Effect of caffeine on platelet inhibition by clopidogrel in healthy subjects and patients with coronary artery disease.
BACKGROUND
Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (cAMP) levels. Caffeine also causes a rise in platelet cAMP. We aimed to test the effect of acute caffeine administration on platelet inhibition by clopidogrel, in healthy volunteers and patients with coronary artery disease.


METHODS
Cohort 1: 12 healthy subjects were enrolled in a 2-week crossover study. Blood samples were drawn at baseline, 2, 4, and 24 hours after 300 mg clopidogrel intake. At the first week, 6 subjects received caffeine (300 mg pill, equivalent to a medium sized coffee drink) 30 minutes after clopidogrel. At week 2, the other 6 subjects received caffeine. One month later the effect of caffeine alone was tested. Platelet function was evaluated by aggregation in response to 5, 10, and 20 micromol/L adenosine diphosphate, 1 microg/mL collagen, and flow cytometric determination of P-selectin expression, PAC-1 binding, and vasodilator-stimulated phosphoprotein phosphorylation. Cohort 2: 40 patients with coronary artery disease receiving aspirin and clopidogrel (75 mg daily) for > or = 1 week were tested at baseline and 2.5 hours after caffeine (300 mg).


RESULTS
In cohort 1 (crossover study), caffeine was associated with lower adenosine diphosphate-induced aggregation at 4 hours, lower activation markers at 2 hours, and lower vasodilator-stimulated phosphoprotein phosphorylation at 4 hours after clopidogrel. Caffeine alone had no effect on the assessed platelet surface biomarkers. In cohort 2, caffeine administration was associated with lower platelet activation markers (P-selectin, PAC-1 binding), without significant effect on aggregation.


CONCLUSIONS
Acute caffeine administration after clopidogrel loading appears to be associated with enhanced platelet inhibition 2 to 4 hours after clopidogrel intake. The mechanism probably involves synergistic increase in cAMP levels.
Lev
Eli I
EI
The Methodist Hospital Research Institute and the Methodist DeBakey Heart Center, Houston, TX 77030, USA.
Arikan
Mehmet E
ME
Vaduganathan
Muthiah
M
Alviar
Carlos L
CL
Tellez
Armando
A
Mathuria
Nilesh
N
Builes
Angela
A
Granada
Juan F
JF
del Conde
Ian
I
Kleiman
Neal S
NS
D000328:Adult; D000368:Aged; D002110:Caffeine / Q000494:pharmacology*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000503:physiopathology / Q000628:therapy; D018592:Cross-Over Studies; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000097:blood; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D006835:Hydrazones; D019007:P-Selectin; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D000077144:Clopidogrel; D013988:Ticlopidine