Impact of Cytochrome P450 3A4-Metabolized Statins on the Antiplatelet Effect of a 600-mg Loading Dose Clopidogrel and on Clinical Outcome in Patients Undergoing Elective Coronary Stent Placement

Abstract

Early studies suggested interactions between statins and clopidogrel. Based on outcome and platelet data, there is now substantial evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with a 600-mg loading dose are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P450 3A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63, and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 μM was similar irrespective of statin treatment at baseline (p = 0.968). RPA at CA was 46.2 ± 16.8% in patients without statin (n = 682), 45.5 ± 17.0% with atorvastatin (n = 255), 45.8 ± 16.3% with simvastatin (n = 335), 47.3 ± 14.9% with fluvastatin (n = 42), and 45.9 ± 16.2% with pravastatin (n = 81; p = 0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n = 553), the one-year incidence of death, myocardial infarction, and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p = 0.645). Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.

Keywords: Clinical trials, antiplatelet drugs, clopidogrel, statins, drug-drug interaction, percutaneous coronary intervention

Introduction

Clopidogrel is an inactive pro-drug converted by cytochrome P450 3A4 (CYP3A4) into its active metabolite, which irreversibly binds to the platelet P2Y12 receptor, inhibiting ADP-induced platelet activation. Previous studies suggested that atorvastatin might attenuate the platelet inhibitory effect of clopidogrel, possibly via metabolic drug-drug interaction at the level of CYP3A4. However, subsequent studies failed to confirm these findings, though their statistical power was limited by small sample sizes.

Clinical outcome data from randomized trials and registries did not provide evidence for unfavorable outcomes in patients on clopidogrel with concomitant CYP3A4-metabolized statins. However, a pharmaco-epidemiological study suggested an association between clopidogrel and atorvastatin use and adverse cardiovascular events post-PCI. Thus, the relevance of this interaction, especially with CYP3A4-metabolized statins (atorvastatin, simvastatin), remained unclear. This study aimed to clarify this issue in a large cohort using a 600-mg clopidogrel loading dose.

Subjects and Methods
Study Population

This was a pre-specified secondary analysis of the EXCELSIOR cohort. Patients with symptomatic coronary heart disease scheduled for cardiac catheterization as potential PCI candidates were eligible. Inclusion required stable statin medication for at least 14 days prior or no statin use in the last 14 days. All patients were on chronic aspirin (≥100 mg/day). Exclusion criteria included acute myocardial infarction, recent thienopyridine treatment, chronic oral anticoagulation, contraindications to aspirin, clopidogrel, or heparin, bleeding diathesis, malignancies, hematological disorders, and thrombocytopenia (<100 × 10⁹/L). Patients undergoing catheterization within two hours of clopidogrel loading were excluded. Glycoprotein IIb/IIIa inhibitors were not allowed except for bail-out. Drug-eluting stents were permitted.

Study Protocol and Blood Sampling

Baseline blood was drawn for platelet function assays. All patients received an oral 600 mg clopidogrel loading dose. The second blood sample was taken during catheterization, before heparin or contrast medium. For patients with PCI, an additional sample was collected the morning after PCI, 2–4 hours after the first maintenance dose of clopidogrel 75 mg. Maintenance clopidogrel therapy was recommended for four weeks (bare metal stent) or six months (drug-eluting stent).

Platelet Aggregometry

Platelet aggregation was assessed by light transmission aggregometry. Residual platelet aggregation (RPA) was measured 5 minutes after addition of ADP (5 or 20 μM) and expressed as a percentage of maximal light transmission. RPA after 5 μM ADP was the primary measure, as it closely reflects clopidogrel-dependent P2Y12 inhibition and predicts major adverse coronary events (MACE).

Flow Cytometry

Platelet surface expression of P-selectin (CD62P), CD63, and activated GPIIb/IIIa (PAC-1) was measured by triple-color flow cytometry after ADP stimulation.

Clinical Follow-Up

Patients undergoing PCI (n = 553) were monitored for creatinine kinase, troponin T, and ECG until discharge. Follow-up at 12 months recorded death, myocardial infarction (MI), and target lesion reintervention (TLR), excluding acute procedure-related events.

Statistics

Discrete variables are reported as counts (percentages), continuous as mean ± SD. Differences between groups were analyzed with the Chi²-test (categorical) and one-way ANOVA (continuous). General linear models adjusted for baseline differences. Kaplan-Meier and log-rank statistics were used for event rates. A p-value <0.05 was considered significant.

Results
Patient Characteristics

Of 1,987 patients, 1,395 were included after excluding those with catheterization <2 hours after clopidogrel. Patients without statins differed from those with statins in history of MI, PCI, CABG, and cholesterol levels, but were otherwise similar.

Residual Platelet Aggregation (RPA)

RPA decreased in all groups after clopidogrel. There were no significant differences in RPA between groups at baseline (p = 0.968) or at catheterization (p = 0.962). Adjusted analyses confirmed no significant differences between patients without statins and those with CYP3A4-statin treatment (mean difference -1.25%; 95% CI: -3.24% to 0.74%; p = 0.217). No dose-related differences were observed for atorvastatin or simvastatin.

Platelet Surface Protein Expression
Inhibition of ADP-stimulated surface expression of P-selectin, CD63, and PAC-1 was similar across all statin groups and doses.

Platelet Function and Clinical Outcomes in PCI Patients

In the PCI subgroup (n = 553), statin treatment did not affect RPA or inhibition of surface protein expression at any time after clopidogrel loading. The 12-month composite rate of death and MI was 3.6% (20/553), with no differences between statin groups (p = 0.596). Inclusion of TLR increased the composite event rate to 12.7%, again with no difference by statin use.

Discussion

This large, adequately powered study found that CYP3A4-metabolized statins (atorvastatin, simvastatin) at standard doses do not attenuate the antiplatelet effect of a 600-mg loading dose of clopidogrel. Platelet function and clinical outcomes were consistent across all statin groups. These findings clarify prior conflicting reports, some of which used smaller cohorts or different methodologies. The lack of interaction was observed regardless of statin type or dose (up to 40 mg daily), and was consistent in both laboratory and clinical endpoints.

Recent evidence suggests that CYP isoforms other than CYP3A4, such as CYP2C19, also contribute to clopidogrel activation, and genetic polymorphisms in CYP2C19 can affect clopidogrel response.

Limitations

Plasma concentrations of clopidogrel’s active metabolite were not measured.

Patients were not randomized to statin groups; possible residual confounding cannot be excluded.

Only statin doses up to 40 mg were studied; effects at higher doses were not assessed.

The study was not powered to detect minor effects of CYP3A4-statins on clinical endpoints or to differentiate between individual statins.

Conclusions

Statins metabolized by CYP3A4 (atorvastatin, simvastatin) at doses up to 40 mg daily have no impact on the early antiplatelet effects of a 600-mg loading dose regimen of clopidogrel. These statins do not curtail the beneficial effects of clopidogrel in patients undergoing PCI.