Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial.
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.
Eikelboom
J W
JW
Department of Medicine, HGH McMaster Clinic, McMaster University, Hamilton, Ontario, Canada. eikelbj@mcmaster.ca
Hankey
G J
GJ
Thom
J
J
Claxton
A
A
Yi
Q
Q
Gilmore
G
G
Staton
J
J
Barden
A
A
Norman
P E
PE
D000244:Adenosine Diphosphate; D000368:Aged; D016718:Arachidonic Acid; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D000077144:Clopidogrel; D003094:Collagen; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009391:Nephelometry and Turbidimetry; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000188:drug therapy*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin