旨在指导或改变临床实践的大型RCT，通常会考察某种治疗策略能否减少关键的临床结局，如死亡、心肌梗死、卒中、住院、血运再重建和心绞痛症状。规模较小的试验，很多是为了建立生物标志物和关键临床结局之间的可能关联，但有人认为，在将这种关联解释为因果关系时，须谨慎。

在大规模的随机对照试验中，旨在提高高密度脂蛋白(HDL)的药物并没有与改善临床结果相关，尽管流行病学和生物标志物数据表明，在冠状动脉疾病患者中，提高HDL可以像降低LDL一样改善临床结果，而且降低Lp(a)的随机对照试验尚未完成。所有这些经验都支持这样一种观点，即仅了解治疗干预的生物学机制不足以了解其对人类健康的影响;相反，需要适当设计的随机对照试验来测量和报告有意义的临床结果

与安慰剂对照相关的问题可能是这里最重要的教训。在其行业指南，对照组的选择和临床试验的相关问题，FDA注意到…安慰剂对照设计，允许盲法和随机化，包括一组接受惰性治疗，控制所有对实际或明显的疾病过程的潜在影响，而不是由试验药物的药理作用引起的影响。

Appropriately designed and conducted randomized clinical trials (RCTs) are foundational for the practice of evidence-based medicine, including the regulatory approval of therapeutics and the inclusion of those therapies into clinical practice guidelines. Broadly defined, RCTs can be considered in two categories: explanatory or mechanistic trials that examine the effect of an intervention on biologic measures and clinical outcome trials that are testing the impact of a treatment on what matters to patients and clinicians, including living longer, feeling better, avoiding unpleasant experiences, or spending less money. Many years ago, Topol and Califf noted that “both types of trials are needed to advance the clinical treatment of acute myocardial infarction. Mega-trials can provide definitive evidence about the mortality reduction afforded by a class of therapy so that broad changes in clinical practice can be justified. Mini-trials can explain why a treatment is effective to allow development of more effective approaches attacking the identified mechanisms (1).” In the intervening years since Topol and Califf put forth this observation, cardiovascular clinical investigators have performed both types of trials in looking to reduce the risk of complications that arise from the development and progression of atherosclerotic coronary artery disease.  RCTs, intended to guide or change clinical practice, have typically examined whether or not a proposed therapeutic strategy can reduce important clinical outcomes, such as death, myocardial infarction, stroke, hospitalizations, revascularization procedures and anginal symptoms. Trials, typically smaller and sometimes embedded into a larger outcomes RCT, have also been performed to establish a possible relationship between a biomarker and the more important clinical outcomes.  Although, it is also well-accepted that care must be taken in the interpretation of such relationships as being causal (2).

文章连接：

https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.122.060649

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