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

CREST-2 （clinicaltrials.gov编号：NCT02089217）是一对平行的、积极招募的程序性试验，旨在比较：1)颈动脉内膜切除术（CEA）和强化医疗管理（IMM）与单独的IMM，以及2)颈动脉支架植入术（CAS）和IMM与单独的IMM。CREST-2的平均随访期约为3年（最长4年）。截至2020年10月29日，已随机分配1735例患者。CREST-2 IMM包括集中迭代滴定，以达到治疗高血压和高脂血症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。我们建议采用一种高成本效益、集中的流程，包括电话和远程医疗访问，并审查医疗记录，以监测卒中终点，以及在患者从CREST-2毕业后进行家庭健康访问，以监测血管危险因素的控制，以严格评估有或没有颈动脉血运重建的强化医疗管理的可转移性和现实世界的长期有效性。无论CREST-2结果如何，我们提出的长期观测延长（LOE）都是重要的。如果血运重建术没有显示出优势（即，如果仅imm治疗优于或没有显著差异），血运重建术的支持者会争辩说，平均随访时间不够长，不足以证明该手术的益处。在无症状颈动脉粥样硬化研究中，风险曲线的交叉点在研究开始后约2年被注意到，这支持CEA与医疗管理相比的益处。当代IMM很可能将交叉点向外推。如果在CREST-2中显示血运重建的优势，那么由于可能的再狭窄，血运重建的益处在平均3年随访后的持久性将受到质疑。我们建议所有CREST-2患者获得书面知情同意，继续随访5年，平均随访7.5年，其中一部分患者随访至10年。将通过创新的后续方法实现成本效益。我们的方法也旨在减少病人的负担和最大限度地保留。本建议的主要目的是评估血运重建术联合IMM与单独IMM之间的术后治疗差异。目前资助的CREST-2试验将提供长达约3年的术后治疗差异数据。延长随访时间将使我们能够评估中期（4-6年）和长期随访（7-10年）是否能保持术后获益；因此，测试耐久性。CREST-2 LOE的主要结局是随机化后44天内卒中和死亡的综合结果，以及此后随机化血管的同侧缺血性卒中。我们的LOE方法很重要，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.