for an average patient using actuarial data and the Columbia AVM data bank. Multiple studies have found a 20% to 30% risk of disability after hemorrhage.24-28 ApSimon et al25 found that active management of BAVMs lowers mortality from 24.6% to 3.9%, that first hemorrhage carries a 4.6% risk of mortality, and that the majority of BAVMs bleed and become symptomatic. This controversy surrounding hemorrhage rates and morbidity after hemorrhage highlights one of the many differences in opinion regarding BAVM management and is part of the explanation for why 500 patients either refused participation or were treated outside the ARUBA trial. Limitations of ARUBA In the ARUBA trial, medical management was found to be superior to interventional therapy for the prevention of death or

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stroke overall.1 Primary end-point event rates by Spetzler-Martin grade are reported, but rates of impaired functional outcome at follow-up are not separated by grade. Analysis of primary endpoint events and clinical outcome by treatment modality was not reported. Furthermore, radiographic cure rates were not an outcome measure in the ARUBA trial. The published ARUBA data propose that medical management was superior for all types of BAVMs but fail to state whether this finding remains true for specific categories of BAVM. ARUBA also does not categorize outcomes on the basis of treatment modalities, which also limits analysis and application of the results. The Scottish Audit of Intracranial Vascular Malformations Study A prospective, population-based cohort study (Scottish Audit of Intracranial Vascular Malformations [SAIVMs]) was recently published that again demonstrated the superiority of conservative management over treatment (ie, surgery, embolization, or radiosurgery) for progression to death or handicap during the first 4 years of follow-up, but similar rates were found during the course of the study.29 However, the rates during the first 4 years were similar between the groups (36 vs 39 events; 9.5 vs 9.8 events per 100 person-years), and the cumulative proportion progressing to primary outcome after 12 years appeared to favor treatment, but this may have been confounded by age differences between the cohorts. Furthermore, the rate of progression to secondary outcome may have been confounded by treatment modality and events that may have occurred before treatment because only 7 events occurred during the first month after treatment. The SAIVMs study indicates that the results of ARUBA may be less certain and ultimately will require long-term follow-up to solidify the conclusions. Limitations This study of ARUBA-eligible patients has limitations. It is a retrospective review of the experience of a single center, which yields a relatively low number of patients and limits the statistical power. The database was not prospectively collected, and for this reason, there were no data from an untreated cohort from our institution. Thus, patients evaluated during this period but not treated were not included in the study, so there is no appropriate control cohort or group to define potential features favoring medical management. All patients underwent treatment, and the decision to treat is biased toward the clinician’s expertise and experience. The follow-up varied by treatment modality, with radiosurgery patients being followed up longer than surgical patients. Clinical outcomes are reported at last follow-up because of the variability of follow-up time frames in this treatment cohort. The mean radiosurgery follow-up was limited (2.9 years), and with longer follow-up, obliteration rates after radiosurgery would be expected to be higher. Clinical assessments were not blinded and were performed retrospectively, which may bias the results and limits generalizability. Records from clinicians

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TREATMENT OUTCOMES OF ARUBA-ELIGIBLE PATIENTS

involved in the care of the patients were in part used for outcome assessment. The data presented are that of a single-center experience, with biases in treatment paradigms and differences in expertise, which limit the generalizability. Treatment Philosophy BAVM embolization at our institution serves mainly as an adjunct to surgery and radiosurgery, and a higher proportion of patients undergo multimodality therapy compared with the ARUBA trial. This highlights the need for a multidisciplinary, collaborative environment for the assessment of patients who could benefit from BAVM treatment. This philosophy likely contributed to the patient and radiographic outcomes seen herein and may help explain why clinical outcomes in ARUBA favored medical management because most patients underwent singlemodality therapy with high rates embolization alone, with the caveat that many patients had ongoing treatment at the time randomization was halted and may undergo future therapy in addition to embolization. This study reports the clinical and radiographic results of a consecutive series of ARUBA-eligible patients treated at a highvolume center. Differences in outcome based on BAVM characteristics and treatment modality are well established in the literature. This study shows that grade I/II ARUBA-eligible patients can have excellent clinical outcomes after treatment and confirms the challenges of treating higher-grade, unruptured BAVMs. The similar rates of impaired functional outcome in ARUBA-eligible patients compared with ARUBA as-randomized to medical management patients challenge the assertion that medical management is superior.

