Non-inferiority trials using a surrogate marker as the primary endpoint: An increasing phenotype in cardiovascular trials.
Non-inferiority trials using a surrogate marker as the primary endpoint: An increasing phenotype in cardiovascular trials.
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DOI：
10.1177/1740774520949157
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Krumholz HM
中科院分区：
文献类型：
--
作者：
Bikdeli B;Caraballo C;Welsh J;Ross JS;Kaul S;Stone GW;Krumholz HM
心血管医学领域的非劣势试验正在增加，许多药物和设备都是在此类研究的基础上获得批准的。作为主要终点的替代标记物也被更频繁地用于心血管干预的有效评估。然而，它们与临床结果的一致性尚不确定。使用替代标记物作为主要终点的非劣势设计在临床解释中可能会带来特殊的挑战。我们试图探索使用主要替代标记物作为主要终点的非劣势心血管试验的发表趋势、方法和报道特征。我们检索了从1990年1月1日到2018年12月31日的六种高影响力的期刊(NEJM，JAMA，Lancet，JACC，循环和EHJ)，并确定了使用替代标记物作为主要终点的非劣势心血管试验。我们评估了手稿和其他可公开获得的平台(例如，PROTOCOL，Clinicaltrials.gov)中报告的非劣势边际。我们还确定了以替代标记物为主要终点的纳入的非劣势试验是否随后进行了临床结果试验。我们筛选了15,553篇出版物，确定了247项使用非劣势设计的心血管试验。在这些试验中，37个有替代标记物作为主要终点(18个药物试验，13个装置试验，其他6个)。所有这些具有替代结果的非劣势试验都是在2000年以后发表的，主要发表在心脏病学期刊上(13篇发表在《美国心脏病学会杂志》上，9篇发表在《欧洲心脏杂志》上，8篇发表在《循环》杂志上，6篇发表在《柳叶刀》杂志上，1篇发表在《新英格兰医学杂志》上)，它们的发表比率随着时间的推移而增加(线性趋势P<；0.001)。初步分析中患者的中位数为300人(IQR：202-465)。只有13个(35.1%)试验公开了研究方案或方法论文，其中4个试验没有报告非劣势边缘。在16个研究(43.2%)中，手稿没有承认使用替代终点的局限性，或者没有明确的临床结果试验的必要性。34项试验(91.9%)得出结论，所测试的干预措施符合非劣势标准。然而，只有5例(13.5%)进行了临床结果试验，其结果并不总是证实非劣势。使用替代标记作为主要终点的非劣势试验正在越来越多地进行。然而，这些审判在设计、报告和解释方面提出了特别的挑战，这些问题没有得到系统和一致的处理或报告。
Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate markers as primary endpoints have been also more frequently used for efficient assessment of cardiovascular interventions. However, there is uncertainty about their concordance with clinical outcomes. Non-inferiority design using a surrogate marker as a primary endpoint may pose particular challenges in clinical interpretation. We sought to explore the publication trends, methodology and reporting features of non-inferiority cardiovascular trials that used a primary surrogate marker as the primary endpoint. We searched six high-impact journals (NEJM, JAMA, Lancet, JACC, Circulation, and EHJ) from January 1, 1990, to December 31, 2018 and identified non-inferiority cardiovascular trials that used a surrogate marker as a primary endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g., protocol, clinicaltrials.gov). We also determined whether the included non-inferiority trials with surrogate markers as primary endpoints were followed by clinical outcome trials. We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a surrogate marker as a primary endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in JACC, 9 in European Heart Journal, 8 in Circulation, 6 in Lancet, 1 in NEJM), and their publication rate increased over time (P<0.001 for linear trend). The median number of patients in the primary analysis was 300 (IQR: 202 – 465). The study protocol or a methods paper was publicly available for only 13 (35.1%) trials, of which the non-inferiority margin was not reported in 4. In 16 studies (43.2%) the manuscript did not acknowledge the limitations of using a surrogate endpoint, or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority criteria. However, only 5 (13.5%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority. Non-inferiority trials that use a surrogate marker as a primary endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting and interpretation, which are not systematically and consistently addressed or reported.
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影响因子：
39.3
作者：
Sabaté M;Windecker S;Iñiguez A;Okkels-Jensen L;Cequier A;Brugaletta S;Hofma SH;Räber L;Christiansen EH;Suttorp M;Pilgrim T;Anne van Es G;Sotomi Y;García-García HM;Onuma Y;Serruys PW
通讯作者：
Serruys PW
影响因子：
158.5
作者：
Ellis, Stephen G.;Kereiakes, Dean J.;Stone, Gregg W.
通讯作者：
Stone, Gregg W.
影响因子：
3.7
作者：
Acuna, Sergio A.;Chesney, Tyler R.;Baxter, Nancy N.
通讯作者：
Baxter, Nancy N.
影响因子：
24
作者：
Gao, Runlin;Yang, Yuejin;Stone, Gregg W.
通讯作者：
Stone, Gregg W.
影响因子：
2.3
作者：
Moliterno, David J.
通讯作者：
Moliterno, David J.