SAN ANTONIO — There is little information available on the natural history of intracranial stenosis, but even less on treatment outcomes, said experts at a session here at the American Stroke Association's International Stroke Conference in February.
The session moderator Anthony J. Furlan, MD, Section Head for Stroke and Neurologic Intensive Care at the Cleveland Clinic Foundation, said studies since the mid-1980s have found a very consistent eight percent annual risk of ipsilateral stroke in patients with intracranial carotid, middle cerebral-vertebral, or basilar disease. “But each of the sites of intracranial stenosis has a different natural history,” he said.
Proximal vertebral lesions are fairly benign and are often found coincidentally when the patient has headache or some other non-focal symptoms. But distal disease in the vertebral-basilar junction and basilar artery are often discovered when the patient has a vertebral-basilar stroke.
“The vertebral-basilar lesions have the highest risk of stroke during follow-up, usually in the vertebral-basilar territory, whereas the proximal basilar strokes can be carotid or vertebral-basilar distribution,” Dr. Furlan said. “Unfortunately, that's about all we know about the natural history of those lesions.”
Existing data show no statistical correlation between the severity of middle cerebral artery (MCA) stenosis and the risk of stroke, but patients who show progression of MCA stenosis over time are at a much higher risk than those with stable lesions.
“About 40 percent of intracranial lesions will show progression over a two year period, although the amount of progression is usually in the less than 10 percent range,” he said. “We are probably looking at plaque dynamics and clot that is coming and going; it is not all atherosclerosis.”
DEBATE ON ANTITHROMBOTIC THERAPY
Risk-factor management must play a part in medical therapy for these patients, said Marc Chimowitz, MB, ChB, of the Section of Neurology at Emory University in Atlanta. Dr. Chimowitz focused on the two choices for antithrombotic therapy – antiplatelet agents or anticoagulation.
“If there is little data on the natural history, there is probably less on the outcomes of patients treated medically,” Dr. Chimowitz said. He said the benefits of aspirin to prevent cerebral stroke are still debated. And while other antiplatelet agents have been approved by the Food and Drug Administration for stroke prevention – ticlopidine, clopidigrel, and aspirin/dipyridamole – the benefits of these drugs over aspirin alone are also still debated.
“None of these agents have been evaluated specifically in patients with intracranial stenosis,” he said, “so we have no data showing that these agents alone or in combination are more effective than aspirin.”
In anticoagulation therapy, early warfarin studies suggested it could lower risk of stroke, and warfarin is frequently used today for this disease, but Dr. Chimowitz said there have been no prospective studies of patients with angiographically-proven intracranial stenosis.
ROLE OF WARFARIN
A small, retrospective non-randomized pilot trial for the ongoing WASID study (Warfarin versus Aspirin for Symptomatic Intracranial Disease) found a 3.6 percent stroke rate with warfarin versus 10.4 percent for aspirin, Dr. Chimowitz said. But major hemorrhage was significantly higher with warfarin.
The pilot study also suggested that the degree of stenosis predicted severity of ipsilateral stroke. Patients with moderate stenosis had a stroke rate of 1.6 percent per year with warfarin, and 5.4 percent with aspirin. The stroke risk increased greatly in patients with more severe stenosis, and patients with stenosis of 70 percent and greater were at the highest risk of ipsilateral stroke.
“The risk was still substantial even on warfarin, especially for patients with vertebral-basilar disease,” Dr. Chimowitz said. But he emphasized that this was a retrospective non-randomized study and conclusions must be considered with caution.
While the WARSS report (Warfarin-Aspirin Recurrent Stroke Study) focused on a non-intracranial-disease population (those with non-cardioembolic stroke), Dr. Chimowitz said it nonetheless raised the burden for warfarin to prove itself for intracranial stenosis since the trial failed to show a significant difference between warfarin and aspirin.
The randomized double-blind NIH-funded WASID trial will involve more than 50 centers, comparing the efficacy and safety of warfarin with high dose aspirin (1300 mg/day) to prevent both ischemic and hemorrhagic stroke and vascular death in patients with symptomatic stenosis of a major intracranial artery.
The primary hypothesis is that warfarin will reduce the rate of stroke and vascular death by 33 percent over three years compared with aspirin. Patients enrolled have had a transient ischemic attack or non-severe non-disabling stroke attributed to stenosis of greater than 50 percent in a major intracranial artery as documented by angiography.
Another objective is to identify patients whose rate of ischemic stroke in the territory of the stenotic artery is sufficiently high to justify a subsequent trial that would compare intracranial angioplasty stenting with whatever medical therapy wins in WASID.
“We are making assumptions that the stroke and vascular death rates will be about 33 percent over three years in the aspirin arm and 22 percent in the warfarin arm,” he said, “so we need a sample size of 403 patients per group.”
Approximately half the required patients have been recruited. The minority and gender breakdowns are what the investigators anticipated, Dr. Chimowitz said, but the mean age is somewhat younger at 63 years. The trial should end in 2006. Dr. Chimowitz issued a call for other sites interesting in participating in the WASID trial.
The final speaker here said there is also little information on endovascular management of intracranial stenosis. “Most of our knowledge of cerebral revascularization and our attitude toward it has grown out of our experience with carotid bifurcation atherosclerosis and with endarterectomy,” said Peter Rasmussen, MD, Associate Professor of Cerebrovascular and Endovascular Surgery at the Cleveland Clinic Foundation.
“But access to cerebral sites is far more limited than for carotid bifurcation, and the biology may be different from intracranial lesions, so we don't know the risk of complications associated with the endovascular procedures, or the long-term risk of restenosis or recurrence of stroke.”
He confined his remarks to posterior circulation lesions, he said, because there is no meaningful experience with angioplasty for anterior-circulation lesions, and to angioplasty with stenting because he believes that is preferable to angioplasty alone.
Dr. Rasmussen presented data on midterm results with posterior circulation angioplasty and stenting on 29 patients, which show morbidity at about 25 percent. Two patients died during or immediately after the procedure, one due to a dissection generated proximal to the stent placement and one who sustained a massive pontine infarction. Another died a cardiac death in rehabilitation, and the fourth due to acute cholecystitis.
Among the 25 surviving patients, 24 remained asymptomatic at two years on aspirin alone. The single patient with intermittent symptoms had a very long segment stenosis.
Dr. Rasmussen showed scans of a patient whose mean stenosis decreased from 86 percent pretreatment to 10 percent afterward. “We are satisfied with a reduction of 10 to 20 percent,” Dr. Rasmussen said. “Shooting for a zero-percent stenosis or complete resolution is not the safest thing to do because it is possible to generate dissection on either end of the stent placement, and you can't position another stent on top of those dissections because the risk of hemorrhage is great.”
The 29 patients were offered surgical treatment after they failed medical therapy, had ongoing symptoms or had stroke while on medical treatment.
Answering a question from the audience, Dr. Rasmussen said endarterectomy for middle cerebral artery disease has not usually been successful because of its size and the high risk of rethrombosis.
“Angioplasty of the middle cerebral artery for small focal lesions would be the way to go if the anatomy is favorable for positioning of the stent,” he said.
Dr. Furlan added that he is much more amenable to moving to surgery than he has been in the past. “Two or three years ago, early in the learning curve with these procedures, we would have waited,” Dr. Furlan said. “But we are moving faster and faster to intervene in patients we feel are at high risk because of an unstable clinical course or high-grade stenosis.
“This is a high-risk procedure and no one would put a stent in for 50 percent stenosis. But for a long basilar lesion, medical management might not be the right way to go.”