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Background. Polymorphic variants of the genes encoding these isoenzymes and carrier proteins involved in the pharmacokinetics of direct oral anticoagulants (DOAC) may alter their function and, therefore, hypothetically may increase the risk of bleeding associated with the use of DOAC. Aims to study the possible relationship between the presence of polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746) and CYP3A4 (rs35599367) genes on the residual equilibrium concentration (Cmin,ss /D) of apixaban, CYP3A isoenzyme activity and bleeding development in patients with AF and CKD C3C4 stages. Methods. The study included 142 patients with AF combined with chronic CKD stages C3 and C4, receiving apixaban therapy, aged 58 to 99 years (median age 84 years). Pharmacogenetic, pharmacokinetic testing and assessment of CYP3A isoenzyme group activity were performed. Results. Plasma concentration of apixaban depended on the stage of CKD: a higher level of Cmin,ss /D was observed in patients with CKD stage C4 compared to patients with CKD stage C3a and with CKD stage C3b. When studying the effect of rs1045642 (C3435T) polymorphism of ABCB1 gene on apixaban pharmacokinetics, it was found that carriers of homozygous TT genotype had lower median apixaban concentration in blood compared to carriers of CC and TC genotypes (p = 0.027 and 0.034 respectively). For rs2032582 polymorphism of ABCB1 gene, we recorded that patients with GG genotype had higher Cmin,ss /D level of apixaban compared to GT genotype carriers (p = 0.037). CYP3A metabolic activity was statistically significantly lower (p = 0.036) in the group with a history of bleeding compared with that in patients in the group without a history of bleeding (0.8 (0.5; 1.3) and 1.2 (0.7; 2.1); p = 0.036). CYP3A metabolic activity did not differ between patients with different CYP3A5 (rs776746) and CYP3A4 (rs35599367) polymorphism genotypes. For the rs1045642 polymorphic variant, there were fewer carriers of the heterozygous TC genotype (16 (45.7%) patients) among patients with bleeding during the follow-up period compared to patients with no bleeding (43 (53.1%) patients; p = 0.024). Conclusions. The results of the study indicate the presence of an association between genome-wide changes (polymorphic variants of the ABCB1 (rs1045642) and CYP3A5 (rs776746) gene and the presence of apixaban-associated bleeding in patients with AF and CKD stages 34. Mechanisms of such an association require further study.

Chronic kidney disease is one of the most common diseases in general medical practice, due to their secondary damage to the kidneys in arterial hypertension, chronic heart failure, and diabetes mellitus. The coexistence of hypertension and diabetes increases the likelihood of developing chronic kidney failure tenfold. In turn, chronic kidney disease is an important independent risk factor for the development of cardiovascular complications, including fatal ones, due to the direct relationship of the pathogenetic mechanisms of cardiorenal relationships. Approaches to the treatment of chronic kidney disease should be aimed both at preventing the risks of developing renal dysfunction, and at treating existing pathology. The multifactorial nature of the disease and the complex etiopathogenetic relationships determine the need to optimize existing approaches to the treatment of chronic kidney disease in multimorbidity patients with concomitance cardiovascular diseases and diabetes mellitus. This is also due to the fact that, unlike other target organs, compensation for background disease does not always prevent further deterioration of kidney function. According to the recommendations of the main scientific communities, in such cases, it is advisable to start therapy with the most effective angiotensin-converting enzyme inhibitors that combine nephro-and cardioprotective effects and have a dual route of elimination from the body, which is especially important in multimorbidity, the aim to prevent polypharmacy, reduce the risk of drug interactions and, consequently, side effects. This article reviews the literature data indicating the high efficacy and safety of the angiotensin converting enzyme inhibitor fosinopril in patients with chronic kidney disease in combination with cardiovascular diseases and diabetes mellitus.

