Kastelein John J P, de Groot Eric
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Eur Heart J. 2008 Apr;29(7):849-58. doi: 10.1093/eurheartj/ehn070. Epub 2008 Mar 11.
Cardiovascular disease remains a substantial cause of morbidity and mortality in the developed world, and is becoming an increasingly important cause of death in developing countries too. While current cardiovascular treatments can help to reduce this disease burden, a substantial number of patients still retain a high risk of experiencing a life-threatening cardiovascular event. Thus, the development of new therapies capable of reducing this residual risk remains an important healthcare objective. The time taken to bring new therapies to the patient in need is lengthened by the unavoidable requirement to demonstrate a statistically significant benefit in terms of clinical events beyond that achievable with current treatments. However, clinical trials utilizing surrogate endpoints-biomarkers of disease progression that manifest before potentially fatal cardiovascular events occur-have the potential to enhance the process of drug development by enabling a statistically sound assessment of the efficacy of new therapies several years in advance of the availability of data from clinical endpoint trials. Two vascular ultrasound imaging techniques, measurement of carotid intima-media thickness (CIMT) and intravascular ultrasound (IVUS) of the coronary arteries, are increasingly being used to assess novel cardiovascular therapies in surrogate endpoint trials forming integral components of larger trial programmes utilizing both surrogate and clinical endpoints. The rationale for the use of CIMT- and IVUS-based surrogates, with supporting evidence from historical and recent trials, is presented in this review article.
在发达国家，心血管疾病仍然是发病和死亡的主要原因，在发展中国家，它也正成为一个日益重要的死亡原因。虽然目前的心血管治疗方法有助于减轻这种疾病负担，但仍有相当数量的患者面临危及生命的心血管事件的高风险。因此，开发能够降低这种残余风险的新疗法仍然是一项重要的医疗保健目标。由于需要证明在临床事件方面具有统计学上显著的益处，且这种益处要超过现有治疗所能达到的水平，这一不可避免的要求延长了将新疗法带给有需要患者的时间。然而，利用替代终点——在潜在致命心血管事件发生之前出现的疾病进展生物标志物——的临床试验，有可能通过在临床终点试验数据可用前数年就对新疗法的疗效进行统计学上合理的评估，来加快药物开发进程。两种血管超声成像技术，即颈动脉内膜中层厚度（CIMT）测量和冠状动脉血管内超声（IVUS），越来越多地用于替代终点试验中评估新型心血管疗法，这些试验构成了同时使用替代终点和临床终点的更大试验项目的组成部分。本文综述了使用基于CIMT和IVUS的替代指标的基本原理，并给出了来自历史和近期试验的支持证据。
