IntroductionIschemic heart disease (IHD) is one of the main causes of death and disability in developed countries [1]. Despite the fact that in recent decades mortality from IHD in Western countries has gradually decreased, the disease still remains the cause of one third of all deaths in people over 35 years of age [2]. In most clinical cases, IHD coexists with various comorbid pathologies that have a significant negative impact on the progression of the disease due to similar pathogenetic mechanisms. For example, the risk of developing IHD is estimated at 11–16% [3], but the prevalence of IHD in patients with atrial fibrillation (AF) is 3–4 times higher than in the general population [2, 3]. In addition to the fact that AF is a major risk factor for ischemic stroke, it is also associated with a higher risk of myocardial infarction (MI) and chronic heart failure (CHF) [4]. Timely diagnosis, effective pharmacotherapy, as well as continuous monitoring and management of risk factors are the key to improving outcomes in patients with coronary artery disease and AF and reducing the risk of complications [3]. Patients with coronary artery disease and concomitant AF after stenting require dual antithrombotic therapy, which includes clopidogrel and direct oral anticoagulants (DOACs) [5], since the need to prevent ischemic events is beyond doubt. However, this approach is inextricably associated with a higher risk of bleeding, and, consequently, a higher risk of mortality, which indicates the need for regular review of the treatment, correction of bleeding risk factors and assessment of the benefit-risk ratio. The HAS-BLED scale is used to stratify the risk of major bleeding in patients with AF [6], but this scale takes into account only a few risk factors for bleeding. It should be noted that the presence of a high risk of bleeding according to this scale is not a contraindication to the use of antithrombotic drugs (ADs), but only indicates the need for regular monitoring of the safety of pharmacotherapy and, if necessary, correction of modifiable risk factors [5].

Currently, there are no generally accepted bleeding risk scales for patients with a combination of coronary heart disease and AF in clinical practice. Modern strategies of antithrombotic therapy in such a situation involve the use of a personalized approach. As is known, the main role in the formation of the active metabolite of clopidogrel at both stages of biotransformation is played by the CYP2C19 isoenzyme, encoded by the gene of the same name [7]. According to an earlier study, CYP2C19*17 carriers had 23% more bleeding compared to patients who did not have this polymorphic variant [8]. The use of pharmacogenetic testing in real clinical practice has demonstrated significant interindividual variability in therapeutic response to antithrombotic drugs. However, the results of studies conducted in different populations are ambiguous and require further study [8].

ObjectiveThe aim of our study was to investigate the possible association between CYP2C19*17, CYP2C19*2, CYP2C19*3 carriage with the development of bleeding in patients with coronary artery disease, including those with concomitant AF, who were receiving combination antithrombotic therapy. The study included 150 patients (median age 65 [60.75; 73] years, men 80%). All patients were receiving dual antithrombotic therapy (DATT): patients with coronary artery disease (n=77) — clopidogrel and acetylsalicylic acid (ASA), patients with a combination of coronary artery disease and AF (n=73) — clopidogrel and rivaroxaban or apixaban. Bleeding was assessed retrospectively at visit 1 and then during the observation period (16 weeks) using a special MCMDM-1 questionnaire [9]. Pharmacogenetic testing for polymorphic variants of CYP2C19*17, CYP2C19*2, CYP2C19*3 was performed using real-time polymerase chain reaction on a CFX96 Touch Real Time System with CFX Manager version 3.0 software (BioRad, USA) with allele-specific hybridization. As a result, during the observation period, there were statistically significantly more "ultrafast" metabolizers among patients with bleeding compared to patients without bleeding (19.2 and 3.4%, respectively, p = 0.01) [10].For illustration, we provide the following clinical case.