Introduction. Polypharmacy and the administration of potentially non-recommended drugs are the causes of adverse drug reactions. The absence of potentially recommended drugs leads to a decrease in the duration and quality of life, an increased risk of complications from various organs and systems.The purpose of the study. To analyze the structure of prescribed drugs in patients over 65 years of age with atrial fibrillation (AF) and chronic kidney disease (CKD) stages 3 and 4 for the presence of рolypharmacy and compliance of prescriptions with the criteria STOPP/START.Materials and methods. 125 case histories were analyzed in patients 65 years and older with AF and CKD. Patients were divided into two groups: group 1 – patients with AF and CKD 3a (n = 51; 84.3 % of women; mean age 86.1 ± 6.4 years; mean score on the CHA(2) DS(2)-VASc scale 6.2 ± 1.1 points; mean score on the HAS-BLED scale 3.00 ± 0.68 points); group 2 – patients with AF and CKD 3b and 4 stages (n = 39; 84.6 % of women; mean age 87.9 ± 4.7 years; mean score on the CHA(2) scale; DS(2)-VASc 6.1 ± 1.2 points; the average score on the HAS-BLED scale is 3.10 ± 0.71 points). All 100 % of patients in both groups had a high risk of stroke on the CHA(2) DS(2)-VASc scale (≥ 2 points for men; ≥ 3 points for women), 82.4 % of patients in group 1 and 79.5 % of patients in group 2 had a high risk of bleeding on the HAS-BLED scale (≥ 3 points). According to the prescribing sheets of medical histories, the frequency of polypharmacy was evaluated, as well as the structure of drug prescriptions according to the STOPP/START criteria.Results. The number of patients who were prescribed ≥5 drugs was 100 % in group 1 and 94.9 % in group 2. The number of patients receiving ≥10 drugs at the same time was 11.8 % and 20.5 % in group 1 and 2, respectively. In 64.7 % of patients from group 1 and in 53.8 % of patients from group 2, potentially non-recommended but prescribed drugs (STOPP) are present in the prescribing lists. At the same time, 96.1 % and 100 % of patients in groups 1 and 2, respectively, were not prescribed drugs that are recommended for elderly patients (START criteria).Conclusion. Patients with AF and CKD aged 65 years and older are often prescribed potentially non-recommended drugs that significantly reduce the quality of life and increase the risk of adverse drug reactions. These patients were also often not prescribed potentially recommended drugs that are necessary to improve the prognosis, reduce the risk of complications, and reduce the number of hospitalizations. The revealed facts dictate the need to optimize pharmacotherapy in elderly and senile patients with AF and CKD in a hospital setting.

Background. Arterial hypertension (AH) is often associated with type 2 diabetes mellitus (DM2), is one of the leading modifiable risk factors for cardiovascular disease, atrial fibrillation (AF), chronic kidney disease (CKD). Progression of renal dysfunction is a powerful predictor of the onset of AF in patients with high blood pressure. Irrational prescription of drugs is a risk factor for adverse drug reactions, which is especially important for elderly patients and leads to an increased risk of adverse clinical outcomes.Objective. To analyze the concordance of pharmacotherapy with the STOPP/START criteria in comorbid elderly patients with AH and combined DM2, CKD and AF treated in a multidisciplinary hospitals.Design and methods. Included data from medical records of 1600 patients aged ≥ 65 years with AH and/or AF admitted to multidisciplinary hospitals in Moscow from July 1, 2018 to June 30, 2019. Patients were divided into two groups — (1) AH in combination with AF (n = 822, women — 73%, median age 87 [79; 90]) and (2) control group (n = 778, women — 79,9%, median age 78 [71; 85]) Evaluation of the appointment of drugs was made according to the “STOPP/START” criteria.Results. The number of patients who were not prescribed the recommended drugs was statistically significant (p < 0,001) and higher in the AH + AF group (785 people, 95,5%) compared to the control group (623 people, 80,1%). The number of patients who were prescribed potentially non-recommended drugs was similarly statistically significant (p < 0,001) higher in the AH + AF group (439, 53,4%) compared to the control group (328, 42,2%). The most common START criteria were: 1. Statins with a documented history of coronary, cerebral or peripheral vascular disease (in the AH + AF group — 672, 81,8% of the number of patients in the group; in the control group — 464, 59,6%; p < 0,001) 2. Clopidogrel in patients with ischemic stroke or a history of peripheral vascular disease (c respectively, 324, 39,4% and 237, 30,5%; p < 0,001) 3. Warfarin/direct oral anticoagulants in AF (in the group AG + FP — 294, 35,8%). The most common STOPP criteria were: 1. Drugs that can increase constipation in chronic constipation, if there is a more suitable alternative (in the AH + AF group — 160, 19,5% of the number of patients in the group; in the control group — 47,6%; p < 0,001). 2. Drugs with anticholinergic activity in chronic constipation (respectively, 111, 13,5% and 74, 9,5%; p = 0,013). 3. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in patients with hyperkalemia (respectively, 26, 3,2 % and 94, 12,1%; p < 0,001). Similar results were obtained in the analysis of subgroups of AH + AF with concomitant DM2, CKD and without them.Conclusions. The results obtained dictate the need to optimize pharmacotherapy in elderly and very old patients with AH and comorbidities in a hospital setting. In practice, START criteria are more common than STOPP, that is, in reality, the necessary drugs are often not prescribed where they are indicated and drugs with an unfavorable safety profile are prescribed relatively rarely in elderly and senile patients.