CREST-2 findings are unchanged using an aggregated control group for the CAS and CEA trial.

INTRODUCTION: CREST-2 comprised two parallel observer-blinded randomised controlled trials evaluating carotid revascularisation (carotid artery stenting - CAS, or carotid endarterectomy - CEA) plus intensive medical management (IMM; supervised pharmacologic therapy and risk factor control and coached lifestyle modification) versus IMM alone in patients with asymptomatic ≥ 70% carotid stenosis. Each trial carried an independent IMM control arm. The primary endpoint (peri-procedural stroke/death or ipsilateral ischaemic stroke thereafter by 4 years) occurred, in the CAS trial, in 2.8% vs. 6.0% (IMM + CAS vs. IMM; p = 0.02). The effect of CEA did not reach significance; 3.7% vs. 5.3% (IMM + CEA vs. IMM; p = 0.24). AIM: To test the hypothesis that the divergent control-arm event rates - rather than true differential efficacy of the interventional treatments - could underlie the CAS efficacy and CEA failure in CREST-2, we used a single combined control group as a balanced reference for both interventional treatment arms. MATERIAL AND METHODS: An Aggregated Control Group of IMM-only (n = 1,252) was formed by merging the CREST-2 IMM control arms patient data and outcomes. Kaplan-Meier analysis was performed for the CAS and CEA treatment vs. the Aggregated Control Group, consistent with the trial statistical methodology (intent-to-treat). RESULTS: In the Aggregated Control Group, the primary endpoint occurred in 5.65% of patients (95% CI: 4.47-7.12). Absolute risk reduction with CAS + IMM (n = 616) was 2.85% (relative risk reduction 50.4%; number-needed-to-treat 35, p = 0.0089). Absolute risk reduction with CEA + IMM (n = 617) was 1.95% (p = 0.0871, a maintained lack of statistical significance). CONCLUSIONS: Aggregated Control Group analysis of CREST-2, minimising control arms biases, confirmed CAS efficacy (50.4% relative risk reduction) and maintained failure of CEA in primary prevention of ipsilateral stroke in patients with asymptomatic carotid stenosis under intensive medical management. This refutes control-arm disparity as an explanation for the divergent outcomes with CAS vs. CEA.