Clopidogrel-Statin Interaction : a Missing Links

Clopidogrel-Statin Interaction: a Missing Links A Zoran M. Todorović1,2, Nina B. Djukanović3, Slobodan D. Obradović4, Dragana D. Protić1, Miodrag Č. Ostojić5 A 1 Department of Pharmacology, Clinical Pharacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia 2 University Medical Center “Bežanijska kosa”, Belgrade, Serbia 3 High Medical School Milutin Milanković, Belgrade, Serbia 4 Clinic of Emergency Medicine, Military Medical Academy, Medical Faculty, University of Defense, Belgrade, Serbia 5 Faculty of Medicine, University of Belgrade, Belgrade, Serbia A SUMMARY


INTRODUCTION
Combined antiplatelet therapy with aspirin and clopidogrel is the main therapy regimen which is applied in patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention [1][2][3][4][5][6].Despite the intensive use of combination of these drugs, the occurrence of adverse cardiovascular events is still signifi cant.Clopidogrel resistance, relative to interindividual variability of response to clopidogrel, is one of the possible reasons for that.Clinical trials have demonstrated that the relationship between inadequate response to clopidogrel and increased risk of future thrombotic events may not be ignored.
Unfortunately, the concept of clopidogrel resistance is still not fully understood, although certain potential mechanisms that may be responsible for this have been promoted [7,8].Th ey mainly include the combination of clinical, biological and genetic infl uences which are expressed on platelet function (Table 1) [9][10][11].
Among the possible mechanisms of clopidogrel resistance, drug interactions which occur on pharmacokinetic level de-serve particular attention.Th e role of statins in changing the pharmacodynamic eff ects of clopidogrel, and the level of platelet reactivity, has been reported, but remains quite controversial [9,[12][13][14].

Clopidogrel and statin metabolism
Clopidogrel, which is a thienopyridine derivative, binds specifi cally and irreversibly to the P2Y12 receptor, thus inhibiting ADP mediated platelet aggregation.Clopidogrel is a prodrug requiring activation by the hepatic cytochrome P450 isoenzymes [15,16].About 85% of the drug is hydrolyzed by esterases to an inactive carboxylic acid derivative [17].Th e remaining part of the drug is oxidized to 2-oxo clopidogrel through a cytochrome P 450 -dependent pathway, in which CYP3A4, CYP3A5 and CYP2C19 have a greater role than the CYP2C9, CYP2B6 and CYP1A2 [15,16,18,19].Hydrolysis of 2-oxo clopidogrel generates the active metabolite which contains a thiol group that binds to a cysteine on the P2Y12 receptor and thus irreversibly block ADP -binding and receptor activation [20].
Any drug which inhibits cytochrome P450 (CYP) enzyme systems, may potentially block the synthesis of the active metabolite of clopidogrel, and hence its eff ect on platelet function.Among these drugs, a special place takes the inhibitors of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) -statins.Th e largest number of statins are lipophilic compounds that are subject to the process of extensive metabolism by the CYP isoenzyme systems.Atorvastatin, simvastatin and lovastatin are substrates of CYP3A4, while CYP2C9 is responsible for the metabolism of fl uvastatin [21,22].Rosuvastatin, although not lipophilic compound, is metabolized by CYP2C9 and to a lesser extent by CYP2C19 [23].In contrast, the pravastatin as a hydrophilic compound, is metabolized by sulfation and not by the family of CYP enzymes (Table 2) [21].
Lau et al. were the fi rst who have shown that the lipophilic statins are capable to inhibit CYP3A4 system and thereby reduce the formation of the active metabolite of clopidogrel, i.e. lead to a reduction of its antiplatelet eff ects [12].Th ey found that atorvastatin, in contrast to pravastatin, reduced the ability of clopidogrel to inhibit the platelet aggregation.Also, in some studies were obtained similar results with other lipophilic statins, such as simvastatin and fl uvstatin [13,27].However, in most trials is not registered that concomitant use of statins reduced clopidogrel responsiveness.Even more interesting, several researches have found that CYP3A4 metabolized statins can actually increase clopidogrel's eff ect on platelets [28][29].Also, in our study, CYP3A4 metabolized statin -simvastain, didn't reduce the antiplatelet response to clopidogrel.Such response was even potentiated in comparison with the group that wasn't receiving statin (simvastatin).Only one of seven patients treated with both clopidogrel and statin had a bad response to clopidogrel, compared to four out of eight patients from the group that was receiving only clopidogrel [30].
Diff erent results obtained in all of these studies are likely the consequence of the number of factors, such are: lacking of the unique protocol and method for the determination of platelet function, small sample size, noncomparative doses of statins, the time when the measurement is carried out and fi nally lack of baseline values of platelet aggregation before the introduction of therapy.
In any case, more important than just the results of ex vivo studies, is whether the potential clopidogrel-statin interaction has an impact on clinical outcomes (Table 3).Diff erent studies have presented diverse results, but most of them have reported that the concomitant clopidogrel-statin use isn't associated with a higher incidence of adverse cardiovascular events.
Authors from CREDO, MITRA PLUS, CHARISMA and PROVE IT-TIMI 22 trials [32][33][34][35] didn't register that concomitant use of these drugs and clopidogrel aff ected the clinical end points.Study of Brophy et al. was www.hophonline.orgone of the few studies that showed that the combined use of CYP3A4 metabolized statins and clopidogrel exerts adverse eff ects and increases the risk associated with clinical outcomes [38].
Recent studies, ACCEL-STATIN and PORTO, again actualized the issue of clopidogrel-statin interaction.Results of the ACCEL-STATIN study have indicated that in clopidogrel-treated patients with high platelet reactivity during concomitant use with atorvastatin, replacing to a non CYP3A4 metabolized statin (rosuvastatin or pravastatin) caused a signifi cant reduction in platelet reactivity and the prevalence of high platelet reactivity [39].In PORTO trial it was observed that non CYP3A4 metabolized statin (pitavastatin) had no aff ect on platelet reactivity in patients who are borderline or non responders to dual antiplatelet therapy, in contrast to the atorvastatin [40].It should be emphasized that the Pelliccia et al. fi nd that the eff ect of atorvastatin is particularly pronounced in patients with high platelet reactivity, in which leads to an increment of the already increased platelet reactivity.