Clinical caseA 61-year-old man was admitted to the emergency department of a multidisciplinary hospital on March 15, 2023, complaining of continuously recurring pressing pain with minimal physical activity. It is known from the anamnesis that in 2020, paroxysmal AF, arterial hypertension (AH) with an increase in blood pressure to 190/110 mm Hg were detected. Against the background of regular intake of antihypertensive drugs, blood pressure stabilized at 130/80 mm Hg. He had been smoking for about 5 years, quit more than 1 year ago. He constantly took metoprolol tartrate, enalapril, acetylsalicylic acid, atorvastatin. It is noteworthy that before hospitalization, despite the presence of a paroxysmal form of AF, the patient was not prescribed anticoagulants. On admission, the general condition is severe, consciousness is clear. On auscultation, breathing in the lungs is harsh, no wheezing; heart tones are muffled, rhythmic. Heart rate (HR) 79 beats / min. Blood pressure (BP) 115/80 mm Hg.Height 176 cm, body weight 78 kg, body mass index 25.1 kg / m2.Electrocardiography (ECG): sinus rhythm, HR 80 beats / min., deviation of the electrical axis of the heart (EOS) to the left, signs of left ventricular myocardial hypertrophy.Laboratory diagnostic methods: troponin I - 0.01 ng / ml. Complete blood count: hemoglobin - 152 g/l, hematocrit - 45.8%, leukocytes - 7.2*10^9/l, platelets - 184*109/l. Blood biochemistry: total protein - 73.4 g/l, lactate dehydrogenase - 154.2 U/l, alanine aminotransferase (ALT) - 25.6 U/l, aspartate aminotransferase (AST) - 24.9 U/l, creatine phosphokinase (CPK) - 57.0 U/l, glucose - 5.53 mmol/l, total cholesterol - 5.49 mmol/l, iron - 22.9 μmol/l, potassium - 4.7 mmol/l, sodium - 138 mmol/l, urea - 7.3 mmol/l, creatinine - 90.1 μmol/l (glomerular filtration rate according to the CKD-EPI formula - 79.03 ml/min/1.73 m2, creatinine clearance according to the Cockcroft-Gault formula is 84 ml/min), total bilirubin is 10.6 μmol/l.

Ultrasound examination of the abdominal organs. The gallbladder is not enlarged (dimensions 6.2*1.2 cm), wall (up to 0.2 cm), the contents are homogeneous. The hepaticocholedochus is not dilated (diameter 0.4 cm), examined along the length - the lumen is homogeneous. The liver is not enlarged (the oblique vertical size of the right lobe is 13.8 cm), with clear, even contours, its tissue is granular in structure, unevenly increased echogenicity, against this background, focal changes were not revealed. The vascular pattern is unchanged. The pancreas has uneven, clear contours, is not enlarged (head - 2.2 cm, body - 1.6 cm, tail - 1.4 cm), diffusely heterogeneous structure, increased echogenicity. The spleen is not enlarged (9.5 * 3.1 cm), homogeneous. In the abdominal cavity, in areas accessible to visualization, no free fluid was detected.Conclusion. Echographic picture of diffuse changes in the liver and pancreas.

Chest radiography. On the chest radiograph in the frontal projection, the lung fields are transparent, the pulmonary pattern is unchanged. No fresh focal or infiltrative shadows are determined. The roots of the lungs are not dilated. The diaphragm is located normally. The sinuses are free. The heart has dilated left sections. The aorta is thickened. Echocardiography. Left ventricular (LV) end-diastolic volume is 88 ml; LV end-systolic volume is 40 ml; LV end-diastolic size is 44 mm; interventricular septum thickness is 11 mm; left ventricular posterior wall thickness is 10 mm; LV ejection fraction (EF) according to Simpson is 54%; right atrium is 34 mm; left atrium is 34 mm; anteroposterior size of the right ventricle is 24 mm; aorta — 32 mm.Conclusion. The walls of the aorta, valve cusps are thickened. The cavities of the heart are not dilated. The walls of the LV myocardium are not thickened. Global systolic function of the LV is preserved (EF — 54%). No areas of impaired local myocardial contractility were identified. Mitral regurgitation stage 1. Tricuspid regurgitation stage 1. Systolic pressure in the pulmonary artery is 22 mm Hg.Transluminal balloon angioplasty (TLBAP) and stenting of the coronary arteries (03/15/2023). Transradial arterial retrograde access on the right.Type of blood supply to the heart: right. The trunk of the left coronary artery (LCA) is usually developed, stenotic in the body by 95%. The anterior descending artery (LDA), diagonal branch of the LAD, circumflex artery (CA), obtuse marginal branch of the OA, right coronary artery, posterior basal branch, posterior interventricular artery are unchanged throughout their entire length.An intracoronary stent Calipso 4.0*13 mm was installed and implanted into the stenosis in the body of the left coronary artery trunk under a pressure of 14 atm. After which TLBAP was performed in the stent (18–22 atm). Satisfactory immediate results of angioplasty were obtained: there was no residual stenosis, no dissection of the arterial wall, blood flow in the LCA was TIMI 3, blood flow in the LAD and OA was preserved (TIMI 3).

