Can Cilostazol Be Added to Plavix and Aspirin?
Yes, cilostazol can be safely added to clopidogrel (Plavix) and aspirin as triple antiplatelet therapy (TAPT) in patients with coronary artery disease, particularly after percutaneous coronary intervention, with evidence showing reduced ischemic events and no significant increase in major bleeding compared to dual antiplatelet therapy alone.
Evidence Supporting Triple Antiplatelet Therapy
Efficacy in Reducing Cardiovascular Events
Triple antiplatelet therapy with cilostazol, aspirin, and clopidogrel significantly reduces major adverse cardiac events (MACE) compared to standard dual therapy. In a randomized trial of 1,212 patients with acute coronary syndrome undergoing PCI, TAPT reduced the composite endpoint of cardiac death, MI, stroke, or target vessel revascularization from 15.1% to 10.3% (P=0.011) 1.
Meta-analysis data demonstrates consistent benefit across multiple outcomes. TAPT reduces the risk of MACE (incident rate ratio 0.68), target lesion revascularization (IRR 0.57), target vessel revascularization (IRR 0.69), and stent thrombosis (IRR 0.63) compared to dual therapy 2.
Restenosis rates are significantly lower with cilostazol-based therapy. In patients with aspirin intolerance receiving cilostazol plus clopidogrel, restenosis occurred in only 1.5% versus 4.9% with standard dual therapy (P=0.035) 3.
Safety Profile and Bleeding Risk
Major bleeding rates are not significantly increased with triple therapy. Multiple studies show comparable major bleeding between TAPT and dual therapy (OR 1.05,95% CI 0.71-1.55, P=0.80) 4. One study even showed a trend toward less bleeding with cilostazol (0.49% vs 2.7%, P=0.063) 3.
The bleeding safety profile is maintained even in the drug-eluting stent era 2.
Mechanism and Platelet Reactivity
Cilostazol provides additive platelet inhibition through different mechanisms than aspirin and clopidogrel. When added to dual therapy, cilostazol reduces platelet reactivity units (PRU) by a mean of 47.73 units (95% CI -61.41 to -34.04, P<0.0001) and increases platelet inhibition by 12.71% 2.
Cilostazol is particularly effective in overcoming high on-treatment platelet reactivity (HTPR). TAPT leads to a 60% reduction in the risk of HTPR (relative risk 0.40,95% CI 0.30-0.53) 2. The greatest benefit is seen in patients with diabetes and HTPR, with mean PRU reductions of 72.9 units 5.
Important Caveats and Considerations
Drug Discontinuation Rates
Adverse drug reactions leading to discontinuation are higher with triple therapy. Drug discontinuation occurs more frequently with TAPT (OR 3.80,95% CI 1.59-9.10, P=0.003), primarily due to rash (OR 2.45), gastrointestinal disorders (OR 2.59), and other side effects 4.
Common side effects include palpitations, headache, and gastrointestinal discomfort, though these are generally manageable 6.
Guideline Context
Current ESC guidelines do not specifically address cilostazol as triple therapy. The 2017 ESC guidelines focus on P2Y12 inhibitor selection (ticagrelor, prasugrel, or clopidogrel) plus aspirin for dual therapy 7.
Clopidogrel is the P2Y12 inhibitor of choice when triple antithrombotic therapy is needed (such as with oral anticoagulation), and this principle extends to cilostazol-based triple antiplatelet therapy 8.
Clinical Scenarios Where TAPT Is Most Beneficial
- High-risk patients derive the greatest benefit, including those with:
Duration of Therapy
- Most studies used cilostazol for 6 months as part of triple therapy 1, though optimal duration remains to be definitively established.
Practical Algorithm
For patients already on aspirin and clopidogrel:
Assess bleeding risk using validated scores (HAS-BLED) and ensure no active bleeding or contraindications 8.
Consider adding cilostazol if:
- High ischemic risk (recent ACS, complex PCI, diabetes with HTPR)
- Acceptable bleeding risk profile
- Patient can tolerate potential side effects (palpitations, GI symptoms)
Typical regimen: Cilostazol 100 mg twice daily added to aspirin 75-100 mg daily and clopidogrel 75 mg daily 1, 2.
Monitor for: Bleeding events, drug-related adverse effects (particularly palpitations, headache, GI symptoms), and consider discontinuation if intolerable side effects occur.
Duration: Consider 6-month course of cilostazol, then reassess need for continuation based on individual risk-benefit profile 1.