Background: Emulating randomized controlled trials (RCT) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT.
Objectives: 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) using administrative claims data.
Methods: Using the South Korean nationwide claims database from Jan 2012 to Aug 2020, we created five separate RWE cohorts mimicking five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs in patients with VTE. The effectiveness outcome (recurrent VTE) and safety outcome (major bleeding) were emulated in each RWE cohort. Patients were followed from initiation of each NOAC or warfarin until the earliest of outcome occurrence, treatment discontinuation or switching, in-hospital death, or end of the study. Propensity score matching was conducted to balance the distribution of 69 covariates within a 2-years interval of index year to minimize a potential channeling bias. Effect estimates for outcomes were estimated using Mantel–Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.
Results: 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 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 RWE emulations except for AMPLIFY and EINSTEIN-DVT yielded consistent results with the safety outcome of RCTs, by demonstrating NOAC-favorable results over conventional therapy: AMPLIFY (RR 0.99, 95% CI 0.73-1.37); RE-COVER II (HR 0.62, 95% CI 0.22-1.77); Hokusai-VTE (HR 0.61, 95% CI 0.25-1.51); EINSTEIN-DVT (HR 1.62, 95% CI 0.70-0.32) and EINSTEIN-PE (HR 0.65, 95% CI 0.35-1.21).
Conclusions: 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.
