Effects of endothelial dysfunction on residual platelet aggregability after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease.
BACKGROUND
Dual antiplatelet therapy with aspirin and clopidogrel is widely used in patients with coronary stents. High residual platelet reactivity (high RPR) after dual antiplatelet therapy is associated with increased cardiovascular events. Endothelial function could affect platelet reactivity in vivo. We hypothesized that endothelial dysfunction could be associated with high RPR after dual antiplatelet therapy in patients with stable coronary artery disease.


RESULTS
We screened patients with stable coronary artery disease for cytochrome P450 (CYP) 2C19 genotypes and enrolled 103 patients who lacked CYP2C19*2 or *3 loss-of-function allele to minimize the effect of this gene on high RPR. All patients received aspirin (100 mg/d) and clopidogrel (75 mg/d for long-term treatment or a loading dose of 300 mg) before the following tests. Platelet aggregability was assessed as P2Y12 reaction unit using the VerifyNow System. High RPR was defined as P2Y12 reaction unit ≥ 230. Peripheral endothelial function was expressed as reactive hyperemia index using reactive hyperemia peripheral arterial tonometry. Fifty-three patients exhibited high RPR. High RPR patients were significantly older, had higher levels of B-type natriuretic peptide, and were predominantly hypertensive compared with non-high RPR patients. Reactive hyperemia index was significantly lower in high RPR patients (0.46 ± 0.15) compared with non-high RPR patients (0.61 ± 0.18; P<0.001). Linear regression analysis demonstrated significant negative correlation between reactive hyperemia index and P2Y12 reaction unit (r=-0.32; P=0.001). Multivariable logistic regression analysis identified reactive hyperemia index as an independent and significant determinant of high RPR (odds ratio, 0.55; 95% confidence interval, 0.39-0.78; P=0.001).


CONCLUSIONS
In patients with stable coronary artery disease, endothelial function was significantly impaired in high RPR patients. Endothelial dysfunction is independently correlated with high RPR after dual antiplatelet therapy.


BACKGROUND
http://www.umin.ac.jp/ctr. Unique identifier: UMIN000008239.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences.
Koichiro
K
Fujisue
Seigo
S
Sugiyama
Takamichi
T
Ono
Yasushi
Y
Matsuzawa
Eiichi
E
Akiyama
Koichi
K
Sugamura
Junichi
J
Matsubara
Hirofumi
H
Kurokawa
Koichi
K
Kaikita
Satomi
S
Iwashita
Hitoshi
H
Sumida
Seiji
S
Hokimoto
Kentaro
K
Oniki
Kazuko
K
Nakagawa
Kunihiko
K
Matsui
Hisao
H
Ogawa
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001241:Aspirin / Q000627:therapeutic use*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D065731:Cytochrome P-450 CYP2C19; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin
antiplatelet agents; atherosclerosis; coronary artery disease; endothelial function; platelet function tests; platelet reactivity; thrombosis