Article In Brief
Longitudinal data from the ARUBA trial suggest that medical management alone was more effective than interventional therapy for unruptured brain arteriovenous malformations. But independent experts raised concerns about selection bias and called for more long-term study of outcomes.
Medical management alone seems to be more favorable than medical management plus interventional therapy for treatment of unruptured brain arteriovenous malformations (AVMs), according to updated results from the much-debated trial published in the July issue of Lancet Neurology.
The study, ARUBA—which stands for A Randomized trial of Unruptured Brain Arteriovenous malformation—was a multicenter non-blinded randomized controlled trial conducted at 39 centers in nine countries. It enrolled adults aged 18 or older who had a brain AVM that had never bled and who were considered by participating centers to be suitable for intervention to eradicate the lesion.
The ARUBA investigators randomly assigned participants to medical management alone (including medication as needed for symptoms such as seizure or headache) or to medical management plus interventional therapy, which included neurosurgery, embolization or stereotactic radiotherapy, or any combination of those therapies.
The study authors last reported outcomes on participants after an average follow-up of 33.3 months. Now, in the current study, the investigators report an average of 50.5 months of follow-up, with outcomes consistent with the earlier findings.
“After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured arteriovenous malformation,” concluded the Lancet Neurology study.
The study said doctors should present the latest data on “disparity in outcomes” between medical management and medical management plus interventional therapy to patients weighing their treatment options for an unruptured AVM. The study's conclusions cautioned, however, that “the even longer-term risks and differences between the two therapeutic approaches remains uncertain.”
The much-awaited follow-up data may not change the minds of some clinicians who already had misgivings about ARUBA, including that it had possible participant selection bias.
The multicenter study was launched in 2007 amid limited research on how best to treat AVMS, which are very rare but still the leading cause of intracerebral hemorrhage in young adults.
Jay P. Mohr, MD, the Daniel Sciarra Professor of Clinical Neurology at Columbia University and lead investigator, said it was assumed that if an “AVM has been discovered when it hasn't any trouble then it has to be removed so it can't cause trouble.”
It is thought that unruptured AVMs have about a 1.0 percent annual risk of hemorrhage, though it is hard to predict at an individual level whether an unruptured AVM will end up bleeding or not throughout the course of a person's lifetime, he said.
Of 1,740 patients assessed for eligibility, 226 were randomly assigned to medical management alone or to medical management plus interventional therapy. Patients and study investigators were not masked to treatment assignment, but investigators at other centers and at the trial's coordinating center were not aware of which individuals were in which arm of the study.
The primary outcome was death from any cause or symptomatic stroke (hemorrhage of infarction) documented on CT or MRI and documented by a neurologist and independent committee. Enrollment began in 2007 but was halted in 2013 before full enrollment was achieved because a scheduled interim analysis by the study's data and safety monitoring board found that the results were trending strongly in favor of medical management with a mean follow-up of 33.3 months.
The study did not get funding to continue following patients until the five-year mark because the request received a low priority score from the National Institute of Neurological Disorders and Stroke, so Dr. Mohr enlisted a private donor to pay for the analysis of the longer-term results that are being reported in the current study.
The new report found that after an average of 50.4 months of follow up, the incidence of death or symptomatic stroke was lower with medical management alone (15 events in the cohort of 110, or 3.39 events per 100 patient-years) compared to medical management plus interventional therapy (41 events in the cohort of 116, or 12.32 events per 100 patient years.)
There also were fewer adverse events in the medical management group compared to the interventional therapy group (283 versus 369). “We can tell patients that an intervention carries a higher hazard of leaving them with a disability than not doing an intervention,” said Dr. Mohr, though it is not known whether that would hold true the more time goes by.
An accompanying editorial pointed out that “critics of ARUBA have repeatedly raised concerns about the external validity of the trial, particularly about selective recruitment.”
“However, the proportion of eligible patients recruited into the trial (226 of 726) is substantially higher than in many other trials, and the clinical characteristics of the patients recruited are comparable with those in a population-based study of arteriovenous malformations,” said editorialist Peter Rothwell, of the University of Oxford.
“I have been critical of the external validity of many trials, and trials of surgical interventions do pose particular problems, but I do not think that this is really any greater an issue for ARUBA than for most other similar trials.”
Dr. Rothwell said that the National Institute of Neurological Disorders and Stroke should have funded a long-term follow-up of ARUBA, noting that “insufficient follow-up is indeed the major shortcoming for ARUBA.”
Given the young age of the trial cohort (mean 44.4 years) and the low mortality at 5 years (3 percent), average life expectancy of these patients is likely to be several decades, and so follow-up to at least 10 years, and ideally 20 years, would have been desirable.
