Post-ARUBA Era Treatment of Cerebral Arteriovenous Malformations

Cerebral arterio-venous malformations (cAVMs) are complex cerebrovascular lesions and the optimal treatment strategy is often controversial.[1]

The natural history of cAVMs includes the risk of hemorrhage and hemorrhagic recurrence. In two studies of 790 and 282 patients with untreated cAVMs, intracerebral hemorrhage was the initial event in 47% and 45% of patients, respectively, and the initial hemorrhage was associated with risk of recurrence. Furthermore, the annualized bleeding rate for unruptured cAVMs was 2% at 10 years and 1.3% at 2.2 years of follow-up, respectively.[2],[3]

Treatment decisions for unruptured cAVMs are based on weighing the risk of bleeding from natural history studies against the risk of treatment. A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) was the first trial to compare the risk of death or symptomatic stroke (primary endpoint) between medical management alone vs. medical management plus interventional therapy (microsurgery, embolization, radiosurgery or a combination of treatment modalities) in 223 patients with unruptured cAVMs. The primary endpoint was significantly lower in the medical management group (10%) than in the treatment group (30.7%), and this threefold difference remained stable up to a follow-up period of 50.4 months.[4][5] 62% of patients had a Spetzler-Martin score of ≤2, with lower scores being more frequent in the interventional arm. These patients were considered to be an optimal population for treatment of unruptured cAVM; however, only a small number underwent microsurgery (15.7%),[4] despite documented higher nidus obliteration rates, in contrast to embolization and radiosurgery.[5] At the time of final data collection, only 44% of treated patients had angiographic evidence of cAVM obliteration.[6]

The ARUBA trial remains controversial due to the study design: heterogeneous treatment modalities in the treatment group, relatively short follow-up, high treatment complication rates and distribution of treatment modalities unrepresentative of standard practice in the USA.[7],[8]

Lately, the impact of the ARUBA trial was studied in the US population. A first national registry analysis from 2021 revealed that the rate of interventions for unruptured cAVMs decreased in the post-ARUBA trial era (2014-2018) compared to the pre-ARUBA trial time period (2006-2013); this finding was based on decreased rates of open surgery, while rates of endovascular treatment and stereotactic radiosurgery remained similar.[9] A second registry analysis from 2022 demonstrated increased incidence of cAVM rupture admissions (13% vs. 34%,) and higher in-hospital mortality (2% vs. 8%) in the post-ARUBA trial era (2014-2019) as compared to the pre-ARUBA trial period (2009-2013).[10] To link these two previous real-world data studies, the authors suggested that withholding treatment of unruptured cAVMs in the post-ARUBA period may have led to their eventual rupture and increased mortality.[10] Several post-ARUBA period studies suggest that treatment for unruptured cAVMS is safe.[7] A recent example was provided by the analysis of the NVQI-QOD AVM registry published in 2023. The data analysis focused on the safety of individual cAVM treatment modalities. A total of 173 ARUBA-eligible patients underwent intervention, with 75 patients receiving microsurgery (+/- embolization). The median follow-up was 8.8 months. Compared to the ARUBA interventional arm, death or stroke occurred less frequently (9% vs. 31%), while neurological disability was decreased (mRS>1 25% vs 46%). However, these results must be interpreted with caution as these are observational data.[11]

In conclusion, treatment of unruptured cAVMs remains controversial, but there are data supporting that interventional therapy is a safe option for prevention of hemorrhage in selected patients. However, these data are mainly retrospective. A randomized controlled trial for unruptured cAVM treatment, focusing on a higher number of participants to allow for comparison of different treatment modalities and a longer follow-up period could end this uncertainty.

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 References:

[1]       R. F. Spetzler, “A proposed grading system for arteriovenous malformations”.

[2]       A. X. Halim et al., “Longitudinal Risk of Intracranial Hemorrhage in Patients With Arteriovenous Malformation of the Brain Within a Defined Population,” Stroke, vol. 35, no. 7, pp. 1697–1702, Jul. 2004, doi: 10.1161/01.STR.0000130988.44824.29.

[3]       C. Stapf et al., “Predictors of hemorrhage in patients with untreated brain arteriovenous malformation,” Neurology, vol. 66, no. 9, pp. 1350–1355, 2006, doi: 10.1212/01.wnl.0000210524.68507.87.

[4]       J. P. Mohr et al., “Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomized trial,” The Lancet, vol. 383, no. 9917, pp. 614–621, Feb. 2014, doi: 10.1016/S0140-6736(13)62302-8.

[5]       J. van Beijnum, “Treatment of Brain Arteriovenous Malformations,” JAMA, vol. 306, no. 18, pp. 2011–9, Nov. 2011, doi: 10.1001/jama.2011.1632

[6]     J. P. Mohr et al., “Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomized controlled trial,” Lancet Neurol., vol. 19, no. 7, pp. 573–581, Jul. 2020, doi: 10.1016/S1474-4422(20)30181-2.

[7]       J. Feghali and J. Huang, “Updates in arteriovenous malformation management: the post-ARUBA era,” Stroke Vasc. Neurol., vol. 5, no. 1, pp. 34–39, Mar. 2020, doi: 10.1136/svn-2019-000248.

[8]       T. R. Meling et al., “On apples, oranges, and ARUBA,” Acta Neurochir. (Wien), vol. 156, no. 9, pp. 1775–1779, Sep. 2014, doi: 10.1007/s00701-014-2140-7.

[9]       W. Wahood et al., “Elective intervention for unruptured cranial arteriovenous malformations in relation to ARUBA trial: a National Inpatient Sample study,” Acta Neurochir. (Wien), vol. 163, no. 9, pp. 2489–2495, Sep. 2021, doi: 10.1007/s00701-021-04936-7.

[10]     A. J. Dicpinigaitis, J. V. Ogulnick, S. A. Mayer, C. D. Gandhi, and F. Al‐Mufti, “Increase in Ruptured Cerebral Arteriovenous Malformations and Mortality in the United States: Unintended Consequences of the ARUBA Trial?,” Stroke Vasc. Interv. Neurol., vol. 3, no. 1, p. e000442, Jan. 2023, doi: 10.1161/SVIN.122.000442.

[11]     A. Alrohimi et al., “Treatment outcomes for ARUBA-eligible brain arteriovenous malformations: a comparison of real-world data from the NVQI-QOD AVM registry with the ARUBA trial,” J. NeuroInterventional Surg., Jan. 2024, doi: 10.1136/jnis-2023-020525.