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Rational Pharmacotherapy in Cardiology

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Vol 16, No 5 (2020)
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ORIGINAL STUDIES

670-677 173
Abstract

Aim. To search for new pharmacogenetic biomarkers of bleeding risk in patients taking rivaroxaban and dabigatran for different indications: atrial fibrillation, endoprosthesis of large joints of lower limbs.

Material and methods. The study enrolled 29 patients (17 patients received dabigatran and 12 –rivaroxaban), who had hemorrhagic complications during taking direct oral anticoagulants. To find new pharmacogenetic biomarkers of bleeding risk, a next generation sequencing (NGS) was performed for selected candidate genes.

Results. Among the patients with bleeding who received dabigatran, 13 variants of the nucleotide sequence showed statistically significant deviation from the population values: 11 in the CES1 gene and 2 in the ABCB1 gene. Among the patients with bleeding who received rivaroxaban, 7 variants of nucleotide sequence showed significant deviation: 4 in the ABCG2 gene, 2 in the CYP3A4 gene, and 1 in the ABCB1 gene.

Conclusion. The identified in this study polymorphisms of candidate genes ABCB1, ABCG2, CES1, CYP3A4 were associated with the risk of bleeding in patients taking rivaroxaban and dabigatran. It makes an important contribution to the pharmacogenetics of direct oral anticoagulants and require additional assessment of clinical significance in further studies.

678-685 105
Abstract

Aim. To determine the role of adherence to the basic drug treatment of heart failure (HF) in prevention of late major adverse events (MAEs) after isolated coronary artery bypass grafting (CABG) in patients with stable coronary artery disease (CAD) and left ventricular (LV) dysfunction at three-year follow-up.

Material and methods. A prospective non-controlled single-center study included 125 consecutive patients with stable CAD and LV EF<50% (62±8 years; 114 [91.2%] males), after isolated CABG. At three-year follow-up MAЕs occurred in 40 (32.0%) patients. The data on pharmacotherapy at followup were obtained in 124 patients: 85 (68.6%) patients without MAEs and 39 (31.4%) patients with MAEs.

Results. The enrolled sample of patients was characterized by high discharge prescription rate of renin-angiotensin system (RAS; 86.3%) blockers (angiotensin-converting enzyme inhibitors or angiotensin-II receptors blockers), beta-blockers (BBs; 97.6%) and mineralocorticoid receptors antagonists (MRAs; 79.0%), being comparable in MAEs and non-MAEs groups. The total coverage of basic HF pharmacotherapy (the combination of RAS blockers, BBs and MRAs) at discharge was 66.1%. At follow-up, about one third of patients in both groups withheld previously prescribed triple HF therapy. The MAEs were associated with more frequent withhold of previously prescribed RAS blockers, as opposed to patients without MAEs (20.5% and 7.1%, respectively; р=0.009). The majority of patients in both groups continued BBs therapy at follow-up (95.0% and 92.9%, respectively; p=0.187). Additionally, we observed the decline of MRAs intake frequency at follow-up (to 43.6% and 49.4%, respectively; p=0.547).

Conclusion. During 3-year follow-up after isolated CABG, about one third of patients with stable CAD and baseline LVEF<50% interrupted triple basic HF therapy (including RAS blockers, BBs and MRAs), mainly due to decrease of RAS blockers and MRAs usage. MAEs in patients with stable CAD and baseline LVEF<50% after CABG were associated with suboptimal use and more frequent interruption of RAS blockers.

686-692 87
Abstract

Aim. To study the changes that have occurred in the pharmacotherapy of atrial fibrillation (AF) in the Saratov Region for 5 years by analyzing the antithrombotic therapy of patients who were admitted in a specialized department of the multidisciplinary hospital in Saratov in 2011-2012 and in 2016-2017.

