BACKGROUND: “High post-clopidogrel platelet reactivity (HPPR)” after percutaneous coronary intervention (PCI) has been associated with the higher risk of long-term ischemic events. Several mechanisms have been identified as inhibitors of conversion into active metabolite. Because cytochrome (CYP) 3A4-metabolized statin can interact with clopidogrel using CYP3A4 pathway, it may contribute to reduced effect of clopidogrel. We sought to assess the impact of non-CYP3A4-metabolized statin on platelet inhibition in HPPR patients.
METHODS: We enrolled 40 HPPR patients treated with PCI. They all received clopidogrel 75 mg/day and atorvastatin 10 mg/day at least 6 month after PCI. They were randomly assigned to change with either rosuvastatin 10 mg/day or pravastatin 20 mg/day. Platelet reactivity (PR) was assessed before change and at 15-days after change with conventional aggregometry and the VerifyNow P2Y12 assay. HPPR was defined as maximal PR (PRmax) ≥ 50% with 20 mol/I ADP stimuli.
RESULTS: All patients completed study protocol without specific side effect. After change with non-CYP3A4-metabolized statin, there were significant reductions of PRmax with 5 and 20 ųmol/l ADP stimuli (52.7 ± 10.7% to 46.2 ± 16.1%, p = 0.004; 66.9 ± 8.1% vs. 60.5 ± 13.9%, p = 0.001, respectively). Likewise, 5 and 20 ųmol/l ADP-induced late PRs were significantly decreased (41.7 ± 14.5% to 34.9 ± 19.0%, p = 0.004; 58.7 ± 13.3% vs. 50.6 ± 20.0%, p = 0.002, respectively). P2Y12 reaction unit on non-CYP3A4-metabolized statin showed a reduced value compared with that on atorvastatin (294.8 ± 64.3 vs. 244.5 ± 79.8, p < 0.001). After 15-days therapy, 9 patients on non-CYP3A4-metabolized statin (22.5%) achieved adequate platelet inhibition by clopidogrel 75mg/day. If we divided patients into two sub-groups, the results did not differ between the groups.
Conclusions: In HPPR patients receiving chronic clopidogrel and atorvastatin, change with non-CYP3A4-metabolized statin can enhance platelet inhibitory effect of clopidogrel. This result suggests a rationale for further studies to assess whether non-CYP3A4-metabolized statin, as compared with CYP3A4-metabolized statin, provides long-term clinical benefits in patients with HPPR.
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