临床试验地点入组情况对患者特征、方案完成情况及终点的影响：来自ASCEND-HF试验（奈西立肽治疗失代偿性心力衰竭的临床疗效急性研究）的见解

Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

作者信息

Greene Stephen J, Hernandez Adrian F, Sun Jie-Lena, Metra Marco, Butler Javed, Ambrosy Andrew P, Ezekowitz Justin A, Starling Randall C, Teerlink John R, Schulte Phillip J, Voors Adriaan A, Armstrong Paul W, O'Connor Christopher M, Mentz Robert J

机构信息

From the Division of Cardiology, Duke University Medical Center, Durham, NC (S.J.G., A.F.H., A.P.A., C.M.O., R.J.M.); Duke Clinical Research Institute, Durham, NC (A.F.H., J.-L.S., A.P.A., P.J.S., C.M.O., R.J.M.); Cardiology, University of Brescia, Italy (M.M.); Division of Cardiology, Stony Brook University, NY (J.B.); Canadian VIGOUR Center, University of Alberta, Edmonton, Canada (J.A.E., P.W.A.); Cleveland Clinic, OH (R.C.S.); Section of Cardiology, San Francisco Veterans Affairs Medical Center, School of Medicine, University of California San Francisco (J.R.T.); and Department of Cardiology, University Medical Center Groningen, The Netherlands (A.A.V.).

出版信息

Circ Heart Fail. 2016 Sep;9(9). doi: 10.1161/CIRCHEARTFAILURE.116.002986.

DOI:10.1161/CIRCHEARTFAILURE.116.002986

PMID:27623769

Abstract

BACKGROUND

Most international acute heart failure trials have failed to show benefit with respect to key end points. The impact of site enrollment and protocol execution on trial performance is unclear.

METHODS AND RESULTS

We assessed the impact of varying site enrollment volume among all 7141 acute heart failure patients from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Overall, 398 sites enrolled ≥1 patient, and median enrollment was 12 patients (interquartile range, 5-23). Patients from high enrolling sites (>60 patients/site) tended to have lower ejection fraction, worse New York Heart Association functional class, and lower utilization of guideline-directed medical therapy but fewer comorbidities and lower B-type natriuretic peptide level. Every 10 patient increase (up to 100 patients) in site enrollment correlated with lower likelihood of protocol noncompletion (odds ratio, 0.93; 95% confidence interval [CI], 0.89-0.98). After adjustment, increasing site enrollment predicted higher risk of persistent dyspnea at 6 hours (per 10 patient increase: odds ratio 1.02; 95% CI, 1.01-1.03) but not at 24 hours (odds ratio, 0.99; 95% CI, 0.98-1.00). Higher site enrollment was independently associated with lower risk of 30-day death or rehospitalization (per 10 patient increase: odds ratio, 0.98, 95% CI, 0.96-0.99) but not 180-day mortality (hazard ratio, 0.99; 95% CI, 0.98-1.01). The influence of increasing site enrollment on clinical end points varied across geographic regions with strongest associations in Latin America and Asia-Pacific (all interaction P<0.01).

CONCLUSIONS

In this large, acute heart failure trial, site enrollment correlated with protocol completion and was independently associated with trial end points. Individual and regional site performance present challenges to be considered in design of future acute heart failure trials.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

摘要

背景

大多数国际急性心力衰竭试验未能在关键终点上显示出获益。研究地点的入组情况和方案执行情况对试验结果的影响尚不清楚。

方法与结果

我们评估了急性失代偿性心力衰竭奈西立肽临床有效性急性研究（ASCEND-HF试验）中所有7141例急性心力衰竭患者不同研究地点入组数量的影响。总体而言，398个研究地点入组了≥1例患者，入组患者数量的中位数为12例（四分位间距为5-23例）。来自入组患者数量较多的研究地点（>60例/研究地点）的患者往往射血分数较低、纽约心脏协会心功能分级较差、指南指导的药物治疗使用率较低，但合并症较少且B型利钠肽水平较低。研究地点每增加10例入组患者（最多增加至100例），与方案未完成的可能性降低相关（比值比为0.93；95%置信区间[CI]为0.89-0.98）。调整后，研究地点入组患者数量增加预示6小时时持续性呼吸困难风险较高（每增加10例患者：比值比为1.02；95%CI为1.01-1.03），但24小时时并非如此（比值比为0.99；95%CI为0.98-1.00）。研究地点入组患者数量较多与30天死亡或再住院风险较低独立相关（每增加10例患者：比值比为0.98，95%CI为0.96-0.99），但与180天死亡率无关（风险比为0.99；95%CI为0.98-1.01）。研究地点入组患者数量增加对临床终点的影响在不同地理区域有所不同，在拉丁美洲和亚太地区关联最强（所有交互作用P<0.01）。