CONCLUSION The decision to treat an unruptured BAVM includes an analysis of the natural history, risks of treatment, and potential benefits of a lifelong cure for each patient. This study shows that unruptured adult and ARUBA-eligible patients with grade I and II BAVMs can be treated with excellent clinical and radiographic outcomes, with surgery offering a higher rate of cure than radiosurgery. The functional outcomes of ARUBA-eligible patients overall were similar to those of patients randomized to medical management in ARUBA, and there were lower rates of functional impairment in ARUBA-eligible patients compared with those randomized to interventional therapy. These results highlight the need for prospective, multicenter data to identify patients who may benefit most from treatment compared with medical management. Disclosures Dr Ghodke is a consultant for Covidien, Inc., and a shareholder in Viket Medical, Inc. Dr Kim is a consultant for Aesculap, Inc and Covidien, Inc and a shareholder in Spi Surgical Inc. Dr Sekhar is a consultant for Viket Medical Inc and a shareholder in Spi Surgical Inc. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

NEUROSURGERY

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NERVA ET AL

26. Halim AX, Johnston SC, Singh V, et al. Longitudinal risk of intracranial hemorrhage in patients with arteriovenous malformation of the brain within a defined population. Stroke. 2004;35(7):1697-1702. 27. Crawford P, West CR, Chadwick DW, Shaw MD. Arteriovenous malformations of the brain: natural history in unoperated patients. J Neurol Neurosurg Psychiatry. 1986;49(1):1-10. 28. Choi JH, Mast H, Sciacca RR, et al. Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation. Stroke. 2006;37(5):1243-1247. 29. Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669.

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arteriovenous malformations with a low Spetzler-Martin grade, treatment outcomes are very favorable. This study furthermore highlights the differences in treatment modality used in a specialized US center compared with that in the ARUBA trial, in which non-US centers predominated and surgical intervention was underrepresented and embolization as the sole therapy was markedly overrepresented. In this series, data on patients not offered treatment in the same time frame would have been informative to provide insights into the selection process for intervention, but unfortunately this information was not available. Results such as those reported in this study can be further expanded and validated in a meaningful way through prospective multicenter adjudicated data collection. The cerebrovascular module of the national registry vehicle, N2QOD, and other such registries are likely to be an important and viable methodology for doing so moving forward. Sepideh Amin-Hanjani Chicago, Illinois

COMMENTS

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his is a retrospective review of a single-institution series of arteriovenous malformations (AVMs) treated with multiple modalities; a subgroup of the patients treated were deemed to have been eligible in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) and so are analyzed separately as ARUBA-eligible subjects. The study has the usual flaws of retrospective studies, and its results are not entirely novel or new. However, the timeliness of its submission with respect to the recently published ARUBA trial is noteworthy. The review reinforces the limitations of medical management for unruptured AVMs and the safety and efficacy of surgical treatment for low-grade lesions. Thus, it highlights the severe limitations of ARUBA, related primarily to the high rates of complications observed in that study as a result of embolization with intent to cure. Unruptured AVMs continue to present a challenge to cerebrovascular surgeons and should be treated at highvolume centers with multiple treatment modalities available to patients who come to medical attention. In our practice, it is routine to continue to recommend treatment for younger patients with low-grade (Spetzler-Martin grade I and II) AVMs, and this treatment is primarily microsurgical. Given the limitations of ARUBA and other difficulties in enrolling patients in large randomized controlled trials involving rare and heterogeneous disease entities, further randomized trials are in my opinion unlikely to be beneficial or costeffective. It is hoped that future registry data will be used to better inform physicians regarding their treatment paradigms for these lesions. Nicholas C. Bambakidis Cleveland, Ohio

A

s the authors note, the results of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) have been met with great skepticism among the neurosurgical community, with several “fatal flaws” in study design and implementation that essentially prohibit translation of the results into a meaningful practice change.1,2 Nonetheless, even though clearly a randomized trial does not represent the best strategy to broadly determine optimal treatment of a relatively rare heterogeneous disease with multiple treatment options, we should seek other more viable venues to inform and corroborate existing and future practice. The present study, although suffering from the shortcomings inherent to single-center and retrospective studies, provides some additional insight into the outcomes that are feasible with intervention. The inclusion of consecutively treated patients is a strength, and outcomes ascertainment was performed by a nontreating physician, which otherwise poses a common potential source of bias in retrospective studies. The findings demonstrate that in

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1. Amin-Hanjani S. ARUBA results are not applicable to all patients with arteriovenous malformation. Stroke. 2014;45(5):1539-1540. 2. Bambakidis NC, Cockroft KM, Hirsch JA, et al. The case against a randomized trial of unruptured brain arteriovenous malformations: misinterpretation of a flawed study. Stroke. 2014;45(9):2808-2810.

CME QUESTIONS: 1. On workup for an intracerebral hemorrhage, a patient is found to have a 4 cm left frontopolar arteriovenous malformation with deep venous drainage. What is the Spetzler Martin Grade of this AVM? A. 1 B. 2 C. 3 D. 4 E. 5 2. A patient is found to have an incidental 2.5 cm right frontal ateriovenous malformation (AVM) with superficial venous drainage. What is rate of morbidity and mortality associated with surgical resection of this AVM? A. 0-10% B. 11-20% C. 21-30% D. 31-40% E. 41-50% 3. A patient has a history of hemorrhage from a basal ganglia arteriovenous malformation (AVM) with exclusive deep venous drainage. What is the annual risk of hemorrhage of this AVM? A. 1-5% B. 5-10% C. 10-15% D. 15-20% E. Greater than 20%

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Treatment outcomes of unruptured arteriovenous malformations with a subgroup analysis of ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-eligible patients.

The design and conclusions of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial are controversial, and its structure li...
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