Is there a clinically significant interaction between calcium channel antagonists and clopidogrel?: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.
BACKGROUND
Clopidogrel is an inactive prodrug; it is converted to its active metabolite through the cytochrome P450 (CYP3A4) pathway, which also metabolizes calcium channel blockers (CCBs). Several studies have reported that CCBs reduce the ability of clopidogrel to inhibit platelet aggregability; one suggested that CCBs reduce the efficacy of clopidogrel.


RESULTS
We performed a post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) study to compare the treatment effect of clopidogrel in patients on CCBs versus not on CCBs. In CREDO, 2116 patients were randomly assigned to pretreatment with 300 mg clopidogrel 3-24 hours before a planned percutaneous coronary intervention followed by 1 year of 75 mg/d clopidogrel, versus 75 mg clopidogrel at the time of the procedure and continued for 28 days only. The primary end points were a combined end point of death, myocardial infarction, and stroke at 28 days and 1 year. Among the 580 patients (27%) on CCBs at enrollment, at 28 days, the combined end point was reached in 17 patients (6%) on clopidogrel versus 28 (9%) on placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.39-1.29). At 1 year, the combined end point was reached in 27 patients (10%) on clopidogrel versus 46 (15%) on placebo (HR, 0.68; 95% CI, 0.42-1.09). The treatment effect of clopidogrel was similar in patients not on CCBs at 1 year (HR, 0.78; 95% CI, 0.56-1.09). After adjustment for differences between patients on and not on CCB, there was still no evidence of an interaction between clopidogrel treatment and CCB (HR for patients not on CCBs, 0.87; 95% CI, 0.62-1.23; HR for patients on CCBs, 0.74; 95% CI, 0.45-1.21).


CONCLUSIONS
In CREDO, there was no evidence that CCBs decrease the efficacy of clopidogrel.
Geisinger Clinic, Danville, PA, USA.
Christopher W
CW
Good
Steven R
SR
Steinhubl
Danielle M
DM
Brennan
A Michael
AM
Lincoff
Eric J
EJ
Topol
Peter B
PB
Berger
D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine