Dual Antiplatelet Therapy with Clopidogrel and Cilostazol for Long-Term Stroke Prevention
Routine long-term dual antiplatelet therapy with clopidogrel and cilostazol is NOT recommended for general secondary stroke prevention, as major guidelines do not endorse this specific combination for routine use, and cilostazol remains primarily studied in Asian populations with limited FDA approval only for intermittent claudication. 1
Guideline-Based Recommendations for Standard Antiplatelet Therapy
The American Heart Association/American Stroke Association explicitly recommends against routine dual antiplatelet therapy for long-term secondary stroke prevention:
Aspirin monotherapy (50-325 mg/day), clopidogrel monotherapy (75 mg/day), or aspirin plus extended-release dipyridamole (25 mg/200 mg twice daily) are the three acceptable first-line options for noncardioembolic stroke prevention. 1
The addition of aspirin to clopidogrel increases hemorrhage risk and is NOT recommended for routine secondary prevention after ischemic stroke or TIA. 1
Long-term antiplatelet therapy should be continued indefinitely, not for a limited duration. 2
Cilostazol's Limited Role in Stroke Prevention
Cilostazol has not achieved mainstream acceptance for routine stroke prevention in Western guidelines:
Cilostazol is FDA-approved only for intermittent claudication, NOT for stroke prevention. 1
Early pilot studies showed cilostazol (200 mg/day) had numerically fewer strokes than aspirin (3.26 vs 5.27 per year), but this was not statistically significant (P=0.18). 1
Cilostazol causes more headache, dizziness, and tachycardia than aspirin, though hemorrhage rates were not increased. 1
Special Circumstance: Intracranial Atherosclerotic Stenosis (ICAS)
The only scenario where cilostazol combination therapy has supportive evidence is in symptomatic intracranial atherosclerosis, and even here, the data comes primarily from Asian populations:
For patients with symptomatic ICAS, cilostazol plus aspirin (≤150 mg/day) showed benefit in Asian trials (TOSS-1, TOSS-2, CATHARSIS, CSPS subgroup analysis). 1
The CATHARSIS trial found cilostazol plus aspirin superior to aspirin alone for preventing vascular events and silent infarcts (10.7% vs 25%; P=0.04) in ICAS patients. 1
However, these trials were conducted primarily in Asian populations, used aspirin doses ≤150 mg/day, and many were unblinded. 1
For ICAS specifically, the 2021 AHA/ASA guidelines suggest short-term dual antiplatelet therapy with either clopidogrel-aspirin OR cilostazol-aspirin, but do NOT recommend the triple combination of clopidogrel-cilostazol-aspirin. 1
Evidence Against Triple Antiplatelet Therapy
- Insufficient evidence supports triple antiplatelet therapy for noncardioembolic stroke prevention, and this substantially increases bleeding complications. 3
Recommended Algorithmic Approach
For general noncardioembolic stroke/TIA patients:
- Start with clopidogrel 75 mg daily OR aspirin/extended-release dipyridamole 25 mg/200 mg twice daily 4, 2
- Continue indefinitely 2
- Do NOT add a second antiplatelet agent for routine long-term prevention 1
For patients with documented symptomatic ICAS (≥50% stenosis):
- Consider short-term (21-90 days) dual antiplatelet therapy with EITHER clopidogrel-aspirin OR cilostazol-aspirin 1
- Transition to monotherapy after the high-risk period 1
- Do NOT use clopidogrel plus cilostazol as the dual combination—this lacks evidence 1
Critical Pitfalls to Avoid
Do not combine clopidogrel and cilostazol for routine stroke prevention—this specific combination lacks guideline support and clinical trial validation. 1
Do not use cilostazol as first-line therapy in non-Asian populations—evidence is limited and FDA approval is only for claudication. 1
Do not continue dual antiplatelet therapy beyond 21-90 days unless there is a separate indication (e.g., recent coronary stent)—bleeding risk outweighs benefit. 5, 6
Recognize that cilostazol's role, if any, is primarily in Asian populations with ICAS, not for general stroke prevention. 1