Should the Patient Be on Xarelto (Rivaroxaban) and Plavix (Clopidogrel) Together?
Yes, rivaroxaban 2.5 mg twice daily plus clopidogrel 75 mg daily is appropriate in specific clinical scenarios—primarily after recent coronary or peripheral artery revascularization, or in patients with stable coronary/peripheral artery disease at high ischemic risk and low bleeding risk—but this combination should be time-limited and requires careful assessment of bleeding versus thrombotic risk. 1
Clinical Scenarios Where This Combination Is Recommended
After Acute Coronary Syndrome (ACS) or Percutaneous Coronary Intervention (PCI)
Within 1 year of ACS with high ischemic risk AND low bleeding risk: Rivaroxaban 2.5 mg twice daily plus aspirin 75–100 mg is the preferred regimen, NOT rivaroxaban plus clopidogrel. 1
After PCI in patients with atrial fibrillation: The combination of rivaroxaban plus clopidogrel (without aspirin) is recommended as "dual antithrombotic therapy" to reduce bleeding risk compared to triple therapy. 1
After Lower Extremity Revascularization for Peripheral Artery Disease (PAD)
Rivaroxaban 2.5 mg twice daily plus aspirin 75–100 mg is the Class I recommendation for patients after endovascular or surgical limb revascularization to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 1
Clopidogrel may be added for ≤30 days post-revascularization as triple therapy (rivaroxaban + aspirin + clopidogrel), but this increases bleeding risk. 2
Stable Coronary Artery Disease (CAD) or PAD Without Recent Revascularization
High ischemic risk AND low bleeding risk: Rivaroxaban 2.5 mg twice daily plus aspirin 75–100 mg is recommended, NOT rivaroxaban plus clopidogrel. 1
Clopidogrel monotherapy is preferred over rivaroxaban plus clopidogrel in patients with low ischemic risk or high bleeding risk. 1
Dosing Considerations
Rivaroxaban Dosing
Standard dose for vascular protection: 2.5 mg twice daily (with food) when combined with antiplatelet therapy. 1, 3
Renal adjustment:
- CrCl 30–49 mL/min: Reduce to rivaroxaban 2.5 mg twice daily (already the standard dose for dual therapy). 3
- CrCl 15–29 mL/min: Use rivaroxaban 15 mg once daily if used for AF, but avoid rivaroxaban 2.5 mg twice daily for vascular protection in severe renal impairment. 3
- CrCl <15 mL/min: Rivaroxaban is contraindicated. 3
Must be taken with food to ensure adequate absorption (39% increase in bioavailability). 3
Clopidogrel Dosing
Standard dose: 75 mg once daily. 1
Loading dose: 300 mg may be used peri-procedurally for PCI, but not routinely in stable disease. 1
Bleeding Risk Assessment
The combination of rivaroxaban plus clopidogrel significantly increases bleeding risk compared to either agent alone. 1, 4
Key Bleeding Data
Rivaroxaban 2.5 mg twice daily plus aspirin increases TIMI clinically significant bleeding compared to aspirin alone (approximately 2.1% vs 1.0% per year in COMPASS). 5
Adding clopidogrel to rivaroxaban further increases bleeding:
Contraindications to Dual Therapy
- Active pathological bleeding 3
- Severe hepatic impairment (Child-Pugh C) 3
- CrCl <15 mL/min 3
- Concomitant use of strong dual CYP3A4 and P-gp inhibitors (e.g., ketoconazole, ritonavir, itraconazole) 1, 3
- High bleeding risk (HAS-BLED ≥3) without compelling ischemic indication 1
Drug Interactions
NSAIDs should be avoided as they substantially increase bleeding risk when combined with rivaroxaban and clopidogrel. 1, 3
Aspirin should NOT be added to rivaroxaban plus clopidogrel outside of the immediate post-PCI period (≤30 days), as triple therapy dramatically increases bleeding. 1, 2
Proton pump inhibitors (PPIs) are recommended for gastroprotection when using dual or triple antithrombotic therapy. 1
Duration of Therapy
Post-PCI in Atrial Fibrillation Patients
- Standard ischemic risk: Rivaroxaban 15 mg once daily plus clopidogrel for 1 month, then rivaroxaban monotherapy. 1
- High ischemic risk: Extend dual therapy to 6 months, then rivaroxaban monotherapy. 1
- After 12 months: Rivaroxaban monotherapy (20 mg once daily, or 15 mg if CrCl 30–49 mL/min). 1
Post-Revascularization for PAD
- Rivaroxaban 2.5 mg twice daily plus aspirin indefinitely. 1
- Clopidogrel may be added for ≤30 days post-procedure, then discontinued. 2
Stable CAD/PAD Without Recent Revascularization
- Rivaroxaban 2.5 mg twice daily plus aspirin is preferred over rivaroxaban plus clopidogrel. 1
- If clopidogrel is used instead of aspirin, this is off-label and not guideline-supported. 1
Common Pitfalls
Do NOT use rivaroxaban 2.5 mg twice daily plus clopidogrel as first-line therapy for stable CAD/PAD—rivaroxaban plus aspirin is the evidence-based regimen. 1
Do NOT continue triple therapy (rivaroxaban + aspirin + clopidogrel) beyond 30 days post-revascularization unless there is an exceptional ischemic indication, as bleeding risk escalates sharply. 1, 2
Do NOT use full-dose rivaroxaban (20 mg once daily) with clopidogrel—the vascular protection dose is 2.5 mg twice daily. 1, 3
Do NOT forget to calculate CrCl using Cockcroft-Gault (not eGFR) for accurate renal dosing. 3
Do NOT add rivaroxaban to clopidogrel in patients already on clopidogrel monotherapy for stable disease without a new indication (e.g., recent revascularization, new AF diagnosis). 1
Monitoring
Renal function: Assess CrCl at baseline and at least annually; more frequently (every 3–6 months) if CrCl <60 mL/min. 3
Bleeding symptoms: Educate patients to report unusual bruising, black/tarry stools, blood in urine, or prolonged bleeding from cuts. 3
No routine coagulation monitoring (INR, aPTT) is required for rivaroxaban. 3