Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation - Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation
Platelet aggregation inhibition of clopidogrel with vs without co-administration of atorvastatin
Atorvastatin inhibits clopidogrel activation by human cytochrome P450 3A4 (CYP3A4)
Patients Enrolled: 71
Mean Follow Up: 30 days
History of thrombocytopenia or bleeding disorder, use of any medications, alcohol, caffeine, tobacco, herbal remedies such as St John's wort, grapefruit juice, birth control pills, or charcoal broiled food
This manuscript summarizes three studies examining the effect and mechanism of atorvastatin on platelet aggregation inhibition with clopidogrel. In the first study, patients undergoing elective stent implantation received clopidogrel (300 mg loading dose and 75 mg/day for 28 days). Patients were taking either atorvastatin (n=19), pravastatin (n=9), or no statin (n=16). Platelet aggregation was measured prior to clopidogrel administration and 24 hours later as well as at day 6 to 8 in 13 patients on clopidogrel and in 13 patients on clopidogrel plus atorvastatin. The second study randomized volunteers to clopidogrel plus erythromycin (a CYP3A4 inhibitor) or clopidogrel plus rifampin (a CYP3A4 inducer) and measured platelet aggregation at days 0, 6, 20, 24, and 30. The third study measured the effect of troleandomycin (a CYP3A4 inhibitor) on CYP3A4 activity and platelet aggregation.
Atorvastatin reduced the antiplatelet activity of clopidogrel in a dose-dependent fashion as demonstrated by higher percent platelet aggregation with increasing doses of atorvastatin (34 ± 23% with no atorvastatin, 58 ± 15% with 10 mg atorvastatin (p=0.027), 74 ± 10% with 20 mg (p=0.002), and 89 ± 7% with 40 mg (p=0.001). No similar effect was observed with pravastatin (46 ± 18%, p=NS vs clopidogrel alone). Platelet aggregation inhibition remained reduced 6 to 8 days after stenting in patients receiving clopidogrel and atorvastatin vs clopidogrel alone (74 ± 13% vs 41 ± 19%, p<0.0001). Platelet aggregation inhibition was diminished with erythromycin (55 ± 12 vs 42 ± 12%, p=0.002) and with troleandomycin (78 ± 18 vs 45 ± 18%, p<0.0003) but was enhanced with rifampin (33 ± 18 vs 56 ± 20%, p=0.001).
The present study shows that while clopidogrel is activated by the cytochrome P450 CYP3A4 enzyme, the lipid lowering drug atorvastatin--a CYP3A4 substrate--inhibits this activation in a dose dependent fashion. As a result, clopidogrel was less effective in inhibiting platelet aggregation when administered with atorvastatin. However, when clopidogrel was administered with pravastatin, which is a hydrophilic drug not metabolized by the CYP system, no reduced effect on platelet aggregation was observed. Given these findings, use of clopidogrel in conjunction with atorvastatin or other statins that the CYP3A4 enzyme metabolizes (e.g., lovastatin and simvastati) may warrant careful consideration and monitoring. This was a small study (n=44 for the stenting study). As such, conclusions drawn regarding clinical practice should be interpreted in light of the small sample size. It is not known what effect the inhibition of clopidogrel activation by atorvastatin has on clinical outcomes such as the risk of subacute stent thrombosis or long term clinical events.
Lau WC, et al. Circulation published on-line November 25, 2002.
Keywords: Cytochrome P-450 Enzyme System, Platelet Aggregation Inhibitors, Lovastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ticlopidine, Heptanoic Acids, Rifampin, Troleandomycin, Purinergic P2Y Receptor Antagonists, Stents, Pyrroles, Erythromycin, Thrombosis, Pravastatin
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