Apixaban has superior effectiveness and safety compared to rivaroxaban in patients with commercial healthcare coverage: A population‐based analysis in response to CVS 2022 formulary changes

To the Editor: CVS Caremark, part of CVS Health, announced the exclusion of apixaban (Eliquis®) from the CVS 2022 Caremark Preferred Drug List contracted with some insurers. Warfarin and rivaroxaban are listed as preferred alternatives. Apixaban is a direct oral anticoagulant (DOAC) indicated for the prevention and treatment of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE). One factor that may have influenced the exclusion of apixaban from CVS formulary coverage was the limited evidence comparing apixaban to other DOACs specifically in younger patients with commercial healthcare coverage. Recently, researchers showed a lower rate of thromboembolic and bleeding events with apixaban compared to rivaroxaban.1, 2 However, these studies focused on Medicare beneficiaries 65 years or older2 or included commercially insured adults with dual enrollment in Medicare.1 To address this policy-relevant gap in evidence, we examined the effectiveness and safety of apixaban compared to rivaroxaban in a new-user cohort of VTE patients with commercial healthcare coverage, excluding patients with dual Medicare enrollment, overall, and stratified by age group. We used commercial data from Optum's deidentified Clinformatics® Data Mart Database, which captures the healthcare experience of a privately insured population in the United States. The administrative database includes deidentified individual-level data on enrollment, patient demographics, outpatient claims, inpatient claims, prescription drug claims, and laboratory data for a subset of beneficiaries. Studies using the Optum Clinformatics Data Mart Database are categorized as exempt from Institutional Review Board approval at the University of Pennsylvania. We conducted a new-user active comparator cohort study. The study design, methods, and outcomes definitions are described in our recent study.1 We included patients ≥18 years, who had ≥1 prescription of apixaban or rivaroxaban dispensed within 30 days of VTE diagnosis, and 12 months of continuous enrollment in medical and pharmacy benefits prior to treatment initiation (i.e., lookback period). To create a cohort of commercially insured patients, we excluded patients with dual enrollment (i.e., use of both commercial and Medicare insurance). We excluded patients with a prescription for any anticoagulant (i.e., dabigatran, edoxaban, and warfarin) during the lookback period and those who had diagnosis of PE or DVT prior to their index VTE. The primary effectiveness outcome was recurrent VTE, a composite of DVT and PE. The primary safety outcome was a composite of gastrointestinal (GI) and intracranial bleeding. Follow-up began on treatment initiation and ended at the earliest occurrence of an outcome of interest, treatment discontinuation, initiation of the comparator, disenrollment from the health plan, or end of the study period. We used propensity score matching to adjust for potential differences in baseline demographics and disease risk factors between new-users of apixaban and rivaroxaban. After propensity score 1:1 matching, we estimated marginal hazard ratios (HRs) and corresponding 95% CI via Cox proportional-hazards regression using a robust variance estimator while adjusting for calendar year. We assessed the potential for effect modification by age group (<65 years and ≥65 years). We performed matching again within each of the selected subgroups. We conducted all analyses using SAS v9.4 (SAS Institute Inc.: Cary, NC). The analysis included 42 143 patients with VTE with commercial healthcare coverage who were new-users of apixaban or rivaroxaban (Table A1). In the matched cohort (n = 15 453 for apixaban and n = 15 453 for rivaroxaban), the mean age was 67 years. Approximately, 39% of patients were younger than 65 years (n = 6049 for apixaban and n = 5952 for rivaroxaban). Covariates were well-balanced after matching including male sex (48% vs. 48%), anemia (13% vs. 13%), chronic lung disease (31% vs. 31%), diabetes (28% vs. 28%), and peripheral vascular disease (20% vs. 20%). In the propensity score-matched cohort of VTE patients, the incidence rate of VTE per 100 person-years of follow-up was 8.9 among apixaban users and 11.2 among rivaroxaban users. After propensity-score matching, use of apixaban (vs. rivaroxaban) was associated with a lower rate of recurrent VTE (adjusted HR, 0.78 [95% CI, 0.69 to 0.90]) (Table 1). The results for the individual effectiveness outcome were similar for DVT (HR, 0.84 [95% CI, 0.73 to 0.97]) and PE (HR, 0.56 [95% CI, 0.31 to 1.01]). The incidence rate of GI and intracranial bleeding per 100 person-years of follow-up was 7.6 among apixaban users and 10.7 among rivaroxaban users. After propensity-score matching, use of apixaban (vs. rivaroxaban) was associated with a lower rate of GI and intracranial bleeding (HR, 0.70 [95% CI, 0.61 to 0.80]) (Table 1). The results were similar for GI bleeding (HR, 0.66 [95% CI, 0.57 to 0.76]) and intracranial bleeding (HR, 0.79 [95% CI, 0.24 to 2.57]). We did not find evidence of effect modification by age among users of apixaban (vs. rivaroxaban) for recurrent VTE (p-value for interaction = 0.64) or bleeding (p-value for interaction = 0.20) (Table 1). In this large, propensity score-matched cohort of commercially insured patients with VTE, we found that apixaban use was associated with a lower rate of recurrent VTE, intracranial bleeding, and GI bleeding compared with rivaroxaban; results did not vary with age. Our results confirm and extend recent findings from observational studies.1, 2 Specifically, our findings suggest that benefits associated with apixaban use to treat VTE are (a) realized by patients with commercial insurance coverage and are not limited to those with Medicare coverage and (b) extend across age groups including those younger than 65 years. Use of DOACs is guideline-recommended over warfarin therapy given their improved safety-efficacy profile and ease of use.3, 4 There are clinical situations in which rivaroxaban may be the most appropriate DOAC (e.g., patients who cannot reliably take twice-daily medications). However, based on the results of our analysis, there is compelling evidence favoring apixaban as compared to rivaroxaban in commercially insured patients with VTE. It is critical that insurance formulary coverage decisions follow the best available evidence and prioritize easy access to treatments with the highest degree of efficacy and safety. Formulary coverage decisions that are not evidence-based may have unintended consequences including inferior outcomes and increased overall healthcare costs. GKD receives funding from the American Society of Hematology and National Institutes of Health. AC has served as a consultant for Synergy; he has received authorship royalties from UpToDate; and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, and Spark. JMC reports consulting and personal fees from Abbott, Anthos, Alnylam, Bristol Myers Squibb, Pfizer, Roche, Sanofi, Takeda and research funding to the institution from CSL Behring. GDB has serves as a consultant for Pfizer/Bristol-Myers Squibb, Janssen, and Acelis Connected Health. The data used for this study are not publicly available. Statistical codes are available upon request from the corresponding author. Protocol and ICD codes used in the current analysis can be found in our previously published work (PMID: 34871048). Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.