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Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized
J W Eikelboom1, G J Hankey, J Thom
1Department of Medicine, HGH McMaster Clinic, McMaster University, Hamilton, Ontario, Canada. eikelbj@mcmaster.ca
Insights
Adding clopidogrel to aspirin enhances antiplatelet effects, particularly in patients with low aspirin inhibition. This suggests targeted use of ADP receptor inhibitors may overcome aspirin resistance.
Area of Science:
- Cardiology
- Pharmacology
- Thrombosis Research
Background:
- Aspirin is a cornerstone antiplatelet therapy for cardiovascular disease prevention.
- Individual variability in aspirin response, termed aspirin resistance, can limit its clinical efficacy.
- Assessing the additive antiplatelet effects of clopidogrel in aspirin-treated patients is crucial for optimizing therapy.
Purpose of the Study:
- To evaluate if adding clopidogrel to aspirin suppresses laboratory measures of aspirin's antiplatelet effects.
- To determine if clopidogrel provides greater platelet inhibition in patients with suboptimal platelet inhibition by aspirin.
- To investigate the interaction between aspirin and clopidogrel on platelet aggregation.
Main Methods:
- A randomized, double-blind, placebo-controlled, crossover trial was conducted.
- 36 patients with peripheral arterial disease, already treated with aspirin, received either clopidogrel (75 mg/day) or placebo.
- Platelet aggregation, thromboxane B2, and markers of platelet activation and inflammation were measured.
Main Results:
- Clopidogrel did not suppress arachidonic acid-induced platelet aggregation or markers of inflammation.
- Clopidogrel significantly inhibited adenosine diphosphate (ADP)-induced (26.2% reduction) and collagen-induced (6.2% reduction) platelet aggregation.
- The most pronounced inhibition of collagen-induced aggregation by clopidogrel was observed in patients with the lowest inhibition of arachidonic acid-induced aggregation by aspirin.
Conclusions:
- The enhanced antiplatelet effect of clopidogrel is most evident in patients with limited response to aspirin.
- This finding suggests that combining clopidogrel with aspirin may be most beneficial for patients exhibiting laboratory aspirin resistance.
- Future clinical outcome studies are warranted to confirm these findings and guide targeted antiplatelet therapy for ADP receptor inhibition.
Objective:
We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin.
Methods:
We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease.
Results:
The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01].
Conclusions:
The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.
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