Stenting pales against meds alone for intracranial stenosis: SAMMPRIS trial

Susan Jeffrey

September 08, 2011

Boston, MA - 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 in a large randomized trial [1]. The advantages of invasive therapy for the primary end point, consisting mostly of stroke or death, and secondary end points were due to a combination of both increased early risk with the stent procedure and better-than-expected results with medical therapy, researchers say.

In fact, both of those major findings were unexpected, according to lead author Dr Marc I Chimowitz (Medical University of South Carolina, Charleston), principal investigator for the trial, called Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS), which was published online September 7, 2011 in the New England Journal of Medicine.

 
T echnically , w e may not be ready for prime time with angioplasty and stenting for intracranial disease.
 

"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 that was about 50% lower than it was in WASID," a previous trial with the same primary end point comparing aspirin and warfarin, on which 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."

The researchers had identified a high-risk group of patients with a recent transient ischemic attack (TIA) or stroke attributed to a 70% to 99% intracranial stenosis and randomized them to receive aggressive medical management, with or without the addition of intracranial angioplasty and stenting using the Wingspan system. The primary end point 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, 2011, enrollment was stopped after 451 patients, out of concern about an increased periprocedural stroke and death risk in the intervention group and because futility analyses showed no chance for benefit from stenting over the follow-up period. An enrollment of >750 patients and a mean follow-up of two years had been planned.

Follow-up continued until all patients had reached the 30-day mark, at which point the rate of stroke or death was significantly higher with angioplasty/stenting than with medical therapy alone and substantially higher than rates previously reported with the Wingspan stent.

P rimary e nd point at 30 days in SAMMPRIS

End point
Intracranial stenting , n=224 (%)
Aggressive medical management , n=227 (%)
p
30- d stroke or death
14.7
5.8
0.002

There were five stroke-related deaths in the stenting group (2.2%) and one non-stroke-related death in the medical-management group (0.4%). Of the 33 strokes in the stent group, 30.3% were symptomatic brain hemorrhages, compared with none in the medical-management group (p=0.04).

Beyond 30 days, nonfatal stroke in the same territory as the qualifying artery occurred in 13 patients in each group, but at one year, rates of the primary-end-point events remained significantly higher in the invasive-therapy group, at 20.0% vs 12.2% with medical management (p=0.009)

Asked whether intracranial stenting should continue in such patients, 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 interventionalists 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 with aggressive medical management, they're comparing it against usual medical management."

A trial done well, but not the answer hoped for

In an accompanying editorial [2], Dr Joseph P Broderick (University of Cincinnati College of Medicine, OH), points out that SAMMPRIS 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.

"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," Broderick said in an interview. SAMMPRIS was funded by the National Institute of Neurological Disorders and Stroke (NINDS).

"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 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," Broderick said. There are patients who have such critical blockages that they are extremely symptomatic and debilitated, so that even a small decrease in the lesion may bring about improvement, despite the fact that they will also be at increased risk for complications.

Clinical trials such as SAMMPRIS are critical, agreed NINDS deputy director Dr Walter Koroshetz. "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," he said when interviewed. "But it still remains a question of whether doing that actually improves the outcome of patients." The answer this time: angioplasty/stenting was not sufficiently safe to provide a benefit.

Real-world risk management

On the other hand, it's not clear that the excellent results seen with aggressive medical management in SAMMPRIS could be replicated in real-world clinical practice as it stands.

Dr Ralph Sacco (University of Miami, FL) pointed out that the medical therapy given in the trial was "very intensive, quite well done; it should be but isn't done in the community as much as it should be." And 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 of recurrent stroke, Sacco said.

"I think technically, we may not be ready for prime time with angioplasty and stenting for intracranial disease."

Dr Philip B Gorelick (University of Illinois College of Medicine, Chicago) said 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 ensure that target goals for risk factors were met and lifestyle modification was seriously undertaken," he said when interviewed. "All of this was done under the supervision of neurologists, another unique practice feature."

The study was supported by the NINDS. Chimowitz has received grants and consulting fees or honoraria from NINDS. Disclosures for the coauthors are listed in the paper. Broderick discloses that the University of Cincinnati was a SAMMPRIS site, but he was not an investigator and did not receive any monies for participation.

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