ARTICLE IN BRIEF
During up to 12 years of follow-up, the risk of a nonfatal stroke or death due to brain arteriovenous malformation, arterial aneurysm, or intervention was lower for patients treated medically compared with those who underwent neurosurgical excision, endovascular embolism, stereotactic radiotherapy, or a combination of these therapies.
Patients with an unruptured brain arteriovenous malformation (AVM) who received conservative medical management fared better in the long term than patients who underwent an intervention, according to a population-based study from Scotland.
During up to 12 years of follow-up, the risk of a nonfatal stroke or death due to brain AVM, arterial aneurysm, or intervention was lower for patients treated medically compared with those who underwent neurosurgical excision, endovascular embolism, stereotactic radiotherapy, or a combination of these therapies.
The Scottish study, published in the April 23/30 edition of Journal of the American Medical Association (JAMA), included 204 patients, 103 of whom underwent an intervention and 101 who did not. The patients, who were at least 16 years old, were diagnosed with an unruptured brain AVM during 1999–2003 or 2006–2010.
Using anonymous data from the Scottish National Health Service, researchers followed the patients prospectively. The patients who underwent an intervention tended to be younger, more likely to have presented with seizures, and less likely to have a large brain AVM (exceeding 6 cm) than those who did not get an intervention.
The study's primary outcome was death or sustained morbidity due to any cause by measure of the Oxford Handicap Scale.
“During a median follow-up of 6.9 years, the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 versus 39 events; a relative risk reduction of 41 percent) but rates were similar thereafter,” the researchers reported.
When it came to the secondary outcome measure — nonfatal symptomatic stroke or death due to brain AVM, associated arterial aneurysm or intervention — “the rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 versus 38 events; a relative risk reduction of 63 percent),” according to the researchers. Seven symptomatic strokes occurred within 30 days of intervention.
The findings align with results reported in a different randomized-controlled clinical trial called ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) that also compared conservative management to intervention for brain AVMs. The ARUBA trial halted enrollment last May after an interim analysis of data found that the conservative approach was superior for preventing stroke and death.
The ARUBA study found that the risk of sustained morbidity or death from any cause in the first four years was 41 percent lower in the patients who did not get intervention compared with those who did, but that difference in risk faded after that. [See Neurology Today's article, “Why the ARUBA Trial on AVMs Was Stopped,” http://bit.ly/1njMTXR.]
“These (latest) findings urge caution about treating unruptured brain AVM, especially in light of the findings of the ARUBA randomized trial,” said the study's lead author, Rustam Al-Shahi Salman, PhD, a professor of clinical neurology at the University of Edinburgh.
“Patients should be provided the information about the relative and absolute risks of brain AVM treatment and conservative management from our study and the ARUBA trial to help inform their decision about whether or not to undergo treatment of an unruptured brain AVM,” he said in an email interview with Neurology Today.
He noted that the similar results from this study and the ARUBA trial “may deter some patients and physicians from intervention.”
The Scottish researchers noted that the limitations of their study included the fact that it was not randomized, so there was some selection bias in which patients underwent an intervention. There also were no baseline measurements of handicap to use for comparison later on in the study. The study was not sufficiently powered to discern whether any one particular mode of intervention might produce better results than another.
“Long-term follow-up in both this study and the ARUBA trial is needed to establish whether the superiority of conservative management will persist or change,” the researchers reported. Dr. Salman said the team currently has funding to follow the patients until mid-2016.
THE DEBATE CONTINUES
Experts not involved with the Scottish study said these new data from JAMA are unlikely to settle the sometimes contentious debate over whether it is riskier to treat unruptured brain AVMs — which exposes the patient to the risk of complications from intervention — or leave them alone — an option that comes with the risk of the AVM rupturing, causing brain injury or even death.
The widely cited statistic is that there's at least a 1 percent risk per year of hemorrhage if an AVM is left untreated. But Jay P. Mohr, MD, FAAN, the Daniel Sciarra professor of neurology at Columbia University and co-principal investigator for the ARUBA trial, said current data from that study show that the hemorrhage rate may be below 1 percent and that the bleeds that do occur tend to be mild. He said a follow-up analysis of data from the ARUBA trial, which is being presented at the 24th European Stroke Conference, suggests it would take anywhere from 12 to 30 years to have the risk of a rupture from an untreated AVM equal the risk of complication from intervention.
“AVMs are imbedded in the brain and the removal of the AVM runs the risk of disruption of brain function and brain injury,” Dr. Mohr told Neurology Today.
The subject was the focus for a debate between Dr. Mohr and University of Pittsburgh neurosurgeon Robert Friedlander, MD, at the AAN Annual Meeting in Philadelphia in April.
Dr. Friedlander — chairman of neurological surgery and the Walter E. Dandy professor of neurosurgery — told Neurology Today that he believed that both the latest study from Scotland and the ARUBA trial were missing the point.
“It's not about treating an AVM. It's about curing an AVM,” he said. He said that in the Scottish study, the AVM was obliterated in only 63 percent of cases of single-mode intervention — a success rate he said was below that found at high-volume centers such as the one at his institution, where he said the “cure rate” from AVM intervention is approaching 100 percent. He noted that the rate of complications from intervention was also higher in the Scottish study than at centers such as his.
“If the AVM is treated but not cured, one is exposing the patient to the risk of treatment and none of the benefits, since the natural history of a partially treated AVM is likely the same as if it were not treated at all,” he said.
“Grade 1 and Grade 2 brain AVMs in expert hands can be treated with a high degree of safety and efficacy,” he said. Grade 3 brain AVMs (based on the Spetzler-Martin classification system of 1 to 5 depending on size and location; 6 for inoperable), fall into a “gray zone,” he said.
Dileep R. Yavagal, MD, director of interventional neurology and an associate professor of clinical neurology and neurosurgery at the University of Miami, said he welcomed the added information provided by the Scottish study.
“There's such a shortage of comparative data on AVM management and even though it is not a randomized controlled study, it is extremely well designed to take out as many biases as possible,” he said.
Dr. Yavagal said that he had already become more conservative in patient selection after the ARUBA findings emerged.
“I really have a much higher threshold for recommending intervention for brain AVMs,” he said, though he noted that “it's hard to apply the study results to every situation.”
He said the fact there is a 1- to 2-percent chance per year of bleeding with an untreated AVM can't be taken lightly, and that cases must be considered on an individualized basis.
“For a younger patient with a small AVM of less than 3 cm in a non-eloquent area with superficial drainage, it might be worth the risk to treat this patient interventionally,” he said. “At the same time, the new study results should provide reassurance to patients who decide they'd rather take a watchful approach.”
For patients, “it's sometimes a matter of attitude as to whether or not you take a risk upfront to ward off the long-term risks and uncertainty or you are okay with a long-term small risk of bleeding and its complications from the AVM,” Dr. Yavagal said.
At the recent AAN meeting, Dr. Friedlander presented the case of a 21-year-old patient with an AVM and seizures whom he recently treated with embolization and microsurgery. The patient was doing well immediately after surgery.
“At the end of the day, you have to make a decision based on the patient in front of you,” he said. “It does not seem reasonable to withhold a curative therapy from a patient who is young and otherwise healthy. The key is that it must be done by expert teams in order to optimize outcomes.”
EXPERTS COMMENT ON THERAPY FOR UNRUPTURED AVMS