On the possible relationship between polymorphic variants of the CYP2C19 gene, residual concentration and the presence of bleeding in patients who have suffered acute coronary syndrome and are receiving clopidogrel as part of dual antithrombotic therapy

Background. The use of clopidogrel-based antithrombotic therapy represents an effective strategy for secondary prevention of ischemic events in patients with atherosclerotic cardiovascular disease, primarily acute coronary syndrome (ACS), but to date there is still uncertainty in the choice of optimal approaches to minimize the risks of hemorrhagic complications, including taking into account the possibilities of personalized medicine, especially when the patient additionally receives acetylsalicylic acid (ASC) or an oral anticoagulant (dual antithrombotic therapy).

Objective. To investigate the possible relationship between carriage of CYP2C19 genetic variants (rs4244285, rs4986893, rs12248560) and bleedings in patients receiving dual antithrombotic therapy with clopidogrel after ACS.

Methods. The retrospective study included 150 patients (women – 20%) who presented ACS 30 weeks ago. Patients with atrial fibrillation (AF) (n=73) received clopidogrel and rivaroxaban/apixaban, while patients without concomitant AF (n=77) received clopidogrel and ASC 75/100 mg/day. Pharmacogenetic (CYP2C19 rs4244285, rs4986893, rs12248560) and pharmacokinetic (Сmin,ss clopidogrel) tests were performed for all patients. Bleeding events were assessed retrospectively for the entire period of antithrombotic therapy, but no longer than 6 months. Information about hemorrhagic events was obtained using the MCMDM-1 questionnaire.

Results. Bleeding occurred in 45 (30%) patients. The most frequent bleeding events were nosebleeds – 23 (15.3%) patients, bruising – 21 (14%), and oral bleeding – 11 (7.3%) patients,. Among patients with hemorrhagic events, there was a trend (p=0.25) toward a higher frequency of TT and CT genotype carriers CYP2C19 rs12248560 compared to patients without bleeding (48.9% vs 37.1%, respectively). Depending on the CYP2C19 genotype, all patients were divided into three subgroups in which hemorrhagic events were also analyzed: 1) carriers of gain-of-function (GOF) allele but without loss-of-function alleles (LOF) (n=50); 2) LOF and GOF carriers (n=11); 3) LOF carriers without GOF allele (n=28). Subgroup 1 had a bleeding rate – 36.0%, subgroup 2 – 36.4%, and subgroup 3 – 21.4% (p>0.05).

Conclusion. According to the retrospective analysis the presence of hemorrhagic events in patients with ACS receiving dual antithrombotic therapy with clopidogrel may be associated with carriage of the T allele (genotypes TT and CT) CYP2C19 rs12248560, while carriage of LOF alleles in the absence of GOF alleles, on the contrary, may be associated with a lower incidence of bleeding. Further prospective studies are required to confirm the identified trends.