Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial

CREST-2 (clinicaltrials.gov number: NCT02089217) is a pair of parallel, actively recruiting procedural trials to prevent stroke comparing: 1) carotid endarterectomy (CEA) and intensive medical management (IMM) to IMM alone, and 2) carotid artery stenting (CAS) and IMM to IMM alone. CREST-2 is designed to have ≈3-year average follow-up (maximum, 4 years). 1,735 patients have been randomized as of 10/29/2020. CREST-2 IMM involves centralized iterative titration to maximum tolerated effect of medications to treat hypertension and hyperlipidemia. We have already demonstrated that CREST-2 IMM results in significant improvements in rates of vascular risk factor control. We propose a highly cost-efficient, centralized process involving telephone and telehealth visits and review of medical records to monitor for stroke endpoints and home health visits to monitor control of vascular risk factors after patients graduate from CREST-2 to assess rigorously the transferability and real-world long-term effectiveness of intensive medical management with or without carotid revascularization. Our proposed long-term observational extension (LOE) is significant regardless of the CREST-2 results. If revascularization fails to show superiority (i.e., if IMM-only treatment is superior or not significantly different), proponents of revascularization will argue that the average follow-up was not sufficiently long to document the benefit of the procedure. The intersection of risk curves in the Asymptomatic Carotid Atherosclerosis Study, which supported benefit of CEA compared to medical management, was noted at ≈2 years following study entry. Contemporary IMM likely pushes the point of intersection outward. If revascularization is shown to be superior in CREST-2, then the durability of the benefit of revascularization beyond the 3-year average follow-up will be questioned due to possible restenosis. We propose obtaining written informed consent on all CREST-2 patients for continued follow-up for an additional 5 years, providing a 7.5-year average follow-up, with a subset of patients followed to >10 years. Cost-effectiveness will be achieved through innovative follow-up methodology. Our approach is also designed to minimize patient burden and maximize retention. The primary aim of this proposal is estimation of post- procedure treatment differences between revascularization and IMM vs. IMM alone. The currently funded CREST-2 trial will provide data on post-procedure treatment differences up to ≈3 years. Extending follow-up will enable us to assess whether post-procedure benefit is maintained during intermediate (4-6 years) and long-term follow-up (7-10 years); thereby, testing durability. The primary outcome for the CREST-2 LOE is the composite of stroke and death within 44 days after randomization and ischemic stroke ipsilateral to the randomized vessel thereafter. Our LOE approach is significant because it can be applied to a wide variety of stroke prevention trials where the therapeutic intervention is a device or procedure.