FDA Panel Considers the Future of Intracranial Stenting

Susan Jeffrey

March 27, 2012

March 27, 2012 — The US Food and Drug Administration's (FDA's) Neurological Devices Advisory Committee considered the continued use of intracranial stenting with the Wingspan Stent System with the Gateway PTA Balloon Catheter (Stryker Neurovascular) at a panel meeting March 23. Although there was no formal vote for or against, panel members appeared to be clear that intracranial stenting has little benefit for most patients according to results of the Stenting vs Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial, at least with the technique as it stands.

However, many panel members weren't ready to give up on it entirely, appearing reluctant to have the option taken away altogether.

The Wingspan system was approved for the treatment of intracranial arterial stenosis on August 3, 2005, under a Humanitarian Device Exemption (HDE) that allowed its use in "improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease, refractory to medical therapy, in intracranial vessels with ≥50% stenosis that are accessible to the system."

However, the unexpected main results from the Stenting vs Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial, published last year in the New England Journal of Medicine, showed that medical management was superior to and safer than similar management with the addition of intracranial stenting in patients with a stroke or transient ischemic attack (TIA) attributed to stenosis of a major intracranial artery. The advantage was the result of both increased early risk with the stent procedure and better than expected results with current medical management.

A subanalysis from SAMMPRIS presented in February at the International Stroke Conference 2012, and reported by Medscape Medical News at that time, showed that the benefit of medical management was similar in patients whether or not they were receiving antithrombotic therapy at the time of their qualifying event for study enrollment.

"These findings support those from the earlier Warfarin-Aspirin Symptomatic Intracranial Disease study, or WASID: that this antithrombotic failure group does not identify a higher-risk subgroup of patients with intracranial stenosis," lead author Helmi L. Lutsep, MD, professor, vice chair, and associate director, Oregon Stroke Center, Department of Neurology, Oregon Health and Science University, Portland, concluded at that time.

In addition, representatives from the FDA did their own subanalyses of the SAMMPRIS data and presented these during the meeting.

"None of the adequately powered subgroup analyses of the SAMMPRIS trial showed a benefit with the use of stenting in addition to aggressive medical therapy for the 30-day endpoint," the FDA presentation concluded. Some subgroup analyses showed nominally worse outcomes with the use of both stenting and aggressive medical management, they noted, but there was insufficient evidence to allow conclusions to be drawn about other subgroup comparisons, and insufficient long-term data.

Three Questions

These findings have now led to the FDA's revisiting the basis of that HDE. They brought several questions forward to the Neurological Devices panel, including some preliminary discussion about how to define "refractory to medical therapy," after the great results with medical management in the SAMMPRIS trial.

After the discussion, panel chair Lynda J. Yang, MD, PhD, from the University of Michigan, Ann Arbor, summed up that medically refractory patients would be those with a 70% to 99% occlusion of an intracranial artery, with a single event (either a TIA or stroke), while receiving blood pressure- and cholesterol-lowering agents or antithrombotic therapy and undergoing smoking cessation, and with consideration for those with impaired hemodynamics.

The panel members then considered 3 main questions posed by the FDA.

1. The approval criteria for an HDE is that the probable benefit to health from use of the device outweighs the risk for injury or illness from its use, taking into account the probable risks and benefits of other available devices or forms of treatment. For the current HDE, then, the FDA asked the panel to consider whether 30-day results from the medically refractory patients in SAMMPRIS, as well as other pre- and post-market data, continue to support probable benefit to health for this indication.

Most panel members answered "no" to this question, given the SAMMPRIS data. Further to this, though, the FDA asked the panel to speculate on any subpopulation of patients allowed intracranial stenting under the HDE who may still benefit, such as those with a history of stroke before their qualifying event, or the type of qualifying event.

This time, panel members were more divided. Larry B. Goldstein, MD, from Duke University Medical Center in Durham, North Carolina, pointed out, "I'm still concerned, as are my interventional colleagues, about that 1 particular subgroup of patients where we are backed up against the wall, and we have no options" — those in whom the symptoms indicate a hemodynamic problem.

"We're talking about a humanitarian device exemption for a population that's going to be vanishingly small, but for whom we have no choice," Dr. Goldstein said. "I'd much rather my interventional colleagues have a device that they feel comfortable with and is superior, at least technically, to a device that wasn't designed for that purpose."

Karen C. Johnston, MD, from the Departments of Neurology and Public Health Science at the University of Virginia, Charlottesville, suggested that if the HDE were withdrawn, any patients who might still benefit could be enrolled into a clinical trial and procedures could perhaps be consolidated into centers of excellence. "Then we could actually take these patients and offer them this treatment in an organized clinical trial mechanism, and actually learn something in a standardized way," she suggested.

Industry representative Sergio J. Gadaleta, PhD, from Becton Dickinson in Franklin Lakes, New Jersey, cautioned that if the HDE were withdrawn, Stryker might elect to withdraw manufacture of the intracranial stent, and that would preclude further study.

