Concomitant administration of clopidogrel with statins or calcium-channel blockers: insights from the TRITON-TIMI 38 (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38).
OBJECTIVE
This study sought to evaluate the clinical relevance of potential clopidogrel drug-drug interactions.


BACKGROUND
Some studies have demonstrated that statins and calcium-channel blockers (CCBs) may attenuate the pharmacodynamic effects of clopidogrel.


METHODS
The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38) enrolled 13,608 patients with an acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), and randomized them to clopidogrel or prasugrel. Use of a statin or CCB was left to the discretion of the treating physician. A multivariable Cox model with propensity score was employed to evaluate the association between statin or CCB use and clinical outcomes.


RESULTS
Of the 6,795 subjects assigned to clopidogrel, 4,794 (70.6%) were on a CYP3A4-metabolized statin, and 966 (14.2%) were on a CCB at randomization. The risk of cardiovascular (CV) death, myocardial infarction (MI), or stroke was similar regardless of baseline use of statins (adjusted hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 0.85 to 1.22) or CCBs (adjusted HR: 1.16; 95% CI: 0.94 to 1.43) in clopidogrel-treated patients. Further, the combined use of a CCB and atorvastatin 80 mg daily (adjusted HR: 0.82; 95% CI: 0.37 to 1.84), or a CCB, statin, and proton pump inhibitor (adjusted HR: 1.04; 95% CI: 0.70 to 1.54) were not associated with an increased risk of CV death, MI, or stroke. The use of statins or CCBs did not modify the relative efficacy of prasugrel versus clopidogrel for the primary endpoint (p for interaction = 0.43, 0.55, respectively).


CONCLUSIONS
In patients with ACS undergoing PCI, the use of statins or CCBs was not associated with an increased risk of CV events in clopidogrel-treated patients. Consistent results were observed when the drugs were administered alone, together, or in combination with proton pump inhibitors.
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Oluseyi
O
Ojeifo
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Stephen D
SD
Wiviott
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Elliott M
EM
Antman
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Sabina A
SA
Murphy
Division of Cardiology, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
Jacob A
JA
Udell
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Eric R
ER
Bates
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Jessica L
JL
Mega
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Marc S
MS
Sabatine
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: modonoghue@partners.org.
Michelle L
ML
O'Donoghue
D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000628:therapy*; D000368:Aged; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000077144:Clopidogrel; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000401:mortality; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D057216:Propensity Score; D016016:Proportional Hazards Models; D054328:Proton Pump Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000401:mortality; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D002121:Calcium Channel Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010879:Piperazines; D054328:Proton Pump Inhibitors; D013876:Thiophenes; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
ACS; CCB; CI; CV; HR; MI; PCI; acute coronary syndrome; calcium-channel blocker; cardiovascular; clopidogrel; clopidogrel response variability; confidence interval; drug metabolism; drug–drug interactions; hazard ratio; myocardial infarction; percutaneous coronary intervention; prasugrel