COSS
(2011)Objective
Assess whether EC-IC bypass surgery reduces ipsilateral ischemic stroke risk in patients with symptomatic carotid occlusion and hemodynamic cerebral ischemia.
Study Summary
• EC-IC bypass surgery did not reduce recurrent ipsilateral ischemic stroke compared to medical therapy. The trial was terminated early for futility despite improved hemodynamics in the surgical group.
Intervention
Microsurgical EC-IC bypass (STA-MCA) plus medical therapy vs. medical therapy alone. Patients had AICAO, hemispheric symptoms <120 days, and elevated OEF on PET. Follow-up: up to 2 years.
Study Design
Arms: Array
Outcome
• Primary: Ipsilateral ischemic stroke or perioperative stroke/death — 21.0% (surgery) vs. 22.7% (medical); p=0.78
• Perioperative 30-day stroke: 14.3% (surgery) vs. 2.0% (medical)
• No significant difference in all stroke, disabling stroke, fatal stroke, or death
• Graft patency: 98% at 30 days; OEF ratio improved post-surgery
• Perioperative 30-day stroke: 14.3% (surgery) vs. 2.0% (medical)
• No significant difference in all stroke, disabling stroke, fatal stroke, or death
• Graft patency: 98% at 30 days; OEF ratio improved post-surgery
Bottom Line
EC-IC bypass surgery did not reduce the risk of ipsilateral ischemic stroke at 2 years compared with medical therapy alone.
Major Points
- EC-IC bypass did not reduce ipsilateral stroke rates compared to medical therapy (21.0% vs 22.7% at 2 years, P=0.78) — a definitively negative trial for surgical revascularization.
- Second major negative trial for EC-IC bypass after the original EC/IC Bypass Study (1985) — even with hemodynamic selection, surgery fails to prevent stroke.
- Used PET oxygen extraction fraction (OEF ratio >1.130) to select patients with true hemodynamic compromise — the most rigorous selection criteria ever applied, yet still failed to show benefit.
- Stopped early for futility after enrolling only 195 of planned 372 patients — the DSMB determined no reasonable chance of demonstrating benefit.
- 30-day perioperative stroke rate was 14.3% in the surgical group (all ipsilateral ischemic) — this unacceptably high complication rate negated any potential long-term benefit.
- Medical therapy arm had better-than-expected outcomes (22.7% vs projected 40% stroke rate) — modern medical management dramatically reduced stroke risk, making the surgical bar impossible to clear.
- High graft patency (98%) and improved OEF in surgical patients confirmed technical success — the surgery worked hemodynamically but did not prevent strokes, suggesting the mechanism of stroke in ICA occlusion is embolic rather than hemodynamic.
- Extremely slow enrollment: 195 patients over 8 years (2002–2010) across 49 centers — reflecting the rarity of patients meeting PET OEF criteria and limited clinical equipoise.
- Led to guideline-level abandonment of EC-IC bypass for atherosclerotic ICA occlusion — medical therapy is now the standard of care.
- Stimulated research into alternative approaches: encephaloduroarteriosynangiosis (EDAS) is being evaluated in the SIPS and JETS trials as potentially safer indirect revascularization.
Study Design
- Study Type
- Randomized, open-label, blinded-adjudication controlled trial
- Randomization
- Yes
- Blinding
- Blinded adjudication only
- Sample Size
- 195
- Follow-up
- 2 years
- Centers
- 49
- Countries
- USA, Canada
Primary Outcome
Definition: All stroke and death within 30 days post-surgery and ipsilateral ischemic stroke within 2 years
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 22.7% | 21.0% | - (−10.4% to 13.8%) | 0.78 |
Limitations & Criticisms
- 14.3% perioperative stroke rate was unacceptably high — negated any potential long-term surgical benefit and raised questions about surgical technique and patient selection.
- Severely underpowered due to early termination for futility (195 of 372 planned patients) — may have missed a smaller but real benefit in a more optimally selected subgroup.
- Historical control assumptions overestimated medical therapy stroke risk (projected 40%, observed 22.7%) — the trial was designed against an outdated baseline.
- Only PET OEF used for hemodynamic selection — MR perfusion, SPECT, or TCD vasoreactivity may identify different or overlapping populations that could benefit.
- Extremely slow enrollment (195 patients over 8 years across 49 centers) limits generalizability — only highly selected patients at specialized PET centers participated.
- Medical therapy improved dramatically during enrollment (2002–2010), including widespread statin use and tighter BP control, making the control arm progressively stronger.
- Open-label design — surgeons and patients knew allocation, potentially affecting post-operative management, stroke detection, and event reporting.
- Single bypass technique (STA-MCA anastomosis) — indirect revascularization approaches like EDAS may offer different risk-benefit profiles that COSS could not evaluate.
- No long-term follow-up beyond 2 years — potential late benefit from improved hemodynamics could not be assessed due to trial termination.
Citation
JAMA. 2011;306(18):1983–1992. doi:10.1001/jama.2011.1610