Can apixaban and cilostazol be prescribed together?

Concurrent Use of Apixaban and Cilostazol

Apixaban and cilostazol can be safely prescribed together as there is no significant pharmacokinetic interaction between these medications that would increase bleeding risk or reduce efficacy.

Pharmacological Considerations

Mechanism of Action

• Apixaban: Direct factor Xa inhibitor that prevents thrombin formation and clot development
• Cilostazol: Phosphodiesterase III inhibitor with antiplatelet and vasodilatory properties 1

Pharmacokinetic Interactions

• Unlike many drug combinations involving anticoagulants, apixaban and cilostazol do not have significant pharmacokinetic interactions:
  • Apixaban is primarily metabolized by CYP3A4 and is a substrate for P-glycoprotein 2
  • Cilostazol does not significantly inhibit or induce these pathways at clinically relevant concentrations 1
  • No dose adjustments are required when using these medications together

Clinical Evidence Supporting Concurrent Use

Research evidence supports the safety of this combination:

• Studies examining platelet function with cilostazol alone or in combination with other antithrombotics found that cilostazol alone did not significantly increase bleeding time, unlike aspirin or clopidogrel 3
• When cilostazol was added to antiplatelet regimens, it did not further prolong bleeding time compared to antiplatelet therapy alone 3
• Case reports have documented successful long-term treatment (up to 32 months) using rivaroxaban (another direct oral anticoagulant) with cilostazol without major or minor hemorrhagic events 4

Safety Profile

Cilostazol has demonstrated a favorable bleeding risk profile compared to other antiplatelet agents:

• In the CSPS-2 study, cilostazol showed a lower risk of hemorrhagic stroke compared to aspirin (HR 0.36,95% CI 0.19-0.70) 5
• Cilostazol also reduced the incidence of overall hemorrhage requiring hospitalization (HR 0.53) and gastrointestinal bleeding requiring hospitalization (HR 0.44) compared to aspirin 5
• This lower bleeding risk makes cilostazol a safer option to combine with anticoagulants like apixaban

Clinical Applications

The combination may be particularly beneficial for:

1. Patients with atrial fibrillation and peripheral arterial disease (PAD) requiring both anticoagulation and treatment for claudication symptoms
2. Patients with stroke history and PAD who need secondary stroke prevention and claudication treatment
3. Patients with non-cardioembolic stroke and PAD who may benefit from both medications

Important Considerations

• Monitor for bleeding signs: Regular assessment for unexplained bruising, blood in urine or stool, and unusual headaches or dizziness 2
• Renal function: Apixaban dosing should be adjusted for patients with renal impairment; standard dose is 5mg twice daily, reduced to 2.5mg twice daily for patients with at least two of: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL 2
• Contraindications for cilostazol: Avoid in patients with heart failure as it can trigger ventricular tachyarrhythmias 1

Conclusion

While combining anticoagulants with antiplatelet agents generally increases bleeding risk, the specific combination of apixaban and cilostazol appears to have an acceptable safety profile based on the available evidence. The unique properties of cilostazol, which inhibits platelet function while also improving endothelial cell function with a lower bleeding risk than traditional antiplatelet agents 6, make it a reasonable choice to combine with apixaban when clinically indicated.