Material and methods. A pharmacoepidemiological retrospective study was conducted. The object of the study was the medical records of inpatients (Form 003/y) with the diagnosis “Atrial fibrillation” (ICD-X code I48), that consecutively admitted to the cardiology department of the multidisciplinary hospital in Saratov from January 1, 2011 to December, 31, 2012 (n=211) and from January 1, 2016 to December, 31, 2017 (n=227). Criteria for inclusion in the study: patients over 18 years of age, established diagnosis of non-valvular AF of ischemic genesis. Exclusion criteria from the study: non-ischemic cardiomyopathy, thyrotoxicosis, congenital heart defects, rheumatic heart damage, acute coronary syndrome, endocarditis, myocarditis, pericarditis, pulmonary thromboembolism, the presence of prosthetic heart valve. Pharmacoepidemiological analysis was carried out for the drugs prescribed during hospitalization and given by doctors at discharge of patients from the hospital. The risk of ischemic stroke was assessed using the CHA2DS2-VASc score, and the risk of bleeding – according to the HAS-BLED score.

Results. When analyzing the risk of ischemic stroke, it was found that 100% of patients in 2011-2012 years and 98.2% in 2016-2017 years had indications for the prescription of oral anticoagulants (OAСs). In 2011-2012 there were no patients with a low risk of stroke (CHA2DS2-VASc=0). High risk of bleeding (HAS-BLED≥3) occurred in 4.7% of patients in 2011-2012 and in 10.6% in 2016-2017, however, due to the high risk of stroke, the refusal to prescribe OAC in these patients was inappropriate in accordance with the recommendations for the treatment of AF. In the group of patients with CHA2DS2-VASc=0 in 2016-2017 antiplatelet therapy was prescribed in 100% at the hospital stage and at discharge, which contradicts the guidelines, according to which antithrombotic therapy is not recommended to patients with CHA2DS2-VASc=0. In patients with CHA2DS2-VASc=1, a low percentage of anticoagulants prescription was noted. In 2016-2017 OACs were prescribed only in 12.5% of patients at all stages of observation. In 2011-2012 OAC alone was prescribed only to 1 person (20%) at the hospital stage, which does not comply with modern guidelines for the treatment of patients with AF, according to which patients with a risk score CHA2DS2-VASc=1 are recommended to receive OACs in the absence of contraindications. OACs prescription in group CHA2DS2-VASc≥2 occurred only in 15% of patients in 2011-2012 and in a third of patients in 2016-2017 (p<0.05). The frequency of isolated use of OACs significantly increased in 2016-2017 compared to 2011-2012 mainly due to the increase in the spectrum of direct OACs (DOACs) (p<0.05).

Conclusion. For 5 years there have been significant changes in the antithrombotic therapy of AF in the Saratov Region. The frequency of prescribing OACs according to indications has increased mainly due to the introduction of the DOACs into clinical practice. However, prevention of stroke remains insufficient.

693-698 73
Abstract

Aim. To perform a pharmacoeconomical assessment of the use of generic statin drugs in patients with high and very high cardiovascular risk (CVR) in real clinical practice based on the data of the study PRIORITY.

Material and methods. The PRIORITY study included 298 patients with high (29; 9.7%) and very high (269, 90.3%) CVR. All patients were recommended to take the reproduced drugs of atorvastatin and rosuvastatin in an individually prescribed dose. After 1 month (B1), if the target level of lowdensity lipoprotein cholesterol (LDL-C) was not reached, the statin dose was titrated. After 3 months of follow-up (B3), the hypolipidemic effect of statin therapy was evaluated. 295 people completed the study, 285 patients had the results of the lipid profile. To perform a pharmacoeconomic analysis and evaluate the “cost/effectiveness” ratio, we used the prices of generic statins in one of the online pharmacies. The effectiveness of statins was determined by the LDL-C reduction, as well as by the percentage of achieving the target LDL-C level.

