Researchers at the London School of Hygiene and Tropical Medicine have conducted a trial emulation study using real-world data from UK patients to compare the effectiveness of apixaban and warfarin in preventing stroke in individuals with non-valvular atrial fibrillation. The study, published in PLOS Medicine, sought to replicate the findings of the pivotal ARISTOTLE trial but found that apixaban was not superior to warfarin in the real-world setting, challenging the original trial's conclusions.
Emulating a Clinical Trial
The researchers utilized routinely collected health data from the Clinical Practice Research Datalink (CPRD) Aurum, linked to Hospital Episodes Statistics, to emulate the ARISTOTLE trial. This involved mirroring the patient eligibility criteria, selection process, and analysis methods of the original RCT. The primary endpoint was the effectiveness of the two drugs in preventing stroke (ischemic or hemorrhagic) or systemic embolism. Key safety outcomes, including major bleeding and all-cause mortality, were also assessed.
Discordant Results
While the ARISTOTLE trial demonstrated the superiority of apixaban over warfarin, the emulation study found that patients prescribed apixaban had similar outcomes to those on warfarin. This divergence was attributed to several factors, including potentially higher quality of warfarin control in the real-world setting, suboptimal dosing of apixaban, and differences in the ethnicity of patients and the use of concomitant medications compared to the clinical trial population. Specifically, the average time in therapeutic range for warfarin users in the emulation study was higher than that reported in ARISTOTLE.
Implications for Underrepresented Populations
The study highlights the potential of using real-world data to assess treatment effects in patient groups underrepresented or excluded from clinical trials, such as the elderly, those with multiple comorbidities, and individuals at higher risk of bleeding. Emma Maud Powell, who led the project, noted that this approach could help fill the evidence gap for population groups largely missing in RCTs. Both the FDA and the European Medicines Agency are interested in the extent to which real-world data can be tapped to “bridge” the evidence gap left after clinical trials.
Limitations and Future Directions
The researchers acknowledged limitations, including potential bias introduced by patients switching between medications. However, they emphasized that the reference trial emulation approach provides a valuable framework for investigating treatment effects for other conditions and for understanding the transferability of clinical trial results to real-world practices. The study underscores the importance of considering differences in standards of care and patient characteristics when interpreting and applying clinical trial findings in diverse populations.
