Clopidogrel: Effect of esomeprazole on platelet activity, clinical outcomes
Daryl Nnani, PharmD Candidate 2016 Albany College of Pharmacy and Health Sciences
Dual antiplatelet therapy with aspirin and clopidogrel is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) who undergo percutaneous intervention. Clopidogrel is an antiplatelet agent that requires two-step bioactivation by CYP2C19 into its active metabolite. Antiplatelet response to clopidogrel may vary as a function of a patient’s CYP2C19 genotype. Clopidogrel’s activation can be affected in patients who possess at least one loss-of-function CYP2C19 (LOF) allele or who are taking medications that may inhibit CYP2C19. In conjunction with clopidogrel’s antiplatelet action, these effects may also increase bleeding risk.
Proton pump inhibitors (PPIs) are used in patients with gastroesophogeal reflux disease and in those at high risk of gastrointestinal (GI) complications such as GI bleeding or ulcers. These agents can also decrease GI complications in patients taking clopidogrel. PPIs are CYP2C19 enzyme inhibitors and can potentially reduce the antiplatelet effects of clopidogrel. The PPI omeprazole is a major substrate of CYP2C19 and is primarily metabolized by this enzyme. Esomeprazole is an optical isomer of omeprazole and less metabolized by CYP2C19. Studies of the combined effects of PPIs with clopidogrel have yielded conflicting results.
In the current trial. Hokimoto et al. investigated whether CYP2C19 polymorphisms or concomitant use of esomeprazole and clopidogrel is associated with increases in residual platelet reactivity and adverse clinical outcomes such as cardiovascular death, stroke, and myocardial infarction in individuals with coronary artery disease following stent placement. The study population was comprised of Japanese patients, who have a high incidence of the CYP2C19 LOF allele. This prospective genotype clinical trial enrolled 361 Japanese men and women with coronary heart disease. Patients were stratified by genotype (1*/1* EM; 1*/2*, 1/3* IM; 2*/2*, 2/3*, 3*/3* PM, respectively) and by PPI treatment (esomeprazole group and non-esomeprazole group), with 50 patients in the esomeprazole group and 311 patients in the non-esomeprazole group. All patients received a loading dose of clopidogrel with platelet function tests performed 24 hours after clopidogrel administration, followed by aspirin 100mg/day and 75mg/day maintenance doses.
There was no significant difference in residual platelet reactivity between the esomeprazole and non-esomeprazole groups. (P = 0.103). There was a significant increase in residual platelet function between the EM and IM groups (P = 0.012) and the IM and PM groups (P = 0.001). There was no significant difference in platelet reactivity between the esomeprazole and non-esomeprazole groups according to CYP2C19 genotype (P = 0.361 for EMs; P = 0.293 for IMs; and P = 0.907 for PMs). There was also no significant difference in the incidence of cardiovascular outcomes between the two groups (cardiovascular death P = 0.689 for cardiovascular death; P = 0.571 for myocardial infarction; and p = N/A for ischemic stroke).
This study is important because a significant difference was demonstrated in platelet reactivity in relation to CYP2C19 genotype, which has also been observed in several clinical trials; however, no such differences were observed based on the presence of esomeprazole. Based upon the results of this study, esomeprazole may represent an appropriate alternative to omeprazole in patients concomitantly prescribed clopidogrel. The effects of esomeprazole on clopidogrel’s antiplatelet efficacy cannot be completely ruled out.
Limitations of the current study included a small patient population making it difficult to detect a difference in residual platelet reactivity or cardiovascular event rate. In addition, patients were only tested for 1*, 2* and 3* alleles and it is possible for patients to possess other alleles that may have influence clopiodgrel metabolism.
Hokimoto S et al. Impact of esomeprazole on platelet reactivity and clinical outcome according to CYP2C19 genotype in coronary heart disease patients during dual antiplatelet therapy. Thromb Res. 2015;135:1081–6.