SAMMPRIS Published: What Next for Intracranial Stenting?

Susan Jeffrey

September 07, 2011

September 7, 2011 — Results of a large, randomized trial show that aggressive medical management was superior to similar therapy plus angioplasty and stenting, using the Gateway-Wingspan stent system (Stryker Neurovascular/Boston Scientific Neurovascular), for patients with symptomatic intracranial stenosis. The advantage was a result of the combination of both increased early risk with the stent procedure and better-than-expected results with medical therapy, researchers say.

Results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial, which was supported by the National Institute of Neurological Disorders and Stroke (NINDS) among others, were published online September 7 in the New England Journal of Medicine.

Both of these major findings were unexpected, lead author Marc I. Chimowitz, MB, ChB, from the Medical University of South Carolina Stroke Program in Charleston, told Medscape Medical News.

Dr. Marc I. Chimowitz

"The stenting complication rate was much higher than we'd anticipated, which was the bad news. The good news, however, was that, as opposed to a 15% risk reduction with usual medical management, we observed risk reduction in the aggressive medical management [group] that was about 50% lower than it was in WASID," a previous trial with the same primary endpoint comparing aspirin and warfarin, on which Dr. Chimowitz was also principal investigator.

"So while we didn't make any advances with stenting in this trial, we made some huge advances with the aggressive medical management strategy," he said.

Important Cause of Stroke

Results of that previous trial, the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, showed aspirin was as effective as warfarin. "But what we found out is there is a subgroup of patients with 70% to 99% intracranial stenosis and recent symptoms [who] were at very high risk for stroke, despite aspirin or warfarin and usual management of risk factors," Dr. Chimowitz said.

Post hoc analysis of that trial suggested that more aggressive medical therapy, defined as combination antiplatelet therapy and intensive management of risk factors such as cholesterol and hypertension, could improve outcomes, he noted. At about the same time, intracranial stenting began to emerge as a promising option, and ultimately the Wingspan stent received a humanitarian device exemption approval in 2005 from the US Food and Drug Administration for use in patients with a 50% to 99% intracranial stenosis and a transient ischemic attack or stroke despite antithrombotic therapy.

In SAMMPRIS, the researchers identified a high-risk group of patients with a recent transient ischemic attack or stroke that was attributed to a 70% to 99% intracranial stenosis, and randomly assigned them to receive aggressive medical management, with or without the addition of intracranial angioplasty and stenting using the Wingspan system. The primary endpoint was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period, or stroke in the territory of the qualifying artery beyond 30 days.

On April 5 this year, enrollment was stopped after 451 patients on the recommendation of the trial's independent data and safety monitoring board, both because of concerns about increased periprocedural stroke and death in the stenting group and because futility analyses showed no chance for benefit from stenting during the follow-up period. Events in this analysis include those up to April 28, when the last patient enrolled met 30-day follow-up.

At 30 days, the rate of stroke or death was significantly higher with intracranial angioplasty and stenting than that seen with aggressive medical management in this trial, and substantially higher than rates previously reported with the Wingspan stent.

SAMMPRIS: Primary Endpoint

Endpoint Intracranial Stenting Aggressive Medical Management P
30-Day Rate of Stroke or Death (n, %) 33 (14.7) 13 (5.8) .002

There were 5 stroke-related deaths in the stenting group (2.2%) and 1 non-stroke-related death in the medical management group (0.4%). Of the 33 strokes in the stent group, 10 (30.3%) were symptomatic brain hemorrhages compared with none of the medical management events (P = .04).

Beyond 30 days, nonfatal stroke in the same territory as the qualifying artery occurred in 13 patients in each group, but at 1 year, rates of the primary endpoint events remains significantly higher in the stented group, at 20.0% vs 12.2% with medical management (P = .009).

Asked whether intracranial stenting should continue, Dr. Chimowitz cautioned that they have not studied other intracranial stents used off-label. However, "based on a 14% risk of stroke or death with this particular device...if you look at the results of the trial, I think they speak for themselves. I know that I haven't recommended it since the results of the study."

There is another industry-sponsored study still ongoing, he noted, using a balloon-mounted intracranial stent — another approach that reduces manipulation of the artery compared with the self-expanding type of stent that requires angioplasty first. "In practice, many interventionists do use balloon-mounted coronary stents in the brain, but the other trial that's going on is using, I believe, a balloon-mounted stent designed specifically for the brain, and in that trial they're not comparing it to aggressive medical management, they're comparing it against usual medical management."

The SAMMPRIS results echo the debate now ongoing, with regard to carotid stenting in comparison with carotid endarterectomy, about whether best medical management could potentially obviate the need for many of these interventions, and suggesting that a medical management group be included in any comparison of interventional strategies.

The Power of Reimbursement

In an editorial accompanying the publication, Joseph P. Broderick, MD, from the University of Cincinnati College of Medicine, Ohio, points out that this is the third recent trial to show no benefit of revascularization of intracranial vessels over medical management in preventing recurrent stroke, despite the success of these strategies in improving blood flow in the affected arteries.

