Effect of clopidogrel treatment on stress-induced platelet activation and myocardial ischemia in aspirin-treated patients with stable coronary artery disease.
Stress may counteract responses to antiplatelet drug treatment. We investigated if adding clopidogrel to aspirin treatment could attenutate stress-induced platelet activation and myocardial ischemia in patients with coronary artery disease (CAD). Thirty-one male patients with documented CAD-treated with aspirin (75-160 mg daily) were randomized to co-treatment with clopidogrel (n = 16) or placebo (n = 15). A symptom-limited exercise test and 48-hour (h) Holter monitoring were performed before and after two weeks of double-blind treatment. Platelet function was assessed by flow cytometry and impedance aggregometry in whole blood. Exercise-induced and ambulatory ischemia was assessed from electrocardiographic (ECG) recordings. Clopidogrel treatment inhibited ADP-induced platelet P-selectin expression by 64% (22-87%), and attenuated the P-selectin response to thrombin (p < 0.001), and platelet aggregation induced by low-dose collagen (p < 0.01). Exercise ( approximately 110W) increased heart rate similarly, and caused approximately 1.8 mm ST-segment depression both before and after treatment. Exercise caused platelet activation, i.e. increased circulating activated single platelets and platelet-platelet aggregates, enhanced the in-vitro responsiveness to ADP or thrombin stimulation, and increased platelet-leukocyte aggregation. Clopidogrel inhibited ADP-induced platelet activation to a similar relative degree at rest and during exercise, but did not attenuate the platelet activating effect of exercise. Addition of clopidogrel to aspirin treatment did not attenuate either ambulatory or exercise-induced ischemia. In conclusion, adding clopidogrel to aspirin treatment inhibited platelet activation by both ADP, thrombin and collagen in vitro, but did not influence the prothrombotic responses to exercise. Intensified antiplatelet treatment did not reduce ECG signs of either exercise-induced or ambulatory myocardial ischemia.
Karolinska Institutet; Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital , Stockholm, Sweden.
Christina
C
Perneby
N Håkan
NH
Wallén
Claes
C
Hofman-Bang
Per
P
Tornvall
Torbjörn
T
Ivert
Nailin
N
Li
Paul
P
Hjemdahl
D000244:Adenosine Diphosphate / Q000378:metabolism; D000368:Aged; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D000077144:Clopidogrel; D003094:Collagen / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015716:Electrocardiography, Ambulatory; D005080:Exercise Test; D005434:Flow Cytometry; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010979:Platelet Function Tests; D012107:Research Design; D013312:Stress, Physiological / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D013917:Thrombin / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
C508600:IL6 protein, human; D015850:Interleukin-6; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D023201:CD40 Ligand; D000244:Adenosine Diphosphate; D003094:Collagen; D002097:C-Reactive Protein; D000077144:Clopidogrel; D013917:Thrombin; D013988:Ticlopidine; D001241:Aspirin