Holter ECG monitoring.Conclusion. Holter ECG monitoring was performed for 26 hours 41 minutes. Sinus rhythm with an average heart rate of 79 bpm was recorded (min. HR 57 bpm at 3:19, max. HR 119 bpm at 10:20). Six single atrial extrasystoles were detected (max. number per hour 2 from 12:00 to 13:00). One episode of unstable atrial tachycardia with a heart rate of up to 103 bpm, two episodes of stable AF with a ventricular rate of up to 118 bpm were detected. Four single ventricular extrasystoles were detected. Ischemic significant ST segment shifts, changes in PQ and QT intervals, episodes of asystole longer than 2.0 sec were not detected.Treatment: morphine 10 mg; acetylsalicylic acid 100 mg once a day; clopidogrel 600 mg once, then switched to 75 mg per day; during percutaneous coronary intervention (PCI) - sodium heparin 10,000 IU intravenously; sodium chloride 1000 ml intravenously; omeprazole 20 mg 2 times a day during the day and at night; metoprolol 50 mg once a day; atorvastatin 40 mg once a day; enalapril 5 mg once a day.Against the background of the treatment, positive dynamics are observed in the form of stabilization of the patient's condition. The patient was transferred from the intensive care unit to the cardiology department, where, due to the presence of AF (risk of thromboembolic complications according to the CHA2DS2-VASc scale is 2 points, risk of bleeding according to the HAS-BLED scale is 0 points), rhythm-reducing therapy was intensified, antithrombotic therapy was adjusted. Recommended: ASA 100 mg + clopidogrel 75 mg + rivaroxaban 15 mg per day; atorvastatin 40 mg; metoprolol 100 mg; enalapril 5 mg; omeprazole 20 mg. Discharged for outpatient treatment with a diagnosis of: coronary artery disease: unstable angina with an outcome in angina of effort II FC. Coronary angiography with stenting of the left coronary artery trunk on 15.03.2023.Underlying disease: Stage III hypertension, controlled, risk of cardiovascular complications 4 (very high). Target blood pressure 120-129/70-79 mmHg.Complications of the underlying disease. Heart rhythm disturbances: paroxysmal atrial fibrillation. Risk of thromboembolic complications according to the CHA2DS2-VASc scale is 2 points.

Concomitant diseases. Prostatic hyperplasia. Initial senile cataract.

After discharge, the patient was monitored by a cardiologist at the place of residence. During the first week after discharge, while taking triple antithrombotic therapy, the patient developed extensive hematomas up to 15 cm in diameter, nosebleeds; The patient called an ambulance once due to the inability to stop a nosebleed on his own (this episode of nosebleed did not require hospitalization, it was stopped at home). In this regard, the cardiologist of the clinic decided to switch to DAPT (cancellation of ASA) - from 04/03/2023. Against the background of dual antithrombotic therapy, nosebleeds did not recur, but the patient noted the appearance of hematomas > 5 cm in diameter. At the end of August 2023, rivaroxaban 15 mg, by decision of the attending physician, was replaced by apixaban at a daily dose of 10 mg (5 mg 2 times a day). Against the background of the new regimen of dual antithrombotic therapy, the formation of hematomas > 5 cm in diameter was still observed, there were no other types of bleeding.

On September 20, 2023, the patient was examined by the staff of the Department of Therapy and Polymorbid Pathology named after Academician M.S. Vovsi, Federal State Budgetary Educational Institution of Higher Professional Education, Russian Medical Medical Academy of Postgraduate Education, Ministry of Health of the Russian Federation. Bleeding was assessed retrospectively for 19 weeks. At the time of examination, the patient complained of weakness and early unmotivated awakenings. The condition is satisfactory, consciousness is clear. The skin and visible mucous membranes are of normal color, hematomas on the upper and lower extremities are up to 6 cm in diameter. There is no swelling of the legs and feet. On auscultation, breathing in the lungs is harsh, there are no wheezing. RR is 17 per min. On auscultation, the heart sounds are muffled, rhythmic. HR 69 beats / min. BP 110/80 mm Hg. Bleeding was assessed after 4, 8, 12 and 16 weeks at visits 2, 3, 4 and 5, respectively.During dual antithrombotic therapy (clopidogrel 75 mg and apixaban 10 mg per day), hematomas >5 cm in diameter occurred, which did not require medical intervention or drug discontinuation.Based on the results of pharmacogenetic testing, it was revealed that the patient was a carrier of CYP2C19*17/*17, which corresponds to the phenotypic status for the metabolizing activity of CYP2C19 "ultra-rapid metabolizer". The patient was a carrier of the "wild genotype" for the rs1128503 polymorphic variant of the ABCB1 gene, the rs35599367 polymorphic variant of the CYP3A4 gene, and the rs890293 polymorphic variant of the CYP2J2 gene. Of note was the carriage of the rs2032582 polymorphic variant of the ABCB1 gene, which was associated with a higher risk of bleeding, including the occurrence of nosebleeds, when taking rivaroxaban, according to the results of previously published studies [11, 12], as well as the rs776746 polymorphic variant of the CYP3A5 gene, which was associated with a higher risk of bleeding, both when using rivaroxaban and apixaban [12, 13].

