JACC：各中心入组例数差异影响临床试验结果分析

　　一项针对EVEREST试验（加压素治疗心力衰竭疗效：托伐普坦转归研究）进行的分析表明，纳入较多和较少受试者的中心之间基线特征、试验方案和患者转归显著不同，提示每个中心纳入的受试者数量可能影响试验结果。该研究2012年12月12日在线发表于《美国心脏病学会杂志》（J Am Coll Cardiol）。

　　研究者将该研究中359个中心纳入的4133例患者根据纳入例数1~10例、11~30例和>30例对每个中心进行分组。每个中心纳入例数范围为0~75例。北美、南美、西欧和东欧的纳入例数存在显著地区性差异。纳入例数较少的中心受试者更多老年和男性，射血分数和血压更低，病情和实验室指标更差，更少接受血管紧张素酶转换酶抑制剂（ACEI）和醛固酮拮抗剂治疗。中位随访9.9个月，41%的受试者发生终点事件。与纳入例数>30例的中心的事件率（32%）相比，纳入例数为1~10例（51%）和11~30例（42%）的中心事件率显著更高，患者转归更差。各个地区之间此关系相似。校正危险因素后，纳入较少受试者的中心仍有较高不良事件发生率。纳入例数>30例的中心有更多患者完成试验方案。

Relationship Between Clinical Trial Site Enrollment With Participant Characteristics, Protocol Completion, and Outcomes

Insights From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Trial

Objectives  

The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes.

Background  

Whether and how site enrollment volume affects clinical trials is not known.

Methods  

A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization).

Results  

Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001).

Conclusions  

Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.