Surgical Intervention for Unruptured Brain AVMs: The Story Isn’t Over

Cleveland Clinic findings challenge conclusions of ARUBA trial

By Mark Bain, MD, MS

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Surgical treatment of unruptured brain arteriovenous malformation (ubAVM) is associated with a lower risk of stroke or death than a watch-and-wait approach, according to a new retrospective analysis of a large series of cases at Cleveland Clinic. These results add to the controversy generated with the 2014 publication of the Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA),1 which came to the opposite conclusion. Our retrospective analysis of 105 patients between 2001 and 2014 who would have qualified for ARUBA was recently published in Neurosurgery.2

Optimal management of ubAVMs has been a topic of debate since brain imaging made possible the diagnosis of this often asymptomatic or mildly symptomatic condition (an example angiogram of such an AVM is shown at the top of this post). A no-treatment strategy entails a 2 percent to 5 percent annual risk of rupture. While this may seem low, over many years the cumulative chances become daunting. And the outcomes can be devastating: About one-third of patients with a bleed end up in a nursing home, and 10 percent die. But treatment is also not without risk.

What ARUBA found

ARUBA, conducted at 39 clinical sites in nine countries, randomized patients to either interventional therapy (neurosurgery, embolization or stereotactic radiosurgery [Gamma Knife®], either in combination or alone, as determined by the treating physician) or medical management (symptomatic treatment with medications, as needed). The study, which started in 2007, was ended prematurely in 2013 because of superior outcomes in the medical management group. At that point, the study had randomized 223 patients (114 to intervention and 109 to medical management) and had a mean follow-up of 33.3 months. The primary end point, either stroke or death, had occurred in 10.1 percent of the medical management group versus 30.7 percent of the intervention group.

What Cleveland Clinic found

Of the 105 cases in the Cleveland Clinic database that were ARUBA-eligible, 44 patients had undergone microsurgery and 61 patients had undergone stereotactic radiosurgery as their final treatment. Mean follow-up was 43 months (range, 4-136 months). A total of 8 patients (7.6 percent) had a stroke or died, as detailed in the table below.

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This new Cleveland Clinic study2 joins several other retrospective analyses published after ARUBA in finding substantially lower overall risk of stroke or death in the treatment arm than the 30.7 percent reported in ARUBA.3-6 Most importantly, overall risk was lower than the natural disease course, justifying a strategy of surgical intervention for ubAVM.

Why the difference?

Multiple issues have been identified that may account for the different conclusions reached by ARUBA and the other studies.

Treatment choices differed. ARUBA treated 26 percent of patients with endovascular embolization alone, a high rate that may partly explain the elevated rate of stroke or death relative to the subsequent studies. Because of the likelihood of complications from attempting to obliterate an AVM by embolization alone, many institutions, including Cleveland Clinic, reserve its use mainly to reduce AVM nidus size before surgery or stereotactic radiosurgery. With safer embolysates now available, the role of embolization in combined procedures is undergoing a further shift.

Cleveland Clinic uses the following rules of thumb to choose interventions for a patient with ubAVM:

  • Small AVM in a noneloquent area — microsurgery
  • Large AVM in a noneloquent area — embolization to slow the blood flow to the AVM rather than obliterate it, followed by microsurgery later
  • AVM in an eloquent area or deep in brain — stereotactic radiosurgery

Short follow-up. Because most deaths from surgical intervention happen soon after the procedure and the risk of an untreated ubAVM is generally continuous over the years, a comparison of the risks within the first few years is likelier to favor no intervention.

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Treatment of many patients outside the trial. ARUBA was designed such that not all patients who qualified for the trial were randomized, allowing surgeons to elect to operate on patients whose AVMs were deemed ideal for surgery. This ability to treat patients outside the trial could have introduced bias by steering disproportionate numbers of patients with complex or difficult-to-treat AVMs into the trial. This would not have been favorable for the trial’s interventional arm.

How can this controversy be resolved?

Another randomized clinical trial would be ideal, using a more modern algorithm for treatment than was used in ARUBA. But because of the high expense, this is unlikely to happen soon. A second choice would be a prospective study conducted at multiple institutions to follow outcomes of different treatment strategies. Finally, a meta-analysis of the various retrospective studies that have followed ARUBA, including this Cleveland Clinic cohort, would be useful.

Patient management in the face of uncertainty

We believe in providing our ubAVM patients with as much information as possible so that they can fully enter into the decision process for their treatment. They often have strong preferences based on the degree of risk they are comfortable with.

Our inclination to intervene stems from witnessing young, healthy patients meet with poor outcomes from a wait-and-see approach. Our data strongly argue that we have the tools to provide reasonable and safe strategies to improve outcomes for most patients.

References

  1. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformation (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383:614-621.
  2. Lang M, Moore NZ, Rasmussen PA, Bain MD. Treatment outcomes of a randomized trial of ARUBA-eligible unruptured brain arteriovenous malformation patients. Neurosurgery. 2017 Oct 10 [Epub ahead of print].
  3. Rutledge WC, Abla AA, Nelson J, et al. Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution. Neurosurg Focus. 2014;37:E8.
  4. Ding D, Starke RM, Kano H, et al. Radiosurgery for cerebral arteriovenous malformations in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients. Stroke. 2016;47:342-349.
  5. Javadpour M, Al-Mahfoudh R, Mitchell PS, Kirollos R. Outcome of microsurgical excision of unruptured brain arteriovenous malformations in ARUBA-eligible patients. Br J Neurosurg. 2016;30:619-622.
  6. Wong J, Slomovic A, Ibrahim G, et al. Microsurgery for ARUBA Trial-eligible unruptured brain arteriovenous malformations. Stroke. 2017;48:136-144.

Dr. Bain is a neurosurgeon in Cleveland Clinic Neurological Institute’s Cerebrovascular Center. He was primary investigator of the retrospective analysis profiled above.