Apixaban or Rivaroxaban in Acute Venous Thromboembolism?

What Does the COBRRA Trial Published in NEJM Tell Us?

Venous thromboembolism (VTE) is considered the third most common cause of cardiovascular death worldwide after myocardial infarction and stroke. Its incidence in the general population is approximately 1–2 per 1000 people annually and increases significantly with age.

Anticoagulation for at least 3 months is the standard treatment approach for acute VTE, and in recent years direct oral anticoagulants (DOACs) have become widely used in clinical practice. In particular, apixaban and rivaroxaban have become the two most commonly preferred agents in the treatment of acute pulmonary embolism and deep vein thrombosis.

However, until now, an important clinical question remained unanswered:

Is there a real difference in bleeding risk between apixaban and rivaroxaban?

An important study seeking to answer this question was published in the New England Journal of Medicine in 2026: the COBRRA Trial.

COBRRA Trial: Design

The COBRRA trial was an international, randomized, prospective clinical study.

• 2760 patients were included in the study
• Patients were randomized 1:1 into two groups
• Study population:
  • symptomatic pulmonary embolism
  • or proximal deep vein thrombosis

The treatment protocol was as follows:

Apixaban Group

• 7 days: 10 mg twice daily
• Afterwards: 5 mg twice daily

Rivaroxaban Group

• 21 days: 15 mg twice daily
• Afterwards: 20 mg once daily

The follow-up period was planned as 3 months.

The primary endpoint of the study was: Clinically relevant bleeding

This endpoint included the following two conditions:

• Major bleeding
• Clinically relevant non-major bleeding (according to ISTH criteria)

Main Results of the Study

Toplam 2760 hasta randomize edildi.

Klinik olarak anlamlı kanama oranları:

These results were statistically significant:

Relative risk: 0.46 (95% CI 0.33–0.65, p<0.001)

In other words: The bleeding risk was approximately 54% lower with apixaban.

All-cause mortality was quite low:

• Apixaban: 0.1%
• Rivaroxaban: 0.3%

Clinical Significance

This study is important from several perspectives.

1. First Direct Comparative Study

Until now, most DOAC studies were based on comparisons with warfarin.
There had been no direct randomized comparison between apixaban and rivaroxaban.

The COBRRA trial filled this gap.

2. Difference in Safety Profile

While both drugs are considered effective in preventing recurrent thromboembolism, this study demonstrates a clear advantage in favor of apixaban regarding bleeding safety.

3. Possible Impact on Clinical Practice

These results may influence treatment selection especially in the following patient groups:

• elderly patients
• patients at high bleeding risk
• those receiving concomitant antiplatelet therapy
• patients with limited renal function

Will the Guidelines Change?

Current international guidelines generally did not recommend a clear superiority among DOACs. The reason was the lack of direct comparative studies.

Since the COBRRA trial filled this gap, it may provide data in the future that could influence DOAC preference rankings in guidelines such as:

• European Society of Cardiology (ESC)
• American College of Chest Physicians (ACCP)
• American Society of Hematology (ASH)

Conclusion

The COBRRA trial is an important randomized study directly comparing two widely used DOAC agents in the treatment of acute venous thromboembolism.

The main message of the study is clear:

Compared with rivaroxaban, apixaban demonstrated similar efficacy while showing a significantly lower risk of clinically relevant bleeding.

This finding may lead us to reconsider treatment selection, especially in patients at high bleeding risk.

Reference

Castellucci LA et al. Bleeding Risk with Apixaban vs Rivaroxaban in Acute Venous Thromboembolism. New England Journal of Medicine. 2026;394:1051–1060