Results. At the first stage of the pharmacoeconomic analysis, the criterion for the effectiveness of 3-month lipid-lowering therapy was a decrease in LDL-C level by 1 mmol/l. The median and interquartile range of the ratio “cost/effectiveness” indicator for atorvastatin was 658.2 (431.5; 1257.1) RUB/mmol/l, and for rosuvastatin – 621.0 (390.7; 940.6) RUB/mmol/l (p=0.45). The results of a comparative assessment of the “cost/effectiveness” ratio (with the abovementioned effectiveness indicator) in subgroups of patients with high and very high CVR, with the achievement and nonachievement of the target level of LDL-C, adherent and non-adherent to statins, revealed the economic advantage of statins in groups of adherent patients (p=0.35), high-risk patients (p<0.0001) and individuals who reached the target level of LDL-C (p=0.002) when compared with the corresponding comparison groups. Despite the revealed high effectiveness of rosuvastatin at doses of 20-40 mg/day (assessed by the cost/effectiveness of achieving the target values of LDL-C for specific doses of statins), calculation of the “cost/effectiveness” ratio for each reproduced statin, in general, showed a higher economic effectiveness of atorvastatin.

Conclusion. Pharmacoeconomic analysis of therapy with generic statin drugs, performed according to the data of the non-randomized uncontrolled study, allows to justify the economic efficiency and advantages of these drugs in various subgroups of patients who need statin therapy.

699-705 79
Abstract

Aim. A meta-analysis of studies on the CES1 gene c.1168-33A>C polymorphism (rs2244613) carriage influence on the equilibrium concentration and the risk of bleeding during dabigatran taking.

Material and methods. The search was carried out in the Russian Science Citation Index, Google Academy, Medline PubMed, Embase databases. The meta-analysis included patients who according to the indications (atrial fibrillation, stroke, joint orthopedic surgery) were prescribed dabigatran in various doses. The association was identified in rs2244613 allele C carriers (genotypes AC and CC) and non-carriers (genotype AA). Quantitative synthesis was performed using OpenMetaAnalyst software. In statistical analysis the fixed effects model was used to estimate the influence of the allele C carriage on the any bleeding frequency and the random effects model was used to estimate the influence on the equilibrium plasma concentration level of dabigatran. The homogeneity of the analyzed studies was verified by Cochrane Q-test.

Results. The analysis resulted in selection of 5 works matching all meta-analysis inclusion/exclusion criteria. All selected works included 2030 patients in total. The carriage of the rs2246613 allele C was associated with reduction of risk of any bleeding during dabigatran taking (risk ratio [RR] 0.732, 95% confidence interval [CI] 0.629-0.851; p<0.001). The heterogeneity test did not reveal any reliable differences between the study results (Q=2.183; p=0.535). The level of equilibrium residual concentration of dabigatran was not statistically significant lower for the carriers of C allele of the rs2244613 (mean difference -69.324, 95%CI -236.687-98.039; p=0.417). This might be related to the small sample size and the number of studies included in the meta-analysis. The heterogeneity test did not reveal statistically significant differences between studies (Q=0.388; I2=0%, p=0.534).

Conclusion. The carriage of minor C allelic variant of rs2244613 reduces the risk of any bleeding during dabigatran taking, however, no significant association with decrease in dabigatran concentration was found.

706-712 81
Abstract

Aim. To study doctors’ knowledge of the clinical guidelines on the use of oral anticoagulants and identify the reasons for poor adherence.

Material and methods. The results of the 218 questionnaires completed by the doctors trained in the 2018-2019 were analyzed. The questionnaire included 12 items regarding the main aspects of oral anticoagulants use. 71.6% of respondents were cardiologists, 18.8% were therapists (including general practitioners) and 9.6% were representatives of other specialties.

