Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial.
OBJECTIVE
The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up.


BACKGROUND
There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy.


METHODS
The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non-CYP3A4-MET).


RESULTS
Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non-CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non-CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.


CONCLUSIONS
Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.
Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Jacqueline
J
Saw
Danielle M
DM
Brennan
Steven R
SR
Steinhubl
Deepak L
DL
Bhatt
Koon-Hou
KH
Mak
Keith
K
Fox
Eric J
EJ
Topol
D000069059:Atorvastatin; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D017035:Pravastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017035:Pravastatin; D013988:Ticlopidine