U.S. Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, Maryland.
Pharmacotherapy. 2018 Sep;38(9):899-906. doi: 10.1002/phar.2161. Epub 2018 Jul 16.
A target international normalized ratio (INR) of 2-3 has been recommended for patients with atrial fibrillation (AF) and risk factors for thromboembolism. This recommendation is largely based on evidence from observational studies a decade ago. This study utilized collective data from modern trials with warfarin controls to examine the relationship of warfarin anticoagulation, as assessed by INR, on the clinical outcome events of interest.
Data on warfarin-treated patients from three clinical studies supporting the approval of dabigatran (Pradaxa), apixaban (Eliquis), and edoxaban (Savaysa) were pooled. Ischemic stroke, intracranial hemorrhage (ICH), and all-cause death were selected as the outcome events of interest. Multivariate Cox regression modeling was performed to examine the association between time-dependent INR and each outcome event. Benefit-risk assessment was evaluated by summing the estimated annual event rate for ischemic stroke and ICH.
A total of 21,883 patients representing 322 ischemic strokes, 288 ICHs, and 657 all-cause deaths were included in the analysis. The models used suggest that the risk of ischemic stroke is greatly reduced when INR exceeds 2; in contrast, the risk of ICH increases monotonically as INR increases. When combining ischemic stroke and ICH events, the lowest estimated annual event rate was observed between INR of 2 and 2.5; the risk only slightly increased between INR of 1.8 and 3.0. Similarly, a U-shaped relationship between INR and the risk of all-cause death was found.
This study using collective warfarin data from recent large prospective trials indicates that INR between 2 and 2.5 provides the best balance between ischemic stroke and ICH, as well as optimal protection against death in patients with AF.
推荐房颤（AF）合并血栓栓塞高危因素的患者将国际标准化比值（INR）控制在 2-3。这一推荐主要基于 10 年前的观察性研究证据。本研究利用华法林对照的现代试验的汇总数据，评估 INR 评估的华法林抗凝与感兴趣的临床结局事件的关系。
汇总了支持批准达比加群（Pradaxa）、阿哌沙班（Eliquis）和依度沙班（Savaysa）的三项临床研究中接受华法林治疗的患者的数据。选择缺血性卒中和颅内出血（ICH）及全因死亡作为感兴趣的结局事件。采用多变量 Cox 回归模型分析时间依赖性 INR 与每个结局事件的关系。通过对缺血性卒中和 ICH 估计的年发生率进行求和来评估获益-风险评估。
共纳入 21883 例患者，代表 322 例缺血性卒中和 288 例 ICH 及 657 例全因死亡。所使用的模型表明，INR 超过 2 时，缺血性卒中的风险大大降低；相反，随着 INR 的增加，ICH 的风险呈单调递增。当合并缺血性卒中和 ICH 事件时，INR 在 2 至 2.5 之间观察到的估计年发生率最低；INR 在 1.8 至 3.0 之间仅略有增加。同样，发现 INR 与全因死亡风险之间存在 U 型关系。
本研究使用近期大型前瞻性试验的华法林汇总数据表明，INR 在 2 至 2.5 之间为 AF 患者提供了缺血性卒中和 ICH 之间最佳的平衡，并能最佳地预防死亡。
