Apixaban (ELIQUIS) Safer than Rivaroxaban (XARELTO) for Venous Thromboembolism

Venous thromboembolism (blood clots in veins) is an umbrella term that includes deep vein thrombosis (blood clots that occur in deep veins, typically in the leg) and pulmonary embolism (a broken-off part of a clot that interferes with blood flow in the lungs). Blood thinners called direct-acting oral anticoagulants (DOACs), such as apixaban (ELIQUIS and generics), dabigatran (PRADAXA and generics) and rivaroxaban (XARELTO and generics), are an alternative to warfarin (JANTOVEN and generics) for these conditions.[1],[2] However, the comparative safety and efficacy of different DOACs have been difficult to assess because clinical trials have so far not directly compared these drugs with one another.[3] A study published in the March 2026 issue of the New England Journal of Medicine compared apixaban with rivaroxaban, the two most commonly prescribed DOACs for acute venous thromboembolism.[4] Although the drugs had comparable effectiveness during three months of treatment, apixaban was associated with a significantly lower risk of bleeding than rivaroxaban.

Background on venous thromboembolism

The most common symptoms of deep vein thrombosis include swelling, redness and pain at the affected site. Typical symptoms of pulmonary embolism include difficulty breathing, chest pain, fainting and coughing up blood.[5] Because venous thromboembolism does not always cause symptoms, it is underdiagnosed.[6] In the United States, up to 900,000 people may be affected each year, and there are about 60,000 to 100,000 deaths.[7]

Although venous thromboembolism can affect anyone, some people are at higher risk.[8] Risk factors include a family history, older age, injuries to a vein, extended immobility, high estrogen levels (due to pregnancy, hormone therapy or birth control treatments) as well as certain blood clotting conditions such as sickle cell disease. People are generally at the highest risk of venous thromboembolism during or shortly after hospitalization, during or shortly after pregnancy and during cancer treatment.

For those at high risk, maintaining a healthy weight, staying active and wearing compression stockings are important, although DOACs are also sometimes prescribed to prevent blood clots from forming or venous thromboembolism from recurring. About one-third of those with venous thromboembolism will have a recurrence within 10 years.[9]

Apixaban

In 2012, the Food and Drug Administration (FDA) first approved apixaban to decrease the risk of stroke and systemic embolism (a blood clot lodged inside a blood vessel) in adult patients with nonvalvular atrial fibrillation.[10] Subsequently, apixaban was approved to treat and reduce the risk of recurrence of deep vein thrombosis and pulmonary embolism. In adult patients who have undergone hip- or knee-replacement surgery, apixaban is also indicated to reduce the risk of deep vein thrombosis and pulmonary embolism. Apixaban is available in 2.5- or 5-milligram (mg) doses and is taken twice daily.

Apixaban’s product label includes a boxed warning — the FDA’s most prominent warning — because premature discontinuation of any anticoagulant increases the risk of thrombosis except when the anticoagulant is discontinued because of bleeding complications.[11] Moreover, patients treated with apixaban who are undergoing certain procedures, such as a spinal puncture (spinal tap), may develop epidural or spinal hematomas (a pool of mostly clotted blood that forms in an organ, tissue or body space), which may lead to long-term or permanent paralysis. The increased risk of bleeding is the most important health risk associated with all anticoagulants. Importantly, apixaban’s level of anticoagulation cannot be easily tested or monitored, and a safe and effective antidote to reverse the drug’s effects is unavailable.[12]

With the exception of apixaban, Public Citizen’s Health Research Group classifies all DOACs as Do Not Use drugs because their safety concerns outweigh their benefits.[13] Based on recent evidence, as discussed in the April 2024 issue of Worst Pills, Best Pills News, we designate apixaban as Limited Use, a designation further supported by the new study.

The new study

In a prospective, open-label trial, 2,760 adults with acute symptomatic venous thromboembolism were randomized to receive treatment with either apixaban (10 mg twice daily for the first seven days, then 5 mg twice daily) or rivaroxaban (15 mg twice daily for the first 21 days, then 20 mg daily).[14] The study was partially funded by the Canadian Institutes of Health Research.

