SUMMARY

• The COBRRA trial, a pragmatic, international study with a prospective, randomized, open-label, blinded end-point (PROBE) design, compared apixaban and XARELTO in adults with acute venous thromboembolism (VTE). Over the 3‑month treatment period, clinically relevant bleeding occurred in 3.3% of patients treated with apixaban and 7.1% of patients treated with XARELTO (relative risk [RR], 0.46; 95% confidence interval [CI], 0.33–0.65; P<0.001). The rate of recurrent symptomatic VTE was similar between the groups, occurring in 1.1% of apixaban-treated patients and 1.0% of XARELTO-treated patients (RR, 1.08; 95% CI, 0.52-2.23).¹
• An additional citation has been included in the REFERENCES section.²

BACKGROUND

Although treatable, VTE remains the third leading cause of acute cardiovascular events and cardiovascular-related mortality worldwide. Direct oral anticoagulants, particularly XARELTO and apixaban, are widely used for the treatment of acute VTE. However, due to the absence of head-to-head randomized trials directly comparing XARELTO and apixaban with respect to bleeding risk, current clinical practice guidelines do not recommend either agent over the other.¹

CLINICAL DATA

COBRRA Trial

This trial evaluated whether apixaban demonstrates superior safety compared with XARELTO in patients with acute VTE.¹

Study Design/Methods¹

• The COBRRA trial was a pragmatic, international study with a PROBE design that compared apixaban with XARELTO in adults (≥18 years) with symptomatic acute VTE, including proximal deep-vein thrombosis and segmental or more proximal pulmonary embolism.¹
• Patients were randomized 1:1 to receive 3 months of treatment with XARELTO (15 mg twice daily for 21 days followed by 20 mg once daily) or apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily) using a centralized web-based system, with stratification by renal function, antiplatelet use, and study center.¹
• Trial visits were scheduled at enrollment and at 2 weeks (with a window of ±1 week) and 3 months after randomization.¹
• The primary outcome was clinically relevant bleeding, defined as a composite of major bleeding and clinically relevant nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria; secondary outcomes included recurrent symptomatic VTE, death from bleeding, death from recurrent VTE, death from any cause, and treatment adherence.¹

Results¹

Overall, 1370 and 1390 patients were assigned to receive apixaban and XARELTO, respectively. After exclusion of 60 randomized patients (2.2%), 1345 patients in the apixaban group and 1355 patients in the XARELTO group were included in the intention-to-treat analysis.¹

Baseline demographic and clinical characteristics appeared to be well balanced between the treatment groups. The mean age of the patients was 58.3 years, and 1175 patients (43.5%) were female. Approximately 10% of patients reported their race as non-White. Overall, an unprovoked VTE event was reported in 2087 patients (77.3%). Deep vein thrombosis alone occurred in 1409 patients (52.2%), and pulmonary embolism with or without concomitant deep vein thrombosis was reported in 1291 patients (47.8%). A prior history of VTE was documented in 429 patients (15.9%).¹

Primary outcome¹

The intention-to-treat analysis showed that over the 3-month treatment period, clinically relevant bleeding events were observed in 3.3% of patients treated with apixaban (44 of 1345) and 7.1% of patients treated with XARELTO (96 of 1355), corresponding to an RR of 0.46 (95% CI, 0.33-0.65; P<0.001).¹

Secondary outcomes¹

Major bleeding was reported in 5 patients (0.4%) receiving apixaban and 32 patients (2.4%) receiving XARELTO (RR, 0.16; 95% CI, 0.06-0.40). Clinically relevant nonmajor bleeding occurred in 39 patients (2.9%) in the apixaban group and 67 patients (4.9%) in the XARELTO group (RR, 0.59; 95% CI, 0.40-0.86). Recurrent symptomatic VTE was reported in 15 patients (1.1%) in the apixaban group and 14 patients (1.0%) in the XARELTO group (RR, 1.08; 95% CI, 0.52-2.23). Death from any cause occurred in 1 patient (0.1%) in the apixaban group and in 4 patients (0.3%) in the XARELTO group (RR, 0.25; 95% CI, 0.03-2.26). No deaths due to recurrent VTE or from bleeding were reported. Complete medication adherence was reported by 65.7% of patients in the apixaban group and 75.1% of patients in the XARELTO group. Analyses of secondary outcomes were not adjusted for multiplicity, and the widths of CIs should not be used in place of hypothesis testing ¹

Serious adverse events not related to bleeding or venous thrombosis were reported in 36 patients (2.7%) in the apixaban group and 30 patients (2.2%) in the XARELTO group.¹

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 March 2026.