PDF(Pubmed)
Abstract：
Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.
摘要：
冠状动脉粥样硬化性冠状动脉疾病（CAD）是导致全球最主要不良心血管事件（MACE）的因果病理过程。动脉粥样硬化的复杂发展表现为在存在或不存在传统危险因素的情况下发生的内膜斑块。有许多有效的药物可以改善CAD，但新的药物治疗需要越来越大和昂贵的心血管结局试验来评估其对MACE的潜在影响并获得监管部门的批准。对于许多疾病领域，根据对替代终点的有益作用,近一半的药物获得了美国食品和药物管理局的批准.对于心血管疾病，只有低密度脂蛋白胆固醇和血压被批准作为心血管疾病的替代指标.迫切需要CAD的有效替代品，以促进对新颖、有益的治疗和激励投资。幸运的是,非侵入性成像技术的进步为加速CAD药物开发提供了新的机会。冠状动脉计算机断层扫描血管造影（CCTA）是最先进的候选人，具有准确和可重复地测量潜在病因疾病本身的能力。的确,斑块负荷的有利变化已被证明与改善的结局相关，CCTA作为旨在改善CAD结局的治疗的有效替代终点可能具有独特作用.CCTA也有可能在财务上和通过在更高的MACE可能性下丰富参与者来降低基于临床终点的试验的风险。此外，完全非钙化，和高危斑块体积，以及它们随着时间的变化，提供与MACE密不可分的冠状动脉疾病的因果关系度量，并且代表了一种强大的替代成像生物标志物，有可能得到监管机构的认可。关于特定成像终点和最佳临床试验设计方案的全球共识至关重要，因为我们致力于严格的，新的CAD疗法的可持续和分阶段途径。