Results. The obtained data show that therapists are worse than cardiologists aware of indications for oral anticoagulants in atrial fibrillation, and do not always correctly assess the risk of thromboembolism. Only 24.4% of therapists consider prescribing rivaroxaban in a dose of 2.5 mg 2 times a day to a patient suffering from myocardial infarction with an ST segment elevation on the electrocardiogram. One third of therapists either do not know or do not support current recommendations regarding oral anticoagulants use in paroxysmal atrial fibrillation. 65.3% cardiologists are inclined to start anticoagulant therapy only in patients at high risk for thromboembolism, while 36.6% therapists are ready to start such treatment even at moderate risk. Respondents' answers to the questionnaire demonstrate their great alertness regarding possible bleeding. Overestimation of the bleeding risk is more often among therapists than cardiologists (44.9% and 17.1%, respectively). More than one third of therapists (36.6%) are ready to recommend a reduced dose of oral anticoagulant to patients without clear reasons. Fear of bleeding has a greater influence on the decision to prescribe an anticoagulant and the choice of treatment regimen for atrial fibrillation than the desire to effectively prevent thromboembolism.

Conclusion. The results of the survey show that the doctors’ adherence to the clinical guidelines’ basic principles of the use of oral anticoagulants among cardiologists is higher than that of therapists. Wherein, even among cardiologists it cannot be considered sufficient. The lack of doctors’ awareness about the identification, assessment, and modification of risk factors for bleeding was revealed.

713-720 61
Abstract

Aim. To conduct a comparative analysis of clinical and anamnestic characteristics, risk factors, pharmacotherapy and outcomes in patients with previous stroke and myocardial infarction (MI) in outpatient practice based on data from prospective outpatient registries.

Material and methods. On the basis of three outpatient clinics in Ryazan, based on the results of treatment in 2012-2013, an outpatient registry of patients who had stroke of any remoteness (REGION-AR) and an outpatient registry of patients who had previous myocardial infarction (REGATA) were created, which included, respectively, 511 patients (212 men, 41.5%) and 481 patients (247 men, 51.4%). Clinical and anamnestic characteristics, risk factors, prescribed pharmacotherapy, and its compliance with clinical guidelines were evaluated.

Results. Most of the patients in the REGION-AR and REGATA registries were diagnosed with arterial hypertension (AH; 97.1% and 98.5%), coronary heart disease (СHD; 75.1% and 100%), chronic heart failure (CHF; 74.0% and 94.8%), and the proportion of atrial fibrillation (AF) cases were 20.9% and 23.3%, respectively. The share of smokers was significantly higher (23.4% vs 8.9%; p<0.0001) in the REGATA registry, and the share of people with high blood pressure at the inclusion visit (82.6% vs 67.6 %; p<0.0001) and hypercholesterolemia (63.8% vs 45.8%; p<0.0001) was higher in the REGION-AR registry. In both registries, there was a generally insufficient frequency of proper medication prescriptions, while patients in the REGION registry were statistically significantly less likely to receive mandatory prescriptions in general (44.4% vs 58.2%, p<0.0001), including antihypertensive therapy for hypertension, as well as angiotensin-converting-enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) in CHF, beta-blockers in CHF and MI history, statins in CHD, antiplatelet agents in CHD without AF. Over 3 years of follow-up, the degree of compliance of drug prescriptions with clinical recommendations increased both in the REGION-AR registry (from 44.4% to 58.2%) and in the REGATA registry (from 58.2% to 62.9%). For 36 months of prospective observation in the REGION-AR registry, as compared to the REGATA registry, there was a higher mortality rate (22.1% vs 17.0%; p=0.04), moreover the mortality rate among men was higher (22.2% vs 14.2%; p=0.03), and among women it did not differ significantly (22.1% and 20.0%; p=0.56).

