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、积极招募的预防中风的程序性试验：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)颈动脉支架置入术(CAS)和IMM单独的IMM。CREST-2的设计具有≈3年的平均随访时间(最长4年)。截至2020年10月29日，已有1735名患者被随机分组。CREST-2 IMM包括集中迭代滴定，以最大限度地耐受治疗高血压和高脂血症的药物。我们已经证明，CREST-2 IMM显著提高了血管危险因素控制率。我们提出了一种高成本效益的集中化流程，包括电话和远程医疗访问以及审查医疗记录，以监测卒中终点和家庭健康访问，以监测患者从CREST-2毕业后对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，我们提议的长期观测扩展(LOE)都是重要的。如果血运重建术不能显示出优越性(即，如果仅使用IMM的治疗效果更好或没有显著差异)，血运重建的支持者会争辩说，平均随访时间不够长，无法证明该手术的好处。在无症状颈动脉粥样硬化研究中，风险曲线的交叉点支持癌胚抗原相对于药物治疗的益处，在研究进入2年后在≈上被注意到。当代的IMM可能会将这一交叉点向外推进。如果血管重建术在CREST-2中被证明优于CREST-2，那么由于可能的再狭窄，超过3年平均随访的血管重建术的益处的持久性将受到质疑。我们建议对所有CREST-2患者获得书面知情同意，继续随访5年，提供平均7.5年的随访，部分患者随访10年。将通过创新的后续行动方法实现成本效益。我们的方法还旨在最大限度地减少患者负担和最大限度地保留。这项建议的主要目的是评估血管重建术和IMM与单纯IMM之间的术后治疗差异。目前资助的CREST-2试验将提供有关术后治疗差异的数据，最长可达≈3年。延长随访将使我们能够评估在中期(4-6年)和长期(7-10年)随访期间是否保持术后益处；从而测试耐久性。CREST-2 LOE的主要结果是随机化后44天内的卒中和死亡，以及随机化后同侧的缺血性卒中。我们的LOE方法意义重大，因为它可以应用于各种中风预防试验，在这些试验中，治疗干预是一种装置或程序。

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.