Apixaban Bests Rivaroxaban, Warfarin in Preventing VTE Recurrence and Bleeding

In patients with venous thromboembolism (VTE) who are candidates for oral anticoagulation, apixaban results in fewer hospitalizations for recurrence and less major bleeding than rivaroxaban or warfarin, a large analysis suggests.

Compared with warfarin, apixaban (Eliquis; Bristol Myers Squibb) was associated with a 33% lower risk of hospitalization for recurrent VTE over a median follow-up of 5.5 months, while rivaroxaban (Xarelto; Bayer/Janssen) was associated with a 23% lower risk. A separate comparison showed a 13% lower risk with apixaban versus rivaroxaban. The findings were consistent across subgroups stratified by age, sex, cancer, kidney disease, and frailty.

While CHEST guidelines give the nod to direct oral anticoagulants (DOACs) over warfarin as the initial anticoagulation approach in patients with VTE, they don’t recommend specific agents because head-to-head evidence of efficacy and safety is lacking.

On that background, up to 10% of patients experience VTE recurrence within the first 6 months, with rates as high as 30% within the first year, note Sungho Bea, PharmD, PhD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), and colleagues in the paper, which was published this week in JAMA Internal Medicine.

“While we did not observe a substantial difference in mortality rates, patients taking apixaban also had lower rates of a composite event that included VTE recurrence, major bleeding, and all-cause mortality than patients taking warfarin or rivaroxaban,” they write.

The findings are consistent with data from the EINSTEIN-DVT, EINSTEIN-PE, and AMPLIFY randomized trials, as well as study of claims data looking at more than 35,000 new users of apixaban and rivaroxaban that showed lower rates of recurrent VTE and bleeding with apixaban.

Ghadeer K. Dawwas, PhD (Vanderbilt University School of Medicine, Nashville, TN), who led the latter study, said the analysis by Bea and colleagues confirms earlier observations of favorable safety and effectiveness with apixaban.

“In our study, we used data from mostly commercially insured patients, with a portion of them being commercially insured with supplemental Medicare,” she told TCTMD. “In this study, they used multiple databases, which allows for improved generalizability of the findings.”

While the new results are reassuring about the use of DOACs, Dawwas pointed to recent positive data on novel factor XI inhibitors, which could expand options for anticoagulation in a variety of situations in the very near future, particularly for patients with high bleeding risk.

“It will be interesting, if they gain approval, to see how they change the landscape in terms of which medication is favored among clinicians and patients,” Dawwas added.

Lackluster Findings for Warfarin

Bea and colleagues used Medicare and two commercial insurance databases for the analysis of 163,593 patients (mean age 71.4 years; 56.7% women) who initiated an oral anticoagulant between 2016 and 2024 within 30 days of a VTE diagnosis. Of these, 58.5% started apixaban, 25.7% rivaroxaban, and 15.8% warfarin. The index event was pulmonary embolism in about 70% of the population.

Before propensity-score weighting, which yielded roughly 21,000 patients in each treatment group, warfarin patients were older, more likely to present with DVT as the index event, and more apt to have stage 3 chronic kidney disease and prior bleeding episodes than patients in the apixaban or rivaroxaban groups.

Of 3,270 hospitalizations for recurrent VTE, the weighted incidence rate was highest for warfarin users at 38.3 per 100,000 person-years, followed by rivaroxaban at 26.8 and apixaban at 23.3.   

In addition to the lower risk of recurrent VTE, apixaban also was associated with less risk of major bleeding compared with both warfarin (HR 0.70; 95% CI 0.64-0.76) and rivaroxaban (HR 0.69; 95% CI 0.63-0.75). A comparison of rivaroxaban and warfarin showed no difference in major bleeding except in patients younger than age 65 (HR 0.61; 95% CI 0.43-0.87).

The advantage for apixaban in preventing VTE recurrence was consistent across subgroup analyses that accounted for age, sex, active cancer, chronic kidney disease, history of bleeding, and three categories of frailty. For these analyses, propensity scores and weights were reestimated within each subgroup and then pooled across the three databases to ensure control within each subgroup.

Investigators also looked at a secondary outcome of all-cause mortality, which was similar across the three anticoagulant agents. However, when assessing a composite outcome that included all-cause mortality, VTE recurrence, and major bleeding, the weighted hazard ratio was lowest for apixaban compared with either rivaroxaban or warfarin.

In looking at all-cause mortality in the subgroups, patients with active cancer taking apixaban or rivaroxaban had an increased risk compared with warfarin. The researchers say residual confounding cannot be excluded, however, and note that while they adjusted for some cancer-related variables, cancer stage is not included in claims data.

“The first question that comes to my mind is whether this is reverse causality,” Dawwas added. “When you look at the trends in utilization of anticoagulants over the last few years, there is a significant decline in warfarin because many clinicians are feeling confident prescribing DOACs, in many instances due to their favorable safety profile. Warfarin has many drug-drug interactions, so it’s possible that [more patients with] severe cancer are being prescribed apixaban and rivaroxaban, and that’s why we’re seeing that reverse causality.”

According to the study authors, while this study focused on oral anticoagulation as it is implemented in clinical practice, including medically necessary dose adjustments, more focused research on dosing strategies and adjustments could give additional insight into how subtle clinical differences impact outcomes.