Medical Management Still Bests Intracranial Stenting

Pauline Anderson

October 31, 2013

The superiority of aggressive medical management over similar treatment plus stenting in patients with a stroke or transient ischemic attack (TIA) resulting from stenosis of a major intracranial artery has now been extended to up to 4 years.

"We found, sort of unexpectedly, that the medical event rate in the medical management group remained incredibly low, almost half the rate that we had projected based on some very good prospective trials we had done in the past," said lead author, Colin P. Derdeyn, MD, director, Stroke and Cerebrovascular Center, Barnes-Jewish Hospital, and professor, radiology, neurology, and neurosurgery, Washington University School of Medicine, St. Louis, Missouri. "We expected a 2-year risk of stroke in the medical group in the high 20s, and it ended up being about 14%."

The new, longer-term results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial were published online October 26 in the Lancet. Results were presented the same day at joint meetings of the 6th International Conference on Intracranial Atherosclerosis and the 6th Annual Meeting of the Society of Vascular and Interventional Neurology in Houston.

SAMMPRIS Trial

The multicenter SAMPRISS trial began in 2008 with enrollment of patients aged 30 to 80 years who had nondisabling stroke or TIA within 30 days that was attributable to 70% to 99% atherosclerotic stenosis of a major intracranial artery. These patients were randomly allocated to either an aggressive medical management group or a stenting group.

Medical management included dual-antiplatelet therapy (clopidogrel for 90 days, aspirin for the entire follow-up), risk factor management that primarily targeted systolic blood pressure and low-density lipoprotein cholesterol, and lifestyle modification.

The stenting group received the same aggressive management in addition to percutaneous transluminal angioplasty and intracranial stenting with the Gateway-Wingspan stent system (Stryker Neurovascular). The Wingspan was approved in 2005 under the US Food and Drug Administration's (FDA's) Humanitarian Device Exemption program, based on earlier smaller studies.

The primary endpoint was stroke or death within 30 days after enrollment or after either a revascularization procedure for the qualifying lesion during follow-up or a stroke in the territory of the qualifying artery beyond 30 days.

In April 2011, enrollment was halted early on the recommendation of the trial's independent data and safety monitoring board because of concerns about increased rate of stroke and death in the stenting group and a lower than expected stroke rate in the medical therapy group.

Early results, published online September 7, 2011, in the New England Journal of Medicine, and reported by Medscape Medical News at that time, showed that at 30 days, the rate of stroke or death was significantly higher (P = .002) with intracranial stenting (14.7%) compared with that seen with aggressive medical management alone (5.8%).

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 remained significantly higher in the stented group (20.0% vs 12.2% with medical management; P = .009).

At the time the trial was stopped, less than half the 451 patients had been followed-up for longer than 1 year. Now, with follow-up extended for between 2 and 4 years, researchers have released longer-term results for the 227 patients in the medical group and 224 patients in the stenting group.

The new analysis found that the occurrence of primary endpoint events in the medical group compared with the stenting group were 14.1% vs 20.6% at year 2 (P = .07) and 14.9% vs 23.9% at year 3 (P = .0193)

The researchers performed a number of sensitivity analyses to generate data for patients withdrawing or becoming lost to follow-up. None of these analyses resulted in the probability of a primary endpoint being less common in the stenting group than in the medical group.

As for secondary endpoints, the researchers found that the rates of any stroke (P = .0468) and any major hemorrhage (P = .0009) were statistically significantly lower in the medical group than in the stenting group.

"This aggressive medical management regime apparently has a very profound, very dramatic impact," Dr. Derdeyn commented to Medscape Medical News. "Even if we cut the complication rate to about a third of what it was, stenting still would not have been superior because the medical management was so good."

The dual-antiplatelet aspect of the regime likely played an important role in these positive results with medical management, as did risk factor management, according to Dr. Derdeyn. "Dual anti-platelets are probably responsible for the dramatic reduction we see in the first month, but the statins also probably have some impact in the first month. The blood pressure control, the [low-density lipoprotein] control, and probably lifestyle management, along with the statins, have a really profound impact beyond the first 30 days."

Fragile Arteries

Although intervention in the carotid and heart has had very positive results, "angioplasty and stenting in the head is a lot more high risk than anywhere else because the arteries are really fragile," explained Dr. Derdeyn. "There are little microscopic branches that come off the artery right where the plaque is, and just opening it up with angioplasty can cause stroke."

Complications of bleeding in the brain make stenting in this area that much more complex, added Dr. Derdeyn.

In August 2012, the early SAMMPRIS results led the FDA to alter the criteria for using the Wingspan stent. The new guidelines include restricting use of this stent to patients with at least a 70% blockage who have had 2 previous strokes while receiving aggressive medical management.

The researchers now have "a ton of data to pore through," said Dr. Derdeyn. Among the next steps might be addressing the questions of which patients do worse on medical management and whether angioplasty without stenting might be of some benefit.