DiscussionAccording to preliminary estimates, by 2060 the incidence of AF in Europe is expected to increase to 17.9 million people, and in the USA to 12 million people by 2050 [14]. The difference in rates may be due, among other things, to ethnic characteristics of different populations. It is known that at the age of over 50, a higher incidence of AF occurs in Caucasians (2.2%), as opposed to African Americans (1.5%) [14]. When adjusted for age, the prevalence of AF is higher among men [14]. Moreover, in a significant proportion of patients (up to 30%), AF remains undetected due to the low-symptom course of the disease, underdiagnosis, and low patient adherence to physician recommendations [14]. About 35% of patients with diagnosed AF and a high risk of TEC do not take oral anticoagulants [14]. With long-term observation, patient compliance decreases to 50%, and this trend is consistent across many countries [14]. Low patient adherence to treatment causes a high risk of complications. Thus, according to An J et al. [15], in the first 12 months after the start of DOAC therapy, the frequency of TEO in patients who stopped taking them was comparable to that in compliant patients, but in the following 2.5 years, the frequency of TEO in the group of patients who stopped taking DOAC therapy was almost twice as high as in those who continued the recommended anticoagulant therapy. But other results obtained by the authors are also consistent: in the first year of taking DOAC, major bleeding occurred statistically significantly more often in patients taking DOACs compared to the group with low adherence to treatment [15].

Identification of bleeding risk and TEC is of primary importance for effective treatment, as minor bleeding or concern about bleeding is the most common reason for stopping antithrombotic therapy [15]. In a cross-sectional study, patients with the lowest adherence to treatment cited concerns about major or minor bleeding among the reasons for refusing to take oral anticoagulants (39% and 16% of patients, respectively), with 37% of patients not experiencing bleeding during treatment [16]. Concern about potential bruising reached 12% of respondents [16]. Higher adherence to anticoagulant therapy is associated with a history of stroke, older age, drug therapy for other chronic cardiovascular diseases, a higher CHA2DS2-VASc score, and female gender [14]. In carriers of alleles with increased function — CYP2C19*17, an increase in the activity of the CYP2C19 enzyme and, as a consequence, a more pronounced suppression of platelet aggregation activity may be observed compared to carriers of alleles of normal function and non-functional alleles of the CYP2C19 gene. Our patient is a carrier of alleles with increased function (CYP2C19*17), which corresponds to the phenotype of an “ultra-fast” metabolizer. In patients with a high risk of bleeding, de-escalation of antithrombotic therapy is possible without reducing the effectiveness of the treatment [17]. In our study, the incidence of bleeding in patients taking rivaroxaban + clopidogrel and apixaban + clopidogrel did not differ statistically significantly [18]. Similar results were obtained in the study of Hwang YJ et al. [18, 19]. However, in a similar clinical situation in a patient with coronary artery disease and AF with a high risk of hemorrhagic complications after stenting, it is advisable to consider reducing the period of taking triple antithrombotic therapy to ≤1 week and switching to DAPT (clopidogrel + DOAC) at the outpatient stage [17]. In addition, regular contact with patients, including by phone, can be a factor that increases adherence and ensures dynamic monitoring [20]. Evaluation of adverse reactions, especially in the first year after initiation of treatment, can help reduce the incidence of interruption of the prescribed therapy [20].

ConclusionA personalized approach not only facilitates timely identification of patients at high risk of TEC and bleeding, but also prevents the occurrence of adverse drug reactions. The described clinical case demonstrates the possibilities of using pharmacogenetic testing for the CYP2C19*17 polymorphic variant to identify individuals at high risk of hemorrhagic complications, the need for timely de-escalation of antithrombotic therapy in clinical practice.