CONCLUSION
Taking into account all previously disclosed, it is clear that there are many questions which are required to be explained and based on which we could come to some strong and precious conclusion about possible infl uence of concomitant statin use on the variability in patient response to clopidogrel.Perhaps the fi rst step might be to clarify doubts regarding the lack of a unique protocol, ie.precise defi nition and proof method for identifi cation of the clopidogrel resistance.Although there are more available tests for monitoring of clopidogrel therapy [4,35] their routine use is not come to life yet.Considering the cost of these tests and accompanied economic expenses, maybe at the beginning, the measurement of platelet function should be limited to patients with a high risk for poor response to clopidogrel.
Th e absence of cleary defi ned doses of clopidogrel and statins is the next issue should be resolved.When it comes to doses of clopidogrel, the studies have used diff erent doses: loading doses of 300 or 600 mg and 75 mg maintenance dose.Since, it is known that clinical effi cacy of clopidogrel behaves in a dose dependant manner, clinical studies that would explained potentially clopidogrel-statin interaction are still missing in the light of these facts.Th e situation is similar when it comes to doses of statins.
In patients undergoing percutaneous coronary intervention (PCI), time of sampling for analysis is also something that needs to be taken into account.Th is is not only because of clopidogrel dose (loading or maintenance dose), but also due to the impact of intervention that seems to activate platelets, causing platelet hyperreactivity within 24 hours aft er PCI.
In any case, it is expected that the future studies (double-blind, randomized, multicenter with a suffi cient number of respondents) come up with an answer to the dilemmas that accompany the issue of possible interaction between clopidogrel and statins.Particularly in terms of the opportunities offered to patients in whom it is determines that statins reduced antithrombotic eff ect of clopidogrel, whether to increase the dose of clopidogrel (some initial results are not in favor of this thesis) or switch to new antiplatelet drugs.