No Benefit of EC/IC Bypass vs Meds in Large-Artery Stroke

Marilynn Larkin

September 26, 2023

For most symptomatic patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), adding extracranial-intracranial (EC-IC) bypass surgery to medical therapy did not reduce stroke or death in comparison with medical therapy alone in the latest randomized trial comparing the two interventions.

However, subgroup analyses suggest a potential benefit of surgery for certain patients, such as those with MCA vs ICA occlusion, mean transit time greater than 6 seconds, or regional blood flow of 0.8 or less.

"We were disappointed by the results," Liqun Jiao, MD, of the National Center for Neurological Disorders in Beijing, told | Medscape Cardiology. "We were expecting to demonstrate a benefit from EC-IC bypass surgery over medical treatment alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, per our original hypothesis."

Although the study showed improved efficacy and safety for the surgical procedure, he said, "The progress of medical treatment is even better."

The study was published online August 22 in the Journal of the American Medical Association.

Subgroup Analyses Promising

Previous randomized clinical trials, including the EC/IC Bypass Study and the Carotid Occlusion Surgery Study (COSS), showed no benefit in stroke prevention for patients with atherosclerotic occlusion of the ICA or MCA.

However, in light of improvements over the years in surgical techniques and patient selection, the authors conducted the Carotid and Middle Cerebral Artery Occlusion Surgery Study (CMOSS), a multicenter, randomized, open-label trial comparing EC-IC bypass surgery plus medical therapy, consisting of antiplatelet therapy and control of stroke risk factors, with medical therapy alone in symptomatic patients with ICA or MCA occlusion and hemodynamic insufficiency, with refined patient and operator selection.

A total of 324 patients (median age, 52.7 years; 79% men) in 13 centers in China were included; 309 patients (95%) completed the study.

The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization.

Secondary outcomes included, among others, any stroke or death within 2 years and fatal stroke within 2 years.

No significant difference was found for the primary outcome between the surgical group (8.6%) and the medical group (12.3%).

The 30-day risk of stroke or death was 6.2% in the surgery group, vs 1.8% (3/163) for the medical group. The risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2%, vs 10.3% ― nonsignificant differences.

Furthermore, none of the prespecified secondary endpoints showed a significant difference, including any stroke or death within 2 years (9.9% vs 15.3%; hazard ratio, 0.69) and fatal stroke within 2 years (2% vs none).

Despite the findings, "We are encouraged by the subgroup analysis and the trend of long-term outcomes," Jiao said. "We will continue to finish 5 to 10 years of follow-up to see whether the benefit of bypass surgery can be identified."

The team has also launched the CMOSS-2 trial with a refined study design based on the results of subgroup analysis of the CMOSS study.

CMOSS-2 is recruiting patients with symptomatic chronic occlusion of the MCA and severe hemodynamic insufficiency in 13 sites in China. The primary outcome is ischemic stroke in the territory of the target artery within 24 months after randomization.

Can't Exclude Benefit

Thomas Jeerakathil, MD, a professor at the University of Alberta and Northern Stroke Lead, Cardiovascular and Stroke Strategic Clinical Network, Alberta Health Services, commented on the study for | Medscape Cardiology. Like the authors, he said, "I don't consider this study to definitively exclude the benefit of EC/IC bypass. More studies are required."

Jeerakathil would like to see a study of a higher-risk group based on both clinical and hemodynamic blood flow criteria. In the current study, he said, "The trial group overall may not have been at high enough stroke risk to justify the up-front risks of the EC-IC bypass procedure."

In addition, "The analysis method of Cox proportional hazards regression for the primary outcome did not fit the data when the perioperative period was combined with the period beyond 30 days," he noted. "The researchers were open about this and did pivot and included a post hoc relative risk-based analysis, but the validity of their primary analysis is questionable."

Furthermore, the study was "somewhat underpowered with a relatively small sample size and had the potential to miss clinically significant differences between groups," he said. "It would be good to see a longer follow-up period of at least 5 years added to this trial and used in future trials, rather than 2 years."

"Lastly," he said, "it's difficult to ignore the reduction in recurrent stroke events over the 30-day to 2-year time period associated with EC-IC bypass (from 10.3% down to 2%). This reduction alone shows the procedure has some potential to prevent stroke and would argue for more trials."

EC-IC could be considered for patients who have failed other medical therapies and have more substantial evidence of compromised blood flow to the brain than those in the CMOSS trial, he noted, as many of these patients have few other options. "In our center and many other centers, the approach to EC-IC bypass is probably much more selective than used in the trial."

Jeerakathil concluded, "Clinicians should be cautious about offering the procedure to patients with just mildly delayed blood flow in the hemisphere affected by the occluded artery and those who have not yet failed maximal medical therapy."

But Seemant Chaturvedi, MD, and J. Marc Simard, MD, PhD, both of the University of Maryland School of Medicine, are not as optimistic about the potential for EC-IC.

Writing in a related editorial, they conclude that the results with EC-IC bypass surgery in randomized trials "remain unimpressive. Until a better understanding of the unique hemodynamic features of the brain is achieved, it will be difficult for neurosurgeons to continue offering this procedure to patients with ICA or MCA occlusion. Intensive, multifaceted medical therapy remains the first-line treatment for [these] patients."

The study was supported by a research grant from the National Health Commission of the People's Republic of China. Jiao, Jeerakathil, Chaturvedi, and Simard reported no conflicts of interest.

JAMA. Published online August 22, 2023. Abstract, Editorial

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