Apixaban Shows Lower Bleeding Risk Than Rivaroxaban for VTE | NEJM Study

For individuals taking blood thinners to prevent or treat venous thromboembolism (VTE)—conditions like deep vein thrombosis and pulmonary embolism—a new study offers compelling evidence regarding the relative safety of two commonly prescribed medications. Results from the COBRRA trial, published March 11 in the New England Journal of Medicine, indicate that apixaban (Eliquis) is associated with a significantly lower risk of clinically relevant bleeding compared to rivaroxaban (Xarelto) over a three-month treatment period.

VTE encompasses a range of conditions where blood clots form in veins, often in the legs (deep vein thrombosis) or lungs (pulmonary embolism). Direct oral anticoagulants (DOACs) like apixaban and rivaroxaban have become mainstays of treatment, offering convenience over older medications like warfarin. However, a key clinical question has remained: are the bleeding risks equivalent between these two drugs? The COBRRA trial, an international, randomized study, sought to answer that question.

Trial Design and Key Findings

Researchers enrolled 2,760 patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis, randomly assigning them to receive either apixaban or rivaroxaban for three months. The study population had a mean age of 58, with women comprising 44% of the participants. Apixaban was administered at a dose of 10 mg twice daily for the first week, then reduced to 5 mg twice daily. Rivaroxaban followed a regimen of 15 mg twice daily for three weeks, followed by 20 mg daily.

The primary outcome measured was clinically relevant bleeding—a composite of major bleeding or clinically relevant nonmajor bleeding, as defined by the International Society on Thrombosis and Haemostasis. The results were striking: 3.3% of patients taking apixaban experienced a bleeding event, compared to 7.1% of those taking rivaroxaban. This translates to a relative risk of 0.46, meaning patients on apixaban had less than half the risk of bleeding compared to those on rivaroxaban (95% confidence interval, 0.33 to 0.65; P<0.001).

While the study focused on bleeding risk, researchers similarly tracked mortality. One patient in the apixaban group died, compared to four in the rivaroxaban group, though this difference was not statistically significant. Serious adverse events unrelated to bleeding or VTE were reported in a similar proportion of patients in both groups (2.7% vs. 2.2%).

Why the Difference? Initial Dosing May Play a Role

The study authors, led by Dr. Lana A. Castellucci of the University of Ottawa/Ottawa Hospital, suggest that the difference in bleeding risk may be linked to the initial dosing of rivaroxaban. The higher dose given during the first three weeks of rivaroxaban treatment appears to be when the majority of bleeding events occurred. As the researchers note in their publication, further investigation is needed to confirm whether the rivaroxaban dosing regimen specifically contributed to the observed risks.

Understanding Clinically Relevant Bleeding

It’s essential to understand what constitutes “clinically relevant bleeding.” This isn’t simply a nosebleed. According to the International Society on Thrombosis and Haemostasis (ISTH), it encompasses bleeding events that require medical attention, such as hospitalization, transfusion, or interruption of anticoagulation therapy. Major bleeding events are those that are life-threatening or cause significant disability. Clinically relevant nonmajor bleeding events, while not immediately life-threatening, still require intervention and can significantly impact a patient’s quality of life.

Implications for Clinical Practice and Guidelines

The COBRRA trial findings have prompted experts to call for a reevaluation of current treatment guidelines for VTE. In an editorial accompanying the study, Dr. Lisa K. Moores of the Uniformed Services University of the Health Sciences argues that the results suggest apixaban should be favored over rivaroxaban for many patients with acute VTE. “For many patients with acute venous thromboembolism, the choice of anticoagulant is no longer a toss-up,” she writes.

Current guidelines from organizations like the American Society of Hematology generally recommend either apixaban or rivaroxaban as acceptable options for treating VTE. However, the COBRRA trial provides strong evidence to suggest that apixaban may offer a more favorable safety profile. It’s likely that these guidelines will be revisited in light of these new findings.

What Does This Mean for Patients?

If you are currently taking rivaroxaban for VTE, it’s crucial to continue your medication as prescribed and discuss any concerns with your healthcare provider. Do not make any changes to your treatment plan without consulting your doctor. The COBRRA trial does not suggest that rivaroxaban is ineffective; rather, it highlights a potential difference in bleeding risk compared to apixaban.

For individuals newly diagnosed with VTE, this information may be relevant to discussions with their physician about the most appropriate anticoagulant therapy. Factors beyond bleeding risk, such as cost, patient preferences, and potential drug interactions, will also play a role in the decision-making process.

Looking Ahead: Ongoing Research and Surveillance

The COBRRA trial provides valuable insights into the comparative safety of apixaban and rivaroxaban. However, ongoing research is needed to further refine our understanding of these medications and optimize treatment strategies for VTE. Future studies may explore the impact of different dosing regimens, identify patient subgroups who may benefit most from apixaban, and assess the long-term safety and efficacy of both drugs.

Post-market surveillance will also be critical to monitor real-world outcomes and identify any unexpected safety signals. Healthcare providers are encouraged to report any adverse events related to apixaban or rivaroxaban to regulatory agencies like the Food and Drug Administration (FDA).