LOS ANGELES — Five-year follow-up of a trial comparing surgical or endovascular intervention with best medical intervention confirms that despite the higher risk for stroke with an unruptured arteriovenous malformation (AVM), intervention only raises that risk.
ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) was stopped early because of higher event rates in the intervention group after an average follow-up of 3 years. Now, 5-year results continue to show that best medical therapy was associated with a significantly lower risk for stroke and death compared with any intervention.
"The downside is living with an AVM, which is a risk factor for stroke, and the spontaneous hemorrhage rate was 2.1% per year," Christian Stapf, MD, full professor, Université de Montréal, Department of Neurosciences, CRCHUM, Montréal, Québec, Canada, said at a press conference here.
"But this risk goes up by a factor of 4.5 if you start touching the AVM, and the risk of having a functional deficit multiplies by 2.5 and there's no benefit for epilepsy and headaches," he said, and this was true of all treatment modalities and all AVM subgroups.
"Now, ARUBA is a stroke prevention trial that has shown the largest effect ever seen in such a trial, with an 80% risk reduction of death and stroke when you don't touch the disease," Dr Stapf added wryly. "The treatment choice is available world-wide and at low cost."
The findings should be systematically disclosed to patients, he said, "and based on current knowledge, we have to assume that interventions may be dangerous — number needed to harm, 5 (over 5 years) — cannot be safely recommended, and should only be offered as part of another controlled clinical study."
The results were presented here at the International Stroke Conference (ICS) 2016.
AVM, tangles of abnormal brain vessels with falsely linked arteries and veins, is considered a rare disease. It can be asymptomatic or present with headaches, deficits, seizures, or, "worst-case scenario," hemorrhage.
The wider use of MRI has meant that a lot of lesions that are otherwise asymptomatic come to light in clinical practice, Dr Stapf said. "For every 100 MRIs you will find an unruptured aneurysm, for every 500 MRIs you will find an asymptomatic cavernoma, for every 2000 MRIs you will find an asymptomatic AVM."
What to do about those asymptomatic lesions has become a pressing medical issue.
ARUBA was a prospective, multicenter, parallel-design, open, randomized controlled trial comparing medical management with interventional therapy in patients with unruptured AVMs.
At the time the study was begun, the medical management arm was actually the experimental approach, and the interventional arm with the aim of "best possible AVM eradication" was considered the standard of care. Invasive treatment included any combination of interventional procedures, neurosurgery, or radiation therapy.
The primary outcome was death from any cause, or any symptomatic stroke (hemorrhage or infarction). The secondary outcome was risk for death or clinical impairment, defined as a modified Rankin Scale (mRS) score of 2 or higher 5 years after randomization.
The trial was halted in May 2013 by the National Institute of Neurological Disorders and Stroke–appointed Data and Safety Monitoring Board (DSMB) after an interim analysis because of higher than expected event rates in the interventional group.
The risk for death or stroke was significantly lower in patients followed without intervention (hazard ratio, 0.27; 95% confidence interval [CI], 0.14 - 0.54). The DSMB recommended pursuing the planned 5-year follow-up to determine whether these differences persist over time, the authors note.
Overall, 226 of the planned 400 patients (aged 18 years or older, diagnosed with an unruptured brain AVM suitable for curative intervention) were enrolled and randomly assigned to best possible invasive therapy or to medical management alone. By definition, untreatable AVMs were excluded, and more than half were more easily treatable AVMs, Spetzler-Martin I and II.
The primary outcome for patients in the "as randomized" analysis showed that the medical management group continued to have a lower risk for stroke and death, with a hazard ratio of 0.31 (95% CI, 0.17 - 0.56; P < .001).
"If you still considered treatment despite these data, the number needed to harm was 5 patients over 5 years," Dr Stapf said.
These "as randomized" results were based on 41 primary endpoints in the interventional group vs 15 events in the medical management group, he noted. However, 8 patients randomly assigned to medical management crossed over to the interventional group, 15 patients assigned to interventional therapy never received therapy because the trial was halted, and 3 patients sustained a stroke before initiation of the interventional therapy.
When the authors analyzed the data "as treated," the effect was even stronger, Dr Stapf said, "with an almost 80% reduction in death and stroke when you do not touch the AVM (hazard ratio, 0.22; 95% CI, 0.12 - 0.41; P < .0001), and the number needed to harm on treatment is 3 patients."
For the secondary outcome of death or disability in 96 patients in the "as randomized" analysis at 5 years, 38% had an mRS score of 2 or higher in the interventional group vs 18% in the medical management group, mainly because of stroke (relative risk, 0.46; 95% CI, 0.23 - 0.94). "Remember all patients were at Rankin 0 and 1 at entry," he noted. Again the difference was again stronger when analyzed "as treated."
Serious adverse events showed significantly more strokes, focal deficits independent of stroke, and epileptic seizures associated with treatment, and no advantage for intervention in the occurrence of headache.
Sensitivity analysis showed no subgroup on the basis of age, sex, symptomatic status, AVM size, or world regions participating in the trial. "There is one subgroup, the Spetzler-Martin I group, that shows a nonsignificant trend favoring intervention, but that effect disappears in the as-treated analysis," he said.
The intervention was carried out an average of 2 months after randomization, he said, "and if you look at patients undergoing treatment who had a primary endpoint event, the median time between treatment and the event was 1 day, suggesting a relationship."
Among the 66 patients who underwent an endovascular intervention, 33 (50%) had a primary endpoint event; of 22 who had surgery, 41% had a primary endpoint event; and of 57 patients undergoing radiotherapy, 36.8% had a primary endpoint event.
"These effects remained the same if patients were treated only by one modality, or by multimodal treatment," Dr Stapf concluded.
Asked for comment, Mark J. Alberts, MD, vice-chair, Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas, called the findings "enlightening."
"It confirmed what we heard from the first report, that sometimes just good medical therapy is the way to go," Dr Alberts told Medscape Medical News.
"These lesions are very complex, they're very hard to treat, and I think it shows the need from my perspective, of better neurosurgical and other interventions for AVMs," he added. "It's good that doing nothing is a good option," he said, but sometimes intervention is necessary. AVMs bleed, they can cause neurologic deficits and seizures, and they can divert blood from normal brain.
"So while I don't think this should be seen as a failure of surgical and other types of therapy, it should be seen as an opportunity for us to improve our other interventions, get them more effective, and get them safer," Dr Alberts concluded.
ARUBA was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke.
International Stroke Conference (ICS) 2016. Abstract LB11. Presented February 18, 2016.
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Cite this: Less Is More: ARUBA Confirms Intervention Unwise in Unruptured AVM - Medscape - Feb 19, 2016.