Medical Management Bests Stenting in Antithrombotic Failure

Susan Jeffrey

February 10, 2012

February 10, 2012 (New Orleans, Louisiana) — New analysis of data from a randomized trial comparing aggressive medical management with intracranial stenting confirms the advantage of medical management, even among patients with occlusive intracranial stenosis who had a stroke or transient ischemic attack (TIA) while receiving antithrombotic therapy.

This subanalysis, from the Stenting vs Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial, was presented here at the International Stroke Conference (ISC) 2012.

The unexpected main results from SAMMPRIS, published last year in the New England Journal of Medicine, showed that medical management was superior and safer than similar management with the addition of intracranial stenting, using the Gateway-Wingspan stent system (Stryker Neurovascular), in patients with a stroke or 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.

Dr. Helmi L Lutsep

Helmi L. Lutsep, MD, professor, vice chair, and associate director, Oregon Stroke Center, Department of Neurology, Oregon Health and Science University, Portland, concluded that in this new analysis, 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," Dr. Lutsep pointed out.

Although those who had been receiving antithrombotic therapy had more cardiovascular risk factors than those who had not, she added, "we find that, if anything, this makes the results more compelling. Simply, the patients with symptomatic intracranial stenosis had more benefit with medical management than stenting, even if they had failed antithrombotics."

SAMMPRIS: High-Risk Patients

In SAMMPRIS, the researchers identified a high-risk group of patients with a recent TIA or stroke that was attributed to a 70% to 99% intracranial stenosis and randomly assigned them to receive aggressive medical management either with or without the addition of intracranial angioplasty and stenting, using the Wingspan system.

"Of note, SAMMPRIS did not require that patients be refractory to medical therapy to be included," Dr. Lutsep pointed out. Aggressive medical management in this study included antiplatelet therapy, clopidogrel for 90 days, aspirin for the entire follow-up, risk factor management that primarily targeted the systolic blood pressure and low-density lipoprotein cholesterol, and lifestyle modification.

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.

In April 2011, 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.

At 30 days, the rate of stroke or death was significantly higher with intracranial stenting, at 14.7% vs 5.8% with aggressive medical management (P = .002).

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, at 20.0% vs 12.2% with medical management (P = .009). Follow-up is still ongoing.

In this analysis, the researchers compared events that occurred while the patients were receiving medical management and stenting events among those patients receiving antithrombotic therapy and those not receiving antithrombotics at the time of the event that qualified them for the SAMMPRIS trial.

The majority of patients, 286 (63%) of 451, were receiving antithrombotic therapy; 167 patients (37%) were not. Similar numbers of patients in each group were randomly assigned to receive medical therapy or stenting: 140 vs 144 for those receiving antithrombotic therapy, and 87 vs 80 for those not receiving an antithrombotic.

Of those receiving an antithrombotic, most (95.8%) were receiving an antiplatelet, and 22.5% were receiving clopidogrel and aspirin, but only a few (1.4%) were receiving an anticoagulant at the time of their qualifying event.

Patients who had an event while receiving an antithrombotic tended to be older and to have more hypertension, lipid disorders, and prior stroke coronary artery disease, and the qualifying event was more commonly a stroke than a TIA. The symptomatic artery also tended to be more often in the vertebral-basilar distribution, Dr. Lutsep noted.

However, baseline measures for risk factors did not differ except that glycated hemoglobin in patients with diabetes was lower in the antithrombotic group. Concomitant medications at study entry were generally similar, although they may have changed between the qualifying event and actual study entry, Dr. Lutsep noted. There was also a tendency toward more nonstatin lipid-lowering therapy and beta-blockers in those receiving antithrombotics.

The primary endpoint was stroke and death at 30 days, and stroke in the territory of the qualifying artery beyond 30 days.

Among those who were receiving antithrombotic therapy when they had a qualifying event, significantly more patients had a primary endpoint event with stenting vs medical therapy, Dr. Lutsep reported. "The difference is already significant at 30 days," she noted. A similar significant difference was seen for those receiving antithrombotics and a history of stroke. Whether or not it was in the same territory as the qualifying event, "we see that the results, if anything, are even more pronounced."

"Just for interest," the researchers looked at patients who had been receiving clopidogrel and aspirin, and although the numbers are small, the trend was the same: toward fewer events with medical management.

Among patients not receiving antithrombotic therapy at their qualifying event, fewer patients again had primary endpoint events with aggressive medical management, but the trend did not reach significance.