Conclusion. Outpatient registries of patients who survived after acute cerebrovascular accident and myocardial infarction were comparable in terms of the average age of patients, however, women prevailed in the REGION-AR study, and men - in the REGATA registry. In the registry of patients who had myocardial infarction, СHD, CHF, respiratory and digestive system diseases, chronic kidney disease, obesity were more often diagnosed, less often – heart defects and oncological diseases. This category of patients was more often prescribed ACE inhibitors/ARBs, beta-blockers, statins, antiplatelet agents. The proportion of compliance of prescriptions with clinical guidelines was higher in the registry of patients who underwent MI both at the stage of inclusion and during subsequent prospective observation. In both registries, an improvement in the quality of drug therapy was noted after 3 years of follow-up. Mortality from all causes over 3 years of follow-up was significantly higher in the registry of post-stroke patients compared to the registry of those with MI, and this was due to the higher mortality in men (1.6 times), but among women in the compared studies the death rate did not differ significantly.

721-729 131
Abstract

Aim. To study the effect of class III antiarrhythmic drugs (amiodarone and sotalol), and the β-blocker bisoprolol on the spectral parameters of heart rate variability in patients with different forms of atrial fibrillation (AF).

Material and methods. Spectral analysis of heart rate variability of 5-minute electrocardiography intervals was used. The study included patients with newly diagnosed AF and having a duration of the disease from 6 months to 8 years. Arterial hypertension, coronary artery disease, myocardial infarction (in history), conduction disorders and type 2 diabetes mellitus were diagnosed as comorbidities. The following parameters were calculated: the total power (TP) of the spectrum, the power of very low frequencies (VLF), low frequencies (LF) and high frequencies (HF).

Results. In the group of patients with newly diagnosed AF without concomitant diseases after administration of amiodarone, VLF prevails in the spectrum structure, which indicates a significant role of humoral factors in the regulation of heart rate. The power of LF, reflecting the activity of the sympathetic nervous system, prevails over HF power after administration of amiodarone. In patients with newly diagnosed AF, having concomitant diseases, sympathetic influences prevail over parasympathetic ones by 3.6 times after administration of amiodarone. In the group of patients who have reduced the number of comorbidities, the LF/HF decreases and is only 1.66 after administration of amiodarone. The decrease in the number of negative factors is also accompanied by an increase in the influence of the vagus nerve on the activity of the heart. In the study of the effects of sotalol, the LF/HF in this group was twice lower in the group of patients with long-term AF. In patients receiving bisoprolol as antiarrhythmic therapy, the proportion of LF in the group of patients with newly diagnosed AF is 2 times lower, and the proportion of HF is twice higher than in the group of patients with long-term AF.

Conclusion. The effect of antiarrhythmic drugs on the spectral parameters of heart rate variability depends on the duration AF. The presence of concomitant diseases of the cardiovascular system can significantly change the effect of antiarrhythmic drugs on the spectral parameters of heart rate variability and is accompanied by an increase in sympathetic activity. In patients with newly diagnosed AF, amiodarone and sotalol cause a similar effect – the predominance of sympathetic influence; when using bisoprolol, the predominant influence belongs to the vagus nerve. In patients with long-term AF, the opposite effect of drugs is observed: the use of amiodarone is accompanied by a more pronounced influence of the vagus nerve, and bisoprolol – the predominance of sympathetic influence. When using sotalol, sympathetic influences also prevail, more pronounced in patients with newly diagnosed AF.

NOTES FROM PRACTICE

730-736 76
Abstract

Chronic infectious-immune myocarditis of severe course can potentially be considered as a factor that aggravates the course of new coronavirus disease (COVID-19) and increases the risk of adverse outcomes. The interaction of chronic myocarditis and COVID-19 during long-term immunosuppressive therapy has not been studied. We present a description of a 35-year-old female patient with chronic infectious-immune myocarditis (morphologically confirmed, with a history of infarction-like onset and thromboembolic complications), who had continuous immunosuppressive therapy with methylprednisolone and mycophenolate mofetil. The patient also received new oral anticoagulants and tenofovir (for chronic HBV infection). COVID-19 (SARS-Cov-2 RNA+) was diagnosed in May 2020. Risk factors for the adverse course of coronavirus infection included severe obesity, heart failure, and life-threatening ventricular arrhythmias. Correction of immunosuppressive therapy (withdrawal of the cytostatic agent, administration of hydroxychloroquine) and therapy with levofloxacin, an interleukin-17 inhibitor (netakimab) were performed. The severity of pneumonia and respiratory failure was moderate despite high fever and high levels of inflammatory markers in the blood (including interleukin-6). Signs of exacerbation of myocarditis, increased levels of troponin T and anticardial antibodies (compared with the initial ones) were not found. It can be assumed that supportive immunosuppressive therapy for myocarditis has a positive effect on the course of coronavirus pneumonia and avoids exacerbation of myocarditis. Careful continuation of immunosuppressive therapy with temporary withdrawal of aggressive cytostatics can be recommended in chronic myocarditis. Further study of the features of the course of previous myocarditis and COVID-19 pneumonia is necessary.

