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)

Abstract

Objectives: 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.

Keywords: 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.