Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
Diabetes Care. 2017 Sep;40(9):1144-1151. doi: 10.2337/dc17-0068.
Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensure that sample size and duration of follow-up remain reasonable. Combining clinical outcomes into a composite end point increases the numbers of events ascertained and thus statistical power and precision. Historically, composite CV end points in diabetes trials have included a larger number of components, while more recent CVOTs almost exclusively use a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke-the so-called three-point major adverse CV event (3P-MACE) composite-or add hospitalization for unstable angina (HUA) to these three outcomes (4P-MACE). The inclusion of HUA increases the number of events for analysis, but noteworthy disadvantages include clinical subjectivity in ascertainment of HUA and its lower prognostic relevance compared with CV death, MI, or stroke. Furthermore, results from recent CVOTs indicate that glucose-lowering agents seem to have minimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazard ratio (HR) toward the null, which is especially problematic in trials designed to demonstrate noninferiority. The primary outcome of 3P-MACE may offer a better balance than 4P-MACE between statistical efficiency, operational complexity, the likelihood of diagnostic precision (and therefore clinical relevance) for each of the component outcomes, clinical importance, and the aim to adequately capture any potential treatment effect of the intervention. Nevertheless, as individual medications may mechanistically differ in their impact on CV outcomes, no particular individual or composite end point can be seen as a "gold standard" for CVOTs of all glucose-lowering drugs.
近期报告的临床试验显示心血管（CV）结局有所改善，此外，美国食品和药物管理局最近批准恩格列净用于 2 型糖尿病伴有心血管疾病证据的患者，以降低 CV 死亡风险，这重新激发了人们对降低血糖药物的 CV 结局试验（CVOT）的兴趣。复合终点是 CVOT 中的一种实用必要性，以确保样本量和随访时间保持合理。将临床结局组合成一个复合终点可以增加确定的事件数量，从而提高统计效力和精度。从历史上看，糖尿病试验中的复合 CV 终点包括更多的组成部分，而最近的 CVOT 几乎完全使用 CV 死亡、非致死性心肌梗死（MI）和非致死性卒中的组合，即所谓的三点主要不良 CV 事件（3P-MACE）复合终点，或在这三个结局上加上不稳定型心绞痛（UA）住院（4P-MACE）。UA 的纳入增加了分析的事件数量，但值得注意的缺点包括 UA 的临床确定具有主观性，以及与 CV 死亡、MI 或卒中相比，UA 的预后相关性较低。此外，最近的 CVOT 结果表明，降低血糖的药物似乎对 UA 的影响最小。因此，UA 的纳入可能会使风险比（HR）向零值靠拢，这在旨在证明非劣效性的试验中尤其成问题。3P-MACE 的主要结局可能在统计效率、操作复杂性、每个组成部分结局的诊断精度（因此临床相关性）的可能性、临床重要性以及充分捕捉干预措施的任何潜在治疗效果之间提供比 4P-MACE 更好的平衡。然而，由于个别药物在对 CV 结局的影响上可能存在机制上的差异，因此没有特定的单一或复合终点可以被视为所有降低血糖药物的 CVOT 的“金标准”。
