School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea.
BMC Med. 2023 Sep 29;21(1):375. doi: 10.1186/s12916-023-03069-1.
Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).
Five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel-Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.
Compared to trial populations, real-world study populations were older (range: 63-69 years [RWE] vs. 54-59 years [RCT]), with more females (55-60.5% vs. 39-48.3%) and had a higher prevalence of active cancer (4.2-15.4% vs. 2.5-9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70-0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37-0.96; Hokusai-VTE: 0.49, 0.31-0.78; EINSTEIN-DVT: 0.54, 0.33-0.89; EINSTEIN-PE: 0.50, 0.34-0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.
This study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.
通过真实世界证据（RWE）研究模拟随机对照试验（RCT），可以平衡 RCT 的局限性，从而有助于未来的临床和监管决策。我们旨在评估 RWE 研究的结果是否可以支持源自非维生素 K 拮抗剂口服抗凝剂（NOAC）治疗静脉血栓栓塞症（VTE）的 RCT 得出的监管决策。
使用韩国全国索赔数据库（2012 年 1 月至 2020 年 8 月）模拟了 5 项 NOAC 的标志性试验（AMPLIFY、RE-COVER II、Hokusai-VTE、EINSTEIN-DVT 和 EINSTEIN-PE）。我们应用了活性对照和新用户设计，纳入了在 VTE 诊断后 28 天内开始口服抗凝剂的患者。尽可能在每个单独的模拟队列中模拟预先规定的纳入标准、暴露（每种 NOAC，如阿哌沙班、利伐沙班、达比加群和依度沙班）、对照（定义为皮下肝素后华法林的常规治疗）和 RCT 中结局的定义。主要结局与每项试验相同，定义为复发性 VTE 或 VTE 相关死亡。安全性结局为大出血。进行了倾向评分匹配，以平衡暴露组中的 69 个协变量。使用 Mantel-Haenszel 方法和 Cox 比例风险模型估计结局的效应估计值，随后将其与相应的 RCT 估计值进行比较。
与试验人群相比，真实世界研究人群年龄较大（范围：63-69 岁[RWE]与 54-59 岁[RCT]），女性比例更高（55-60.5%与 39-48.3%），且癌症活跃期的患病率更高（4.2-15.4%与 2.5-9.5%）。NOAC 的有效性结局模拟估计值显示出更高的有效性（AMPLIFY：相对风险 0.81，95%置信区间 0.70-0.94；RE-COVER II：风险比 [HR]0.60，0.37-0.96；Hokusai-VTE：0.49，0.31-0.78；EINSTEIN-DVT：0.54，0.33-0.89；EINSTEIN-PE：0.50，0.34-0.74），与显示非劣效性的试验相比。对于安全性结局，除了 AMPLIFY 和 EINSTEIN-DVT 之外，所有模拟结果均与相应的 RCT 一致。
本研究通过使用 VTE 患者的索赔数据，揭示了使用 RWE 研究补充 RCT 的可行性。需要进一步研究考虑 RCT 和 RWE 人群之间不同的人口统计学特征。
