Stroke Risk With Carotid Stenting Persists Over Time: Meta-Analysis

As the debate over the relative benefits of carotid stenting (CAS) and endarterectomy (CEA) continues to simmer, a new meta-analysis including long-term data from some of the largest—and most controversial—trials suggests that the increased risk of stroke with stenting may be even more substantial than previously appreciated. When pooled, the data showed a continued risk of any type of stroke after CAS that lasted out to 10 years. 

“With the observed increased risk of stroke persisting throughout follow-up with stenting, available data suggest that endarterectomy remains the treatment of choice for the management of carotid stenosis,” write Kristian B. Filion, PhD, of McGill University (Montreal, Canada), and colleagues in the October 2015 issue of Circulation: Cardiovascular Quality and Outcomes.

The meta-analysis looked at 8 RCTs conducted between 1992 and 2008 that included a total of 7,091 patients who were randomized to CAS (n = 3,561) or CEA (n = 3,530).

Among the trials included were CREST, ICSS, SPACE, EVA-3S, CAVATAS, and SAPPHIRE. Patient characteristics were relatively similar across trials (mean age range, 68.1 to 72.6 years), and the majority of patients in most trials had ≥ 70% ipsilateral carotid stenosis. The exception was SAPPHIRE, which included mostly asymptomatic patients at high surgical risk.

Long-term Stroke Risk Seen

Median follow up ranged from 2 to 10 years. When data were pooled across trials, CAS patients had a higher risk of any periprocedural stroke and a decreased risk of MI, severe hematoma, and cranial nerve palsy compared with CEA patients. The increased risk of any stroke and ipsilateral stroke (including periprocedural stroke or death) persisted throughout follow-up (table 1).

Additionally, in prespecified subgroup analyses, older patients had a greater risk of long-term stroke with CAS than with CEA (RR 1.54; 95% CI 1.20-1.98). This excess risk was not seen among younger patients (RR 1.01; 95% CI 0.56-1.81). 

Other analyses found that no single trial conveyed any overt influence on any long-term stroke or the composite endpoint (long-term ipsilateral stroke, periprocedural stroke, or periprocedural death).

No Escaping the Controversy

Several of the trials, namely ICSS, EVA-3S and SPACE, have been fraught with controversy. In a letter to Lancet Neurology in 2010, Marco Roffi, MD, of University Hospital (Geneva, Switzerland), and 22 other clinicians said the 3 studies should be considered “ethically questionable,” due to the minimal endovascular experience required of participating operators. EVA-3S, for example, allowed operators with at least 12 CAS procedures, or at least 5 CAS and at least 30 stenting procedures in supra-aortic vessels, to participate. Additionally, embolic protection was not mandated from the start in EVA-3S, although it was after a review by its Data and Safety Monitoring Board concluded that 30-day stroke rates were almost 4 times higher in CAS procedures without vs with embolic protection. 

Additionally, EVA-3S, SPACE and SAPPHIRE all were stopped prematurely. Filion and colleagues said they took these factors into account in the meta-analysis by assigning those studies “an unclear evaluation for the other risk of bias domain.”

They also acknowledge that much of the evidence to support the increased stroke risk with CAS is derived from symptomatic patients.  “Although we did not identify differences in treatment effects between symptomatic and asymptomatic patients in our subgroup analysis, some uncertainty remains on the potential use of stenting in asymptomatic patients,” the authors note.

That uncertainty is the impetus for the CREST-2 trial, which began enrolling late last year. Not without its share of controversy, the trial includes separate CAS and CEA arms, each matched against optimal medical therapy.

Despite the problems and criticisms that some of the CAS vs CEA studies have faced, Philip M. Meyers, MD, a neurointerventionalist at Columbia University Medical Center (New York, NY), noted that “it’s hard to ignore the trial data … but it also lends credence to why the issue should be studied in CREST-2.”

While some may argue that troubled trials should not be included in a meta-analysis such as this one, Meyers noted, the simple fact is they met the inclusion criteria set by the authors. “The role of meta-analyses is to look for a combination of data to give stronger direction for clinical practice. It’s hard to refute [the authors’] perspective or to say that it’s not a valid perspective,” he said. “They used reasonable methodology, and they adhered to standard tenets in their approach.”

Speaking Volumes

In another study in the same issue of the journal, Soko Setoguchi, MD, DrPH, of Duke Clinical Research Institute (Durham, NC), and colleagues found an inverse relationship between the number of CAS procedures an individual physician or center performs and 30-day mortality.

The study population included 19,724 Medicare patients (mean age, 76.3 years; 60.1% men) who underwent CAS performed by 2,045 physicians in 729 hospitals. Median volume of CAS procedures in the prior year was 9 for physicians and 23 for hospitals. However, 30% of all patients were treated by a physician who had performed fewer than 5 CAS procedures in the last year and 1 in 5 patients had CAS performed at hospitals where fewer than 10 procedures had been done that year.

Even after adjustment for all pertinent patient- and hospital-level variables, lower CAS volume was associated with higher 30-day mortality risk.

Compared with physicians doing ≥ 20 CAS per year, the relative risk of 30-day mortality for lower volumes was:

• 1.4 (95% CI 0.90-2.3) for 0 CAS cases in the past year 
• 1.3 (95% CI, 0.9-1.8) for 1-4 cases 
• 1.1 (95% CI 0.8-1.6) for 5-9 cases 
• 0.9 (95% CI, 0.7-1.4) for 10-19 cases 

The inverse relationship also applied to hospital volume.

Setoguchi and colleagues say periodic monitoring of periprocedural complications after CAS “may help in assessing the appropriateness of patient selection and in updating training and proficiency requirements for CAS providers, as necessary.”

Sources: 
1. Vincent S, Eberg M, Eisenberg MJ, Filion KB. Meta-Analysis of randomized controlled trials comparing the long-term outcomes of carotid artery stenting versus endarterectomy. Circ Cardiovasc Qual Outcomes. 2015;8:S99-S108.
2. Jalbert JJ, Gerhard-Herman MD, Nguyen LL, et al. Relationship between physician and hospital procedure volume and mortality after carotid artery stenting among Medicare beneficiaries. Circ Cardiovasc Qual Outcomes. 2015;8:S81-S89. 

Disclosures:

• Drs. Filion and Meyers report no relevant conflicts of interest. 
• Dr. Setoguchi reports receiving research support from Johnson & Johnson and personal income for consulting from Sanofi-Aventis. 

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