It is also important to identify high-risk patients who may still benefit from stenting. This would be a rare group but could include patients who continue to have symptoms despite taking dual-antiplatelet therapy and having their blood pressure and cholesterol brought under control, said Dr. Derdeyn.

"But anything we do next we have to make sure it's in a high-risk group; it's not going to be ethical to take the same type of people who came into the SAMPRISS trial and test therapies on them because we know that the stroke rates are so low with medical therapy."

As well, the researchers plan to look more closely at the role lifestyle management played in the SAMPRISS trial. They expect to present some updated results at a stroke meeting early next year, said Dr. Derdeyn.

"No Longer First-Line Treatment"

In an accompanying commentary, Peter M. Rothwell, MD, PhD, from the Department of Neurology, University of Oxford, and Hugh S. Markus, professor, Department of Clinical Neurosciences, University of Cambridge, United Kingdom, said the new results show that the data and safety monitoring board "seems to have been correct in stopping recruitment" of the SAMMPRIS trial.

They note that the investigators rebutted criticisms of the trial that include the inexperience of the interventionists, the sole use of the Wingspan stent, preclusion of primary angioplasty without stenting, and the high proportion of trial subjects with perforator transient ischemic attacks and strokes.

Although the need for stenting will continue in individual cases, especially after recurrent events on maximum medical treatment, stenting "can no longer be regarded as a first-line treatment for intracranial stenosis," said the commentators.

New approaches to intracranial stenting should now be explored only within the context of randomized controlled trials, they write.

"The value of stenting over and above intensive medical treatment in recently symptomatic vertebral artery stenosis remains uncertain," the commentators point out. "There were few patients with intracranial vertebral stenosis in SAMMPRIS, and none with extracranial stenosis, for which the procedural risks seem to be low."

Ongoing randomized trials of vertebral artery stenting, including the Vertebral Artery Ischemia Stenting Trial (VIST), on which Dr. Rothwell and Dr. Markus are co-chief investigators, should therefore continue, they said.

They also note the low 3-year risk for stroke on intensive medical management alone in the trial and write that this "suggests that the benefits of intensive medical treatment are maintained in the longer term."

Design Issues?

Asked to comment on these new developments, Alex Abou-Chebl, MD, professor, neurology, and director, neurointerventional services, University of Louisville School of Medicine, Kentucky, said that from the beginning, he took issue with the design of the trial and had refused to participate in it.

One of the main issues for Dr. Abou-Chebl was inappropriate patient selection, which he said could have biased the trial toward better outcomes in the medical group. "In my practice, I only put stents in patients who have hemodynamic significant lesions that are assessed by physiologic studies, like [single-photon emission computed tomography] scans or profusion imaging, but that wasn't mandatory in the SAMMPRIS trial, so I think they took patients who were going to do well with medical therapy."

Another of Dr. Abou-Chebl's concerns was operator inexperience. "To be in SAMMPRIS, you didn't even have to have used that stent before; all you had to have done is employ a similar stent in people with aneurysms," he said. "Well, that's a different disease."

Although the investigators were well intentioned, Dr. Abou-Chebl said, the trial took place "before the procedure was ready for prime time in a sense."

He also expressed concern about the time lag between the qualifying event and randomization into the trial, which could have resulted in reducing the risk of having another event. The "ideal" patients to be enrolled into a trial like SAMMPRIS, he said, are the ones who have frequent events "over and over again," not the ones who are stable and had only a single event.

"Most of those in SAMMPRIS hadn't failed medical therapy; most of us would not have treated those patients with a stent," said Dr. Abou-Chebl.

Although not a perfect stent, the Wingspan is safe and should not be "written off," he said. "The problem with an across-the-board statement that this procedure should not be done is that there are real people who are having strokes every day who would benefit from this treatment; they just were not studied in this trial."

Dr. Abou-Chebl also responded to the FDA's tightening of criteria for using the Wingspan stent to those having had 2 strokes instead of 1. "So you need to lose even more brain before we will treat you. That doesn't make any sense," he said.

The study was funded by a research grant from the US Public Health Service National Institute of Neurological Disorders and Stroke and by Clinical and Translational Science Awards from the National Institutes of Health to the Medical University of South Carolina, the University of Florida, the University of Cincinnati, and the University of California, San Francisco. Dr. Derdeyn has associations with companies that manufacture medical devices for the treatment of cerebrovascular disease in general, although none directly involved in this study: WL Gore and Associates (scientific advisory board and consultant), Microvention (Angiographic Core Laboratory for clinical trial), Penumbra (Data and Safety Monitoring Board member for clinical trial), and Pulse Therapeutics (chair, scientific advisory board). Dr. Abou-Chebl is a local principal investigator for the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial and is on the speaker's bureau at BMS/Sanofi.

Lancet. Published online October 26, 2013. Article abstract, Commentary extract

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....