In a final part of the question, the FDA asked whether further data on clinical efficacy should be collected on the safety and efficacy with use of the Wingspan device. Most now voted "yes." However, Christopher M. Loftus, MD, DHC (Hon), from Temple University School of Medicine in Philadelphia, did not. "I want to say yes too, but the trouble is I think patients are at risk with this device based on the data that we've seen, so what patients are we going to say we should keep doing it to?"

Neurosurgeon Donald E. Richardson, MD, from the Department of Neurosurgery at Tulane University Health Science Center School of Medicine in New Orleans, Louisiana, pointed out that continued study of intracranial stenting will require evolution of the technique. "This falls under the Einstein Principle, that you can't keep doing the same thing and expect different results."

Early efforts with many operations were risky for patients, but they have evolved into life-saving options, he pointed out.

2. The FDA noted in their second question that of the 33 strokes that occurred in the stenting group, 25 occurred within 1 day of the procedure, a higher rate than seen in previous uncontrolled studies of the Wingspan stent. They asked the panel to discuss the types and rates of periprocedural events in SAMMPRIS, and what strategies might mitigate these rates.

Dr. Johnston noted that the point estimate of the 30-day rate of stroke and death is 14.7%, a percentage that falls well within the confidence intervals of all the previous studies. "So what I think we have now is a precise and valid estimate," from a randomized trial, she said.

Dr. Goldstein agreed that the point estimate for stroke and death in SAMMPRIS was not essentially different from that seen in previous studies. "As for strategies that could mitigate it, that's a multivariate question. I think there are a legion of potential things that could go wrong and do go wrong — potentially could go wrong during procedures," he added. He pointed out, though, that most strokes were in the vascular territory fed by the vessel stented.

"I'm wondering whether some of these hemorrhages might have been ischemic strokes with secondary hemorrhagic conversion given that these patients were on a whole bunch of other things including dual antiplatelet therapy," he noted. Still, about a quarter of strokes were in other territories in both the medical group and the stent group, Dr. Goldstein added, underlining that this population is at very high overall risk for stroke.

Huy M. Do, MD, from Stanford University School of Medicine, California, said he felt the early events were probably due to perforation and "so [were] technically related; there may be a few that are due to hypoperfusion due to long-standing misery perfusion, perhaps." He suggested that doing an angioplasty first, and then considering placement of a stent if the angioplasty is not sufficient, might cut down on the risks associated with each step. "Each time you navigate into the intracranial vasculature, that's another risk factor that you take."

Dr. Loftus reiterated that the highest level of evidence is the randomized trial. "The randomized trial represents what trained people can do who presumably were expert at the time of their vetting and selection, and what we can anticipate would happen if the device was released for general use across the population," he said.

Dr. Loftus compared the disappointing SAMMPRIS results to those seen in the recently reported Carotid Occlusion Surgery Study (COSS), which showed, again, that extracranial-intracranial carotid bypass surgery offered no benefit, and has changed practice with that procedure.

"We were looking for little itty-bitty indications to do it in the face of an atherosclerotic indication that was disproved, and we have learned, despite some displeasure, to accept that," he said.

Dr. Yang summed up, saying that the procedural complications were "on everybody's mind, and experience and teamwork, and some regulation of the training might be in order, especially to avoid what Dr. Loftus said about releasing this into inexperienced hands, that may cause unexpected complications."

3. Finally, the FDA asked whether panel member believe that the available data are adequate to assess any potential long-term benefit of the Wingspan System. From the available information, they were asked to discuss the potential for longer-term benefit in the setting of shorter-term perioperative risk for patients.

The short answer for the first part of question 3 was "no" for most panel members, Dr. Yang noted. Most felt it would be instructive to see the long-term data, although she agreed with at least 1 of the panel members who pointed out that the risk in the medical group would have to go up significantly for the curves to cross as it stands.

Although some pointed out that the long-term data from SAMMPRIS are unlikely to change the view that medical therapy is superior, others pointed out that the long-term data would be useful.

Scott R. Evans, MD, from Harvard Medical School in Boston, Massachusetts, held this latter view. "I think it's good we'll get some long-term data in the trial. It's very difficult to interpret what would happen if the Kaplan-Meier curves crossed." It would require more sophisticated statistical techniques, some of the assumptions would no longer hold, "and if you wait long enough, they come together anyway," he noted wryly, drawing laughter from the panel.

However, future long-term trials might be difficult to get past institutional review, he added, because they "aren't going to allow serious differences early on to continue throughout, so I think the SAMMPRIS trial was probably our opportunity to find out what's happening long-term," he said.

Some also pointed out that longer-term data would allow some evaluation of whether the benefits in the medical group were also maintained over time.

Dr. Do said he will be interested to see what the stent restenosis rate will be and whether any restenosis is symptomatic. "Also I wish there was a way to continue to follow those who failed aggressive medical management, the 12%, and what subsequently is offered to those patients and what happens to them."

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