SAN DIEGO—Should a patient with an unruptured arteriovenous malformation (AVM) be referred for intervention? How clinicians answer that question may depend largely on their interpretations of the results of the recent ARUBA study, as reported at the 2014 International Stroke Conference.
An international, multicenter, randomized controlled trial, ARUBA (A Randomized Trial of Unruptured Brain AVMs) compared the risk of death and symptomatic stroke in participants with unruptured brain AVMs assigned to medical management alone or medical management and interventional therapy (ie, neurosurgery, embolization, or stereotactic radiotherapy alone or in combination). An independent data and safety monitoring board halted the trial, which was funded by NINDS, because of the superiority of the medical management group.
Based on outcome data available for 223 patients—114 randomized to interventional therapy and 109 to medical management—the ARUBA investigators concluded that medical management alone is superior to medical management and interventional therapy for preventing death or stroke in patients with unruptured AVMs followed up for 33 months. But the absence of a widely recognized standard of treatment for unruptured AVMs makes it difficult to interpret the study’s findings.
Conflicting Interpretations of the ARUBA Study
The ARUBA results are not applicable to all patients with unruptured AVMs, said Sepideh Amin-Hanjani, MD, Professor and Codirector of Neurovascular Surgery at the University of Illinois at Chicago. ARUBA’s study design had the conceptual flaw of grouping all unruptured AVMs together, she said. The study’s implementation also had flaws, including a failure to account for enrollment bias, a lack of meaningful credentialing criteria for study sites, and a length of follow-up that precluded the assessment of disease-relevant outcomes, she added.
“Ultimately, ARUBA doesn’t really address [the question of whether] a patient should be treated because the generalizability and follow-up of the selected cohort [were] limited,” said Dr. Amin-Hanjani. “It doesn’t address which patients should be treated because heterogeneous diseases were lumped together. It doesn’t address which modality [should be used] because the treatments were not standardized or compared…. ARUBA as a justification for implicit denial of treatment to all unruptured AVMs would be, at best, irresponsible on the part of the medical community, and at worst, negligent.”
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| Sepideh Amin- Hanjani, MD | J. P. Mohr, MD |
Yet negative outcomes were more common among patients who received intervention and medical management than among patients who received medical management alone. As of month 84, when patients had been followed up for a mean period of four years, two AVM-related deaths had occurred in the interventional arm, compared with none in the medical management arm, said J. P. Mohr, MD, Daniel Sciarra Professor of Neurology at Columbia University Medical Center in New York City and one of the lead investigators of the ARUBA study. The difference between the two groups for such end points as death or stroke, all-cause or AVM-related stroke, and first stroke (ie, all, hemorrhagic, or ischemic) was large.
“We have been faced with the prospect of having to consider the ARUBA results definitive,” said Dr. Mohr. Statisticians have demonstrated that it would take between 12 and 30 years for the two groups’ outcome rates to converge. “Some cynics would say, ‘Why don’t we do the intervention now, and the patient would be spared the anxiety of having a stroke at some future time?’ Our view would be that maybe the patient should be spared the concern that the intervention might generate the stroke ahead of schedule.”
Different Treatments May Have Different Complication Rates
During a pro/con symposium at the conference, a neurologist and a neurosurgeon debated whether a 25-year-old woman with an unruptured, Spetzler–Martin grade 3 AVM should be referred for interventional treatment or managed with medical therapy alone. When clinicians encounter a patient with an unruptured AVM, rupture should be their primary concern, according to Dr. Amin-Hanjani, who cited data from meta-analyses, as well as from the prospective medical arm of ARUBA, which indicated a rupture risk of approximately 2% per year.
Rather than group all treatment modalities together when considering complication rates, as has been done in recent meta-analyses, it is more helpful to identify rates for specific treatments and types of patients, said Dr. Amin-Hanjani. For example, Spetzler–Martin grades are a useful risk-stratification tool for predicting complications of surgery by looking at the AVM size, eloquence, and venous drainage. “This [tool] was never a grading system for hemorrhage risk but … for complication risk from surgery,” said Dr. Amin-Hanjani. “We know from many publications that grade 1 and 2 AVMs tend to do favorably with surgery, grade 4 and 5 AVMs don’t do well with surgery, and what we’re left with is grade 3 AVMs in the gray zone.”