Dileep Yavagal, MD, FAAN, director of interventional neurology and clinical professor of neurology and neurosurgery at University of Miami, said he welcomed the updated ARUBA results, noting that the new findings settled a lot of the debate regarding best treatment for unruptured brain AVMS and would be useful in advising patients. (Dr. Yavagal said Miami was a site for the trial, but he was not an investigator.)
He said patients with unruptured AVMs often get quite comfortable with a “waiting and watching approach” after they are presented with actual numbers on the risks and benefits of medical management compared to interventional/surgical therapy.
Some patients go from fearing there is a ticking time bomb in their head to “being quite peaceful once they know what the numbers mean,” he said, particularly when it comes to possible surgical risks such as paralysis.
Dr. Yavagal said that based on the original ARUBA results from 2013 he is currently taking a wait and watch approach to about 10 to 15 patients with unruptured AVMs and none have bled. He follows up every two to three years with MRI or CT angiograms to look for the development of aneurysms on the arteries feeding the AVM and tells the patients to be alert for possible troubling signs, such as sudden severe headache.
Dr. Yavagal said even with the new ARUBA findings, however, it is important to do a risk-benefit analysis based on the patient's presentation and circumstances.
“The (cumulative) risk of bleeding would be higher in a younger person and the risk of surgery is also lower,” so intervention may make sense depending on the size and location of the AVM, he said. On the other hand, an older person generally has a lower cumulative risk of bleeding with a newly-found AVM and may not tolerate surgery as well as a younger person, so that could tip the scale in favor of medical management only.
Guillermo Linares, MD, associate professor of neurology at Saint Louis University, said the expanded ARUBA trial “is a very valuable study in that AVMs are not that common and there has been a longstanding debate on what the best management strategy is.”
But he does not think the debate will necessarily end because the results from ARUBA are still short-term.
“Any treatment that is invasive, like surgery, will have an upfront cost in complications, so the question is ‘how much time has to pass before any benefits can outweigh the initial upfront complications rate?’”
He said that might not become clear for 10, 15 or more years. He also cautioned that results from the ARUBA trial should not be applied to AVMs that have bled, which have a higher risk of bleeding again.
Dr. Linares said many factors go into deciding treatment for an unruptured AVM, including size and location of the lesion—is it in an eloquent part of the brain?— the presence of high-risk features such as associated aneurysms or venous abnormalities, the batter of blood flow, and the patient's age.
“If you are counseling a 20-year-old it might be different than counseling an 85-year-old,” he said.
Hesham Masoud, MD, a vascular and interventional neurologist at Upstate Medical Center in Syracuse, NY, said the latest ARUBA findings still leave him unconvinced.
He said the trial was designed with the hypothesis that medical management was superior to interventional therapy. He also said that it did not allow for a distinction for the different types of intervention, putting surgery, embolization and radiosurgery all into one category.
“It assumes that all interventions for AVM are the same,” said Dr. Masoud, assistant professor in the departments of neurology, neurosurgery and radiology at Upstate Medical University.
He said the study also for the most part lumps all AVMs together. ‘“Treating AVMs is very nuanced. It's not like you're dealing with only one type of disease,” he said, adding, “I don't think ARUBA helps us with the problem of patient selection.”
Dr. Masoud also said that even if a few more years of follow up were added to ARUBA, it would likely not be enough to come to a definitive conclusion about medical management versus interventional therapy.
For AVMs, “the natural history is not just five years, it's over the course of a person's lifetime,” he said. Helen Kim, PhD, professor in the departments of anesthesia and perioperative care, and epidemiology and bostatistics at University of California, San Francisco, and coauthor of the latest ARUBA report, said an ongoing observational study she heads called MARS (Multicenter Arteriovenous Malformation Research Study) may answer some of the questions that remain after ARUBA.
MARS aims to collect and analyze data on more than 3,000 unruptured AVM cases collected from 11 participating sites including ARUBA. Among the goals of the study: to identify risk factors for-intracranial hemorrhage in unruptured AVM patients; compare long-term outcomes in treated versus untreated patients; and to develop 10-year risk prediction models that could be used for individual patient prediction and counseling.
“Our hope is that we will be able to provide complementary information to ARUBA for clinicians and patients, and potentially offer a resolution for disparate viewpoints,” said Dr. Kim, director of the UCSF Center for Cerebrovascular Research.
She said there is still a lot to be learned about brain AVMs, including biological and genetic factors. “We are trying to understand...why some lesions are more active than others,” she said.
Drs. Mohr, Linares, and Kim had no relevant disclosures.