What is the role of Rivaroxaban (Xarelto) 2.5 mg orally (po) twice daily (bid) in secondary prevention of cardiovascular events in patients with established atherosclerotic vascular disease?

Rivaroxaban 2.5 mg Twice Daily for Secondary Prevention in Atherosclerotic Vascular Disease

Rivaroxaban 2.5 mg twice daily plus aspirin is strongly recommended for secondary prevention in patients with established atherosclerotic vascular disease as it significantly reduces the risk of major adverse cardiovascular events compared to aspirin alone, with an acceptable bleeding risk profile. 1, 2

Efficacy and Clinical Evidence

The COMPASS trial provides the strongest evidence for this recommendation:

• Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily significantly reduced the risk of major adverse cardiovascular events (MACE) compared to aspirin alone in patients with stable atherosclerotic vascular disease 1, 3
• The primary composite endpoint (cardiovascular death, myocardial infarction, or stroke) was reduced by 24% (HR 0.76; 95% CI 0.66-0.86) 2, 3
• All-cause mortality was reduced by 18% (HR 0.82; 95% CI 0.71-0.96) 3
• The benefits were consistent across subgroups, including patients with diabetes mellitus 1

Patient Selection Algorithm

Best Candidates for Rivaroxaban 2.5 mg BID + Aspirin:

1. Patients with established coronary artery disease (CAD) and/or peripheral artery disease (PAD)
2. Patients with multiple vascular beds affected (polyvascular disease)
3. Patients with type 2 diabetes mellitus and stable CAD
4. Patients with heart failure or renal disease with established atherosclerotic disease
5. Patients not requiring dual antiplatelet therapy

Contraindications/Caution:

1. Patients requiring dual antiplatelet therapy (excluded from COMPASS)
2. Patients with severe renal impairment (CrCl <30 mL/min) 2
3. Patients at high risk of bleeding (especially those with recent bleeding events)
4. Patients with bronchiectasis/pulmonary cavitation, active cancer, or active gastroduodenal ulcer 2

Bleeding Risk Considerations

• Major bleeding events were increased with rivaroxaban 2.5 mg twice daily plus aspirin compared to aspirin alone (3.1% vs 1.9%; HR 1.70) 3
• However, there was no significant increase in fatal bleeding or intracranial hemorrhage 1, 3
• The net clinical benefit favored the combination therapy, with the reduction in cardiovascular events outweighing the increased bleeding risk 4

Mechanism of Action

Rivaroxaban 2.5 mg twice daily provides "dual anti-thrombotic pathway inhibition" when combined with aspirin:

• Aspirin inhibits platelet activation through cyclooxygenase 1-derived thromboxane A2
• Rivaroxaban inhibits factor Xa, reducing thrombin generation and subsequent platelet activation 1
• This dual pathway approach targets both platelet and coagulation processes involved in atherothrombosis 4

Important Clinical Pearls

• The 2.5 mg twice daily dose is specifically approved for this indication and differs from doses used for other indications like atrial fibrillation (20 mg daily) or VTE treatment (15-20 mg daily) 2
• This dose should not be confused with the 15 mg or 20 mg doses used for stroke prevention in atrial fibrillation 1
• The vascular protection dose (2.5 mg twice daily) is lower than the anticoagulation doses used for other indications 2
• Consistent dosing twice daily is important for maintaining efficacy

Common Pitfalls to Avoid

1. Using the wrong dose of rivaroxaban (using AF or VTE doses instead of 2.5 mg twice daily)
2. Adding rivaroxaban to dual antiplatelet therapy (triple therapy increases bleeding risk substantially)
3. Not considering patient-specific bleeding risks before initiating therapy
4. Confusing this indication with extended VTE treatment (which uses 10 mg daily or 2.5 mg twice daily after 6 months of initial therapy) 1

In summary, rivaroxaban 2.5 mg twice daily plus aspirin represents an important advancement in secondary prevention for patients with established atherosclerotic vascular disease, offering significant reductions in cardiovascular events and mortality with a manageable bleeding risk profile.