Table. Primary Endpoint Events With Aggressive Medical Management vs Intracranial Stenting

Subgroup Aggressive Medical Management Aggressive Medical Management Plus Intracranial Stenting P
Qualifying event while receiving antithrombotic (%) 10.3 18.8 .14
Qualifying event while receiving antithrombotic and history of ischemic stroke (%) 14.3 35.3 .014
Qualifying event while receiving clopidogrel + aspirin (%) 13.5 18.5 .56
Not receiving antithrombotic therapy (%) 10.3 18.8 .14

A "key question," Dr. Lutsep added, is whether patients treated in the medical management groups had similar outcomes whether or not they had been receiving antithrombotics when they had their qualifying event. A total of 12.1% of those who had been receiving antithrombotics had an event vs 10.3% of those who had not (P = .78), "so we can say that these patients, whether or not they'd been on antithrombotic...had similar numbers of primary outcome events," she concluded.

Questions Remain

After the presentation, an audience member noted that during an earlier symposium on the SAMMPRIS results at this meeting, attendees had been polled on whether they would consider stenting if a patient had failed the medical treatment paradigm used in the trial. "It seemed like a lot of people were clicking 'yes' they would, and there doesn't seem to be much logic to that for me, because the data shows that stenting is more risky than not stenting, and I don't know why that would change after you've had another event," he said.

Dr. Lutsep pointed out that this analysis only looked at the dual antiplatelet issue, and not the full medical management, including lipid lowering. "Certainly I completely agree with you that it does not make sense to stent these people if they failed dual antiplatelet therapy, that there is no benefit from stenting in those patients," she said. "I think it still leaves a little bit of a question whether patients may need to be treated differently if they failed all the steps of aggressive medical management; we don't have the answers to that."

A second commenter from the audience followed-up on this point. "I think we have to be cautious here," he said. "SAMMPRIS is 1 trial that had 1 approach, 1 specific protocol for the majority of patients with intracranial disease," he noted. "We should not assume that all stenting has the same complication rate.

"I can't say that it is safe, but I think we have to leave the window open, that it may be, if performed differently, with different devices, we may be able to achieve good outcomes," he added. "If a patient fails medical therapy, and they're lying flat in bed, and every time you sit them up they're having TIAs, they can't walk, I think we have to consider this as an alternative to medical therapy."

Dr. Lutsep acknowledged that SAMMPRIS does not answer every question about stenting in this setting.

Finally, session comoderator Scott E. Kasner, MD, professor of neurology and director of the Comprehensive Stroke Center at the University of Pennsylvania in Philadelphia, asked Dr. Lutsep whether she was willing to venture an opinion about what definition should be used for "refractory to medical therapy" for the purposes of the current Humanitarian Device Exemption (HDE) under which the Wingspan stent has approval for use.

"No, Scott, thank you," she replied, laughing. "I think moving from the trial to the HDE brings another hairy set of issues with it, a lot of regulatory and political twists involved," she added. "I would say that we don't know exactly what it means to be refractory to medical therapy yet, but certainly having an event on the dual antiplatelets does not get you different treatment in my mind."

Potent Means to Prevent Recurrence

Asked for comment on these findings, Philip B Gorelick, MD, MPH, medical director of the Hauenstein Neuroscience Institute, St. Mary's Hospital, Grand Rapids, Michigan, pointed out that those who have a stroke or TIA while receiving antithrombotic medications have been deemed by some as "antithrombotic failures," and are thought to be at higher risk for subsequent stroke or other vascular events.

Two main clinical points arise from this exploratory analysis by Dr. Lutsep and colleagues, Dr. Gorelick told Medscape Medical News. "(1) The benefit of aggressive medical management is similar in patients who were or were not treated with antithrombotic therapy prior to entering into SAMMPRIS, and (2) study patients in this trial of high-grade intracranial stenosis had more benefit from aggressive medical management than with angioplasty and stenting with the Wingspan stent system, although they had 'failed' antithrombotic therapy," he said.

When dealing with the so-called "antiplatelet or antithrombotic therapy failure" patient, clinicians should ask the following question: "Have I adequately controlled stroke and cardiovascular risk factors?"

The findings need to be further validated, but support the practice concept of aggressive medical risk management as a key factor in the prevention of subsequent stroke in patients with high-grade intracranial occlusive disease, Dr. Gorelick concludes.

"When dealing with the so-called 'antiplatelet or antithrombotic therapy failure' patient, clinicians should ask the following question: 'Have I adequately controlled stroke and cardiovascular risk factors?' " he said. "Aggressive and successful control of such factors can be a potent means to prevent stroke recurrence, as observed in the SAMMPRIS trial."

The SAMMPRIS trial was supported by the National Institute of Neurological Disorders and Stroke. AstraZeneca donated rosuvastatin (Crestor) to study patients. Stryker Neurovascular provided study devices and supplemental funding for third-party distribution of devices. Nationwide Better Health-INTERVENT provided the lifestyle modification program at a discounted rate. Dr. Lutsep and Dr. Gorelick have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2012: Abstract LB5. Presented February 2, 2012.


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