737-741 56
Abstract

This article presents the clinical observation of hereditary thrombophilia, complicated by the formation of a thrombus in the cavity of the right ventricle, in a 40-year-old patient with first diagnosed ulcerative colitis. Despite the standard drug therapy, the patient had a persistent fever. Transthoracic echocardiogram revealed a formation in the right ventricle. A differential diagnosis was made between the vegetation and thrombus. Due to the high risk of infective endocarditis, the antibacterial therapy was started. The addition of deep vein and common iliac vein thrombosis required the exclusion of thrombophilia. Molecular genetic testing allowed to diagnose hereditary thrombophilia: heterozygous carriage of mutations in the genes of factor V Leiden, fibrinogen, platelet receptor for collagen, plasminogen activator inhibitor I. The diagnosis of thrombophilia and ineffectiveness of antibacterial therapy led to the conclusion that there was a thrombus in the right ventricle. The treatment of ulcerative colitis was continued. At the same time, anticoagulant therapy was started, and antibiotics were canceled. As a result, clinical remission of ulcerative colitis, regression of venous thrombosis and complete dissolution of the thrombus in the cavity of the right ventricle were achieved. Ulcerative colitis may be complicated by venous trombosis and hereditary thrombophilia increases this risk.

742-748 54
Abstract

Background. The thrombolytic therapy is absolutely recommended for patients in shock or hypotension because the benefits are clearly outweighing the risks. However, in hemodynamically stable patients, including those with acute right ventricular dysfunction and/or myocardial damage, thrombolysis has a significantly lower evidence level.

Aim. To study the criteria based on which doctors decide to conduct thrombolytic therapy in normotensive patients in real clinical practice according to the retrospective data.

Material and methods. A single-center retrospective cohort study analyzed medical records of patients hospitalized in 2006-2017 with a verified diagnosis of pulmonary embolism (PE) and who had a systolic blood pressure >90 mm Hg at the time of admission.

Results. The present study population included 299 patients with a verified diagnosis of PE from 2006 to 2017 years. Patients were divided into two groups: with thrombolysis (group 1) and without thrombolysis (group 2). Logistic regression analysis showed that age younger than 60 years, the presence of varicose veins of the lower extremities, skin cyanosis, syncope in the debut of PE were independent clinical factors that significantly influence the doctor's decision to perform thrombolysis. Increased troponin I, right ventricular dysfunction, and the severity of PE according to the PESI score showed no significant impact on this decision. In-hospital mortality in the group 2 was 1.9% (5 patients), while there were no deaths in the group 1. But the analysis of the association of thrombolysis with survival was difficult to perform due to the low incidence of deaths and the small number of patients in the group with thrombolysis (odds ratio 0.34; 95% confidence interval 0.03-8.18; р=0.856). No major bleeding was registered in any group.

Conclusion. We were not able to clearly identify independent clinical or instrumental factors that influence the decision to perform thrombolysis in patients with PE outside the framework of evidence-based medicine. Further research is needed.