During the three-month trial period, clinically relevant bleeding, the primary outcome, was significantly lower among participants in the apixaban group (3.3%) than among those in the rivaroxaban group (7.1%).[15] For the secondary outcomes, there were no significant differences between the two treatment groups. For example, death from any cause occurred in 0.1% of those in the apixaban group and in 0.3% of those in the rivaroxaban group. The rate of serious adverse events unrelated to venous thrombosis or bleeding were similar between the apixaban group (2.7%) and the rivaroxaban group (2.2%). The trial also found that the reduced bleeding risk associated with apixaban did not compromise the drug’s efficacy: The risk of recurring symptomatic thromboembolism was comparable between the apixaban (1.1%) and the rivaroxaban groups (1.0%).

The trial excluded some patient groups at high risk for venous thromboembolism, such as cancer patients and pregnant patients. Moreover, about 90% of the trial participants were white, and data were collected for only three months. Because the starting and maintenance doses of rivaroxaban are much higher than for apixaban, it is not known whether the observed differences in bleeding risk would persist with longer-term treatment.[16]

What You Can Do

For acute venous thromboembolism or to reduce the risk of a recurrence, discuss with your clinician which treatment would work best for you. Apixaban is not recommended for certain patients including those with mechanical heart valves, severely impaired kidney function or pregnancy.[17]
 

References

[1] Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: Second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608.

[2] Lip GY, Stevens SM. Venous thromboembolism: Anticoagulation after initial management. UpToDate. Updated March 24, 2026.

[3] Moores LK. The COBRRA trial — Ending the venous thromboembolism safety toss-up. N Engl J Med. 2026;394(11):1123-1124.

[4] Castellucci LA, Chen VM, Kovacs MJ, et al. Bleeding risk with apixaban vs. rivaroxaban in acute venous thromboembolism. N Engl J Med. 2026;394(11):1051-1060.

[5] Cleveland Clinic. Venous thromboembolism. Updated February 22, 2022. https://my.clevelandclinic.org/health/diseases/22614-venous-thromboembolism. Accessed April 30, 2026.

[6] Centers for Disease Control and Prevention. About venous thromboembolism (blood clots). March 5, 2025. https://www.cdc.gov/blood-clots/about/index.html. Accessed April 30, 2026.

[7] Centers for Disease Control and Prevention. Data and statistics on venous thromboembolism. January 27, 2025. https://www.cdc.gov/blood-clots/data-research/facts-stats/index.html. Accessed April 30, 2026.

[8] Centers for Disease Control and Prevention. About venous thromboembolism (blood clots). March 5, 2025. https://www.cdc.gov/blood-clots/about/index.html. Accessed April 30, 2026.

[9] Centers for Disease Control and Prevention. Data and statistics on venous thromboembolism. January 27, 2025. https://www.cdc.gov/blood-clots/data-research/facts-stats/index.html. Accessed April 30, 2026.

[10] Bristol-Myers Squibb. Label: apixaban (ELIQUIS). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/202155Orig1s039,s040lbl.pdf. Accessed April 30, 2026.

[11] Ibid.

[12] Unsafe blood-thinner antidote andexanet (ANDEXXA) finally withdrawn. Best Pills, Worst Pills News. June 2026. LINK MISSING. Accessed XXX.

[13] The blood thinner apixaban (ELIQUIS): An update. Worst Pills, Best Pills News. April 2024. https://www.worstpills.org/newsletters/view/1589. Accessed April 30, 2026.

[14] Castellucci LA, Chen VM, Kovacs MJ, et al. Bleeding risk with apixaban vs. rivaroxaban in acute venous thromboembolism. N Engl J Med. 2026;394(11):1051-1060.

[15] Ibid.

[16] Moores LK. The COBRRA trial — Ending the venous thromboembolism safety toss-up. N Engl J Med. 2026;394(11):1123-1124.

[17] Bristol-Myers Squibb. Label: apixaban (ELIQUIS). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/202155Orig1s039,s040lbl.pdf. Accessed April 30, 2026.