Waliszewski Matthias, Rittger Harald
Medical Scientific Affairs, B.Braun Melsungen AG, Sieversufer 8, Berlin 12359, Germany
Klinikum Fürth, Fürth, Germany.
Ther Adv Cardiovasc Dis. 2016 Oct;10(5):314-26. doi: 10.1177/1753944716656150. Epub 2016 Jul 4.
Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs.
The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used.
Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations.
From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited.
随机对照试验是证明冠状动脉介入治疗器械（无论是否伴有药物治疗）安全性和有效性的金标准。随着新一代药物洗脱支架的出现，其技术特性和长期临床效益得到增强，要证明其在血管造影或长期临床疗效方面的增量效益变得更具挑战性。本综述的目的是概述介入心脏病学中最常见和替代的研究终点及其潜在的报销价值。此外，我们旨在描述统计局限性，以证明潜在治疗组之间的差异。此外，还针对未来的研究设计，为给定患者数量提供了谨慎的终点建议。
针对各种研究设计，如具有硬临床终点的非劣效性检验假设和各种替代终点，估计每个治疗组的患者数量。为了检验各种替代终点情况下的差异，探讨了相应的患者组规模。为了评估这些终点对报销的影响，使用了英国国家卫生与临床优化研究所（NICE）介入心脏病学技术评估的首选终点。
即使采用最严格的实验控制以减少引入偏差的因素，以主要不良心脏事件（MACE）发生或靶病变血运重建（TLR）率等硬主要临床终点的研究仍然是金标准，每组患者数量达到300 - 700例。使用血流储备分数（FFR）降低或支架小梁覆盖率的研究设计可以进行统计学制定；然而，对患者的临床影响仍有待讨论。在非靶血管中采用患者内血管造影对照的非随机研究设计可能值得进一步思考和探索。
从报销影响来看，主要终点MACE和TLR是每组500例患者的中等规模研究人群的最佳选择。在此背景下，血管造影终点，特别是最小管腔直径（MLD），并无用处。FFR降低或支架覆盖率等新兴终点需要的患者人群较少。然而，它们对报销相关决策的影响有限。
