Trials and tribulations of non-inferiority - The ximelagatran experience
Trials and tribulations of non-inferiority - The ximelagatran experience
复制标题
DOI：
10.1016/j.jacc.2005.07.062
复制
发表时间：
2005-12-06
影响因子：
24
通讯作者：
Weintraub, WS
中科院分区：
文献类型：
--
作者：
Kaul, S;Diamond, GA;Weintraub, WS
希美加群是一种新型口服直接凝血酶抑制剂，与房颤患者的标准治疗方法华法林相比具有许多优势。两项大型临床试验，其中一项是开放标签（使用口服凝血酶抑制剂治疗心房颤动预防中风[SPORTIF] III），一项是双盲（SPORTIF V），使用非劣效性设计比较了不进行抗凝监测的固定剂量希美加群与剂量调整华法林的疗效和安全性。根据结果，研究人员得出结论，希美加群在预防中风或全身性栓塞（主要终点）方面与华法林一样有效，因为满足了预先指定的非劣效性标准。然而，使用相当保守的解释标准对数据进行重新分析，揭示了一些缺陷：1）考虑到华法林的基线事件发生率较低，不合理的慷慨裕度可能会偏向于非劣效性； 2）用于估计非劣效性界限的分析方法不恰当； 3) 对希美加群保留至少 50% 华法林疗效缺乏信心（建立非劣效性的先决条件）； 4) 两项试验中观察到的疗效程度存在显着异质性； 5) 希美加群增加 Ever 毒性的安全性问题，但在大出血方面没有显着的抵消优势。这种利益-风险状况的不平衡极大地削弱了研究人员关于希美加群非劣效性的主张，并导致美国食品和药物管理局拒绝申办者对希美加群的申请。尽管已发表的结论相反，但我们得出的结论是，希美加群并未被证明不劣于华法林。这种非劣效性的确定高度依赖于基本假设，图形敏感性分析使这种依赖性变得明确。
Ximelagatran is a novel oral direct thrombin inhibitor that offers a number of advantages over the standard treatment, warfarin, in patients with atrial fibrillation. Two large clinical trials, one open-label (Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation [SPORTIF] III), one double-blind (SPORTIF V), have compared the efficacy and safety of fixed-dose ximelagatran without anticoagulation monitoring with dose-adjusted warfarin using a non-inferiority design. On the basis of the results, the investigators concluded that ximelagatran was just as effective as warfarin in preventing stroke or systemic embolism (the primary end point), because the pre-specified non-inferiority criterion was met. Reanalysis of the data with rather conservative interpretive criteria, however, revealed a number of deficiencies: 1) an unreasonably generous margin that was potentially biased toward non-inferiority, given the low baseline event rate of warfarin; 2) the inappropriateness of the analytical method used to estimate the non-inferiority margin; 3) a lack of confidence that ximelagatran retains at least 50% of warfarin's effect (a prerequisite to the establishment of non-inferiority); 4) significant heterogeneity in the magnitude of efficacy observed in the two trials; and 5) safety concerns regarding increased Ever toxicity with ximelagatran without a significant offsetting advantage in major bleeding. This imbalance in the benefit-risk profile materially undermines the investigators' claim of non-inferiority of ximelagatran and led the Food and Drug Administration to reject the sponsor's application for ximelagatran. Despite published conclusions to the contrary, we conclude that ximelagatran has not been shown to be non-inferior to warfarin. Such determinations of non-inferiority are highly dependent on the underlying assumptions, and graphical sensitivity analyses make this dependence explicit.