ASSOCIATED PROBLEMS OF CARDIOLOGY

749-758 87
Abstract

Worldwide, more than 200 million non-cardiac surgeries are performed annually, and this number is constantly increasing; cardiac complications are the leading cause of death in such surgeries. So, in a multicenter study conducted in 27 countries, cardiovascular complications were present in 68% of cases of death in the postoperative period. Registers of recent years have shown that the number of such complications remains high, for example, with a dynamic assessment of troponins, perioperative myocardial damage was detected in 13-18% of cases. This review provides a critical analysis of the step-by-step algorithm for assessing cardiac risk of non-cardiac operations considering the emergence of new publications on this topic. The review discusses new data on risk assessment scales, functional state assessment, the use of non-invasive tests, biomarkers, the role of preventive myocardial revascularization in the preoperative period, and drug therapy. The issues of non-cardiac operations after percutaneous coronary intervention, perioperative myocardial damage are considered separately. The review emphasizes the difficulties in obtaining evidence, conducting randomized clinical trials in this section of medicine, which do not allow obtaining unambiguous conclusions in most cases and lead to inconsistencies and ambiguities in the recommendations of various expert groups. This review will help practitioners navigate this issue and help to use the optimal diagnostic and treatment strategy before performing non-cardiac surgery.

PREVENTIVE CARDIOLOGY AND PUBLIC HEALTH

759-769 95
Abstract

Aim. To study the relationship of blood pressure (BP) and heart rate (HR) in a sample of men and women 25-64 years old and their predictive value for the development of fatal and non-fatal cardiovascular diseases (CVD) and mortality from all causes.

Material and methods. Prospective observation was for cohorts of the population aged 25-64 years from 11 regions of the Russian Federation. 18,251 people were included in the analysis. Each participant gave written informed consent. All surveyed persons were interviewed with a standard questionnaire. BP was measured on the right hand with an automatic tonometer. BP and HR were measured twice with an interval of 2-3 min with the calculation of the average value. The patients were divided into 4 groups: the first group with BP<140/90 ><140/90 mm Hg and HR≤80 beats/min; the second group – BP<140/><140/90 mm Hg and HR>80; the third group – BP≥140/90 mm Hg and HR≤80; the fourth group – BP≥140/90 mm Hg and HR>80 beats/min. Risk factors and cardiovascular history were analyzed as well. Deaths over 6 years of follow-up occurred in 393 people (141 – from CVD). Statistical analysis was performed using the open source R3.6.1 system.

Results. A HR>80 beats/min was found in 26.3% of people with BP≥140/90 mm Hg, regardless of medication. Analysis of the associations between HR and BP showed that for every increase in HR by 10 beats/min, systolic BP increases by 3 mm Hg. (p<0.0001). The group with HR>80 beats/min and BP≥140/90 mm Hg had the shortest life expectancy (p<0.001). Adding an increased HR to BP≥140/90 mm Hg significantly><0.001). Adding an increased HR to BP≥140/90 mm Hg significantly worsened the prognosis of patients. Similar results were obtained in the analysis of cardiovascular survival. Elevated BP and elevated HR had the same effect on outcomes, except for the combined endpoint, where the contribution of elevated BP was predominant. However, their combined effect was the largest and highly significant for the development of the studied outcomes, even after adjusting for other predictors. With an increase in HR by every 10 beats/min, the risk of mortality increased statistically significantly by 22%.

Conclusion. The prevalence of HR>80 beats/min in people with BP≥140 mm Hg amounted to 26.34%. Every 10 beats/min significantly increases the risk of mortality by 22%. Increased HR with elevated BP leads to increased adverse outcomes.

770-779 85
Abstract

Russia belongs to countries with a high prevalence of arterial hypertension (AH), which is the main cause of premature death in the Russian population. The level of blood pressure (BP) is controlled in less than a third of patients, which may be due to poor adherence to medical recommendations and irregular medication. The manuscript provides a review of studies evaluating the effectiveness of measures to improve adherence to antihypertensive therapy (AHT).

Aim. To prepare