Prospective Monitoring of New Drugs in Older Adults with and Without Frailty: Near-Real-Time Assessment of Effectiveness and Safety of Oral Anticoagulants in Medicare Data

Background And Objective: Prospective sequential analyses after a new drug approval allow proactive surveillance of new drugs. In the current study, we demonstrate feasibility of frailty-specific sequential analyses for dabigatran, rivaroxaban, and apixaban versus warfarin.

Methods: We partitioned Medicare data from 2011 to 2020 into datasets based on calendar year following the date of drug approval. Each calendar year of data was added sequentially for analysis. We used a new-user, active comparative design by comparing the initiators of dabigatran versus warfarin, rivaroxaban versus warfarin, and apixaban versus warfarin. Patients aged ≥ 65 years with atrial fibrillation without contraindication to the anticoagulants were included. Claims-based frailty index ≥ 0.25 was used to define frailty. The initiators of each direct oral anticoagulant were propensity-score matched to the initiators of warfarin within each frailty status. The effectiveness outcome was ischemic stroke or systemic thromboembolism, and the safety outcome was major bleeding. For each calendar year, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards models using all data available up to that year.

Results: As an example of the results, in the 2020 dataset, compared with warfarin, apixaban was associated with a reduced risk of ischemic stroke or systemic thromboembolism (frail: HR 0.73, 95% CI 0.63-0.85; non-frail: HR 0.65, 95% CI 0.59-0.72) and major bleeding (frail: HR 0.63, 95% CI 0.57-0.69; non-frail: HR 0.59, 95% CI 0.56-0.63) in both frail and non-frail patients. We found evidence for apixaban's effectiveness and safety within 1-2 years after the drug approval in frail older patients.

Conclusion: Our frailty-specific sequential analyses can be applied to future near-real-time monitoring of newly approved drugs.