Dr. Joseph P. Broderick

"It's an example of how a trial can be done well, the government does its job correctly, and you get an answer that may not be what you hoped for, but at least it will inform clinical practice," Dr. Broderick told Medscape Medical News. "It's another step," he added. "It's not saying that there will never be an intervention that helps better prevent stroke, it just illustrates the challenges, and it illustrates why we need randomized trials."

In the editorial, he points out that symptomatic intracranial hemorrhage, a rare complication after revascularization of extracranial stenosis, accounted for one third of events, most of which were attributed to reperfusion hemorrhages or subarachnoid hemorrhage from wire manipulations during the procedure.

"This latter complication emphasizes the fact that stenting of the intracranial vasculature is technically more challenging than is stenting of the extracranial carotid artery because of the tortuous course of the internal carotid artery, and arterial diameters that are smaller overall than those in the extracranial circulation," he writes.

So where does this leave stenting? "I think at least at this point in time, using the stents we have available, it leaves a very limited subset of patients who may be still considered for stenting," Dr. Broderick said. There are patients who have such critical blockages that they are extremely symptomatic and debilitated, for whom even a small decrease in the lesion may bring about improvement, despite the fact that the patients will also be at increased risk for complications.

"The SAMMPRIS trial is also a great example of how CMS [the Centers for Medicare and Medicaid Services] can accelerate our understanding of what best practice should be," he added. After the FDA approval, "there was a lot of pressure to have this reimbursed outside of trials, and that can lead to proliferation of devices and their use, and almost an establishment of what's standard practice."

Instead, CMS limited reimbursement to those stents placed within the auspices of a randomized trial. "It just shows the power of how CMS can affect what we do as we establish clinical practice based on scientific trials."

Conversely, devices for clot retrieval for acute stroke are already both approved and reimbursed, whereas randomized trials are only now underway. Dr. Broderick is principle investigator of the Interventional Management of Stroke 3 trial, which is looking at different revascularization strategies, including these devices. "The enrollment in those trials has lagged, and that's probably part of the reason. If they'd only been reimbursed as part of a randomized trial, we'd probably be done," he noted.

Walter Koroshetz, MD, deputy director of the NINDS, agreed that clinical trials such as this one are critical.

"It's a generic issue in vascular disease, in that our technology is advancing, we have very good ability to see the blood vessels, and then in patients who are high risk, to try to use technology to make the blood vessels look better on the pictures is very intriguing," Dr. Koroshetz told Medscape Medical News. "But it still remains a question of whether doing that actually improves the outcome of patients."

In this case, the trial did not show that angioplasty and stenting were sufficiently safe to provide a benefit, underlining the importance of outcomes trials like this one. He also agreed that the limited reimbursement for intracranial stents played a key role in getting this trial done. "Without that, we'd have trouble finishing the trials; if the devices are paid for before the evidence is in, it's hard to get the evidence."

Real-World Risk Management

Despite the excellent results seen with aggressive medical management in this trial, however, it is not clear this could be replicated in real-world clinical practice as it stands.

Ralph Sacco, MD, chairman of neurology at the Miller School of Medicine at the University of Miami, Florida, pointed out that the medical therapy given in the trial was "very intensive, quite well done, and should be, but isn't, done in the community as much as it should be."

Dr. Ralph Sacco

For example, low-density lipoprotein (LDL) levels in the medical group went from 98 mg/dL to 73 mg/dL within 4 months, "which is a big drop in LDL." Blood pressure, and even hemoglobin A1C levels for those with diabetes, was significantly reduced.

Still, aggressive medical management was offered to both groups, but for those offered the additional revascularization procedure, "the angioplasty and stenting wasn't found to be safe enough to alter that risk for recurrent stroke," Dr. Sacco noted. "I think technically, we may not be ready for prime time with angioplasty and stenting for intracranial disease."

Part of the problem with aggressive risk factor management is establishing who is ultimately responsible for it, Dr. Broderick added. "Is it the responsibility of the internist or family practice physician who sees the patients on a regular basis? Is it the responsibility of stroke neurologist, even though there may not be great stroke programs in a lot of regions?"

Philip B. Gorelick, MD, MPH, John S. Garvin professor and head of the Department of Neurology and Rehabilitation, and director of the Center for Stroke Research, at the University of Illinois College of Medicine at Chicago, pointed out that in some trials, investigators are simply encouraged to follow national guidelines for risk factor control. In this trial, however, "an enormous effort was made to assure that target goals for risk factors were met and lifestyle modification was seriously undertaken," he told Medscape Medical News. "All of this was done under the supervision of neurologists — another unique practice feature."

On the basis of the SAMMPRIS findings, however, aggressive medical management should now be the first-choice therapy for patients with symptomatic high-grade intracranial artery stenosis. "A 'one size fits all' [stenting] strategy may not be adequate, and one wonders if in future studies, a more efficacious stent will surface for intracranial occlusive disease, and whether selective angioplasty might be a better strategy for some patients," Dr. Gorelick concludes.

The study was supported by NINDS. Disclosures for researchers and editorialist are available on the journal's Web site.

N Engl J Med. Published online September 7, 2011. Article full text, Editorial

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