CASSISS: No Benefit of Stenting for Intracranial Stenosis

Among patients with a recent TIA or ischemic stroke stemming from severe intracranial atherosclerotic stenosis, adding stenting to medical therapy does not improve clinical outcomes over medical therapy alone, the randomized CASSISS trial shows.

The primary outcome, a composite of stroke or death within 30 days or stroke in the qualifying territory from 30 days to 1 year, occurred in 8.0% of patients who received a stent and 7.2% of those who did not (HR 1.10; 95% CI 0.52-2.35). None of the secondary outcomes involving stroke, TIA, CV events, or death within 3 years were significantly different between groups either.

The findings, published in the August 9, 2022, issue of JAMA with lead author Peng Gao, MD (Xuanwu Hospital, Capital Medical University, Beijing, China), are consistent with the lack of benefits observed with stenting in prior trials, including SAMMPRIS, VISSIT, and a single-center Chinese trial. In the first two of those trials, in fact, stenting was associated with worse outcomes.

Studies done after those trials suggested that refining patient selection (like exclusion of patients with perforator infarcts), waiting for a longer period of time between a TIA/stroke and stenting, and using more-experienced surgeons could reduce the periprocedural risk of the procedure and thereby enhance the benefits. CASSISS was designed to put that idea to the test, but it still failed to demonstrate positive results for stenting.

“The results of this study, together with that from previous trials, support the recent American Academy of Neurology Practice Advisory regarding stroke prevention in symptomatic large-artery intracranial atherosclerosis, which recommends aggressive medical therapy rather than stenting for patients with symptomatic severe intracranial atherosclerotic stenosis,” Gao et al say.

Indeed, senior author Liqun Jiao, MD, PhD (Xuanwu Hospital, Capital Medical University), told TCTMD via email, “Current outcomes still do not support stenting. Medical treatment remains the first-line therapy even after optimizing patient selection and [ensuring use of] experienced operators.”

The CASSISS Trial

For CASSISS, conducted across eight centers in China, investigators enrolled 380 patients with TIA or nondisabling ischemic stroke attributed to severe intracranial stenosis (70% to 99%) who were at least 3 weeks past their latest ischemic symptoms; those with perforator ischemic events were excluded. The main analysis focused on 358 patients (mean age 56.3 years; 73.5% men) who were confirmed to be eligible for the study after randomization.

A lead-in phase of the study was conducted for the credentialing of surgeons and research sites based on procedural volumes and outcomes. Stenting was performed with the Wingspan stent (Stryker Neurovascular) within 3 to 5 days of randomization. In both groups, medical therapy included daily aspirin plus clopidogrel for 90 days followed by single antiplatelet therapy (with either agent), along with medications to control various stroke risks factors.

Current outcomes still do not support stenting. Medical treatment remains the first-line therapy even after optimizing patient selection and [ensuring use of] experienced operators. Liqun Jiao

Overall, Jiao said, the trial results show that “the efficacy of both medical management and endovascular therapy are better than previous studies, and the safety of medical and endovascular treatments is comparable.”

The lack of a significant difference in the primary composite outcome of stroke/death within 30 days or stroke in the qualifying territory from 30 days to 1 year was consistent in a per-protocol analysis.

“From the interventional standpoint, it was good to see that the major complication rate had come down to about 5%, but I think also the stroke rate had come down significantly in the medical treatment group, and so overall there was no difference,” commented Seemant Chaturvedi, MD (University of Maryland School of Medicine, Baltimore), who is system-wide stroke program director at his institution.

And that “reinforces the current American Heart Association guideline, [which states] that intracranial stenting should not be a first-line treatment for patients with intracranial stenosis and that intensive medical therapy should be the primary treatment,” said Chaturvedi, who helped craft the recommendations.

Aggressive Management of Risk Factors

In an accompanying editorial, Craig Anderson, MD, PhD (The George Institute for Global Health, UNSW Sydney, Australia), and colleagues say, “Despite the efforts to improve patient selection and operator experience, the CASSISS trial redemonstrated that any potential benefit of stenting for intracranial atherosclerosis in terms of long-term stroke prevention appears to be at least counterbalanced by the short-term procedural risk, which includes both ischemic and hemorrhagic events.

“Although arguments can be made that the restrictive inclusion criteria inevitably led to a biased, stable, ‘lower-risk’ patient group,” they continue, “the trial further highlights the importance of best medical management of cardiovascular risk factors—in particular, use of statins and blood pressure-lowering agents to achieve guideline-recommended targets in this patient population.”

Chaturvedi said that some could argue the CASSISS investigators didn’t go far enough when controlling risk factors, noting that some guidelines recommend bring LDL cholesterol much lower than the goal of less than 100 mg/dL used in the trial.

“I think clinicians should consider going beyond the current guidelines and being extra aggressive in terms of risk factor modification considering that these patients are high risk,” he said, underscoring the need for dietary and lifestyle modifications in addition to drug therapies.

But endovascular treatments for patients with severe intracranial stenosis should not yet be ruled out, Jiao indicated, pointing to research areas worth exploring. “Simple evaluation of stenosis degree, currently, is relatively rough in terms of accurate diagnosis,” he said. “Vessel-wall and hemodynamic measurements should be brought into evaluation by high-resolution MRI, [optical coherence tomography], or other techniques. Furthermore, the innovation of endovascular devices is a direction for the future as well.”

Chaturvedi said stenting or angioplasty are still considered by some clinicians in patients who continue to have ischemic symptoms despite optimal medical therapy, though a high rate of restenosis remains a concern with angioplasty alone.

In terms of future research, he said improved stents specifically designed for the cerebral vessels would be of interest. Moreover, there’s a question about whether patients at very high risk—with disease in multiple vessels, for example—may benefit from stenting, and that type of population could be evaluated in a small trial, he said, adding that surgical management of intracranial stenosis is another provocative area to keep an eye on.