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

CREST-2（clinicaltrials.gov编号：NCT 02089217）是一对平行的、积极招募的预防卒中的程序性试验，比较：1）颈动脉内膜切除术（CEA）和强化医疗管理（IMM）与单独IMM，以及2）颈动脉支架植入术（CAS）和IMM与单独IMM。CREST-2的设计平均随访时间为3年（最长4年）。截至2020年10月29日，已对1，735例患者进行了随机化。CREST-2 IMM涉及集中迭代滴定，以达到治疗高血压和高脂血症的药物的最大耐受效果。我们已经证明CREST-2 IMM可显著改善血管危险因素控制率。我们提出了一个高成本效益的，集中的过程，包括电话和远程医疗访问和审查的医疗记录，以监测中风终点和家庭健康访问，以监测控制血管危险因素后，患者从CREST-2毕业，严格评估的可转移性和现实世界的长期有效性强化医疗管理与或不颈动脉血运重建。无论CREST-2结果如何，我们提出的长期观察扩展（LOE）都是重要的。如果血运重建未能显示出优越性（即，如果单纯IMM治疗具有上级优势或无显著差异），则血运重建的支持者会认为平均随访时间不足以证明该手术的益处。无症状颈动脉粥样硬化研究中的风险曲线交叉点，支持CEA与药物治疗相比的益处，在研究进入后102年注意到。当代IMM可能会将交叉点向外推。如果CREST-2的血运重建显示出上级优势，则由于可能的再狭窄，血运重建受益在3年平均随访后的持久性将受到质疑。我们建议获得所有CREST-2患者的书面知情同意书，以便继续随访5年，提供平均7.5年的随访，其中一部分患者随访时间>10年。将通过创新的后续方法实现成本效益。我们的方法还旨在最大限度地减少患者负担并最大限度地保留。本提案的主要目的是估计血运重建和IMM与单独IMM之间的术后治疗差异。目前资助的CREST-2试验将提供长达103年的术后治疗差异数据。延长随访将使我们能够评估在中期（4-6年）和长期随访（7-10年）期间是否保持了术后受益;从而测试耐久性。CREST-2 LOE的主要结局是随机化后44天内卒中和死亡以及此后随机化血管同侧缺血性卒中的复合终点。我们的LOE方法是重要的，因为它可以应用于各种各样的中风预防试验，其中治疗干预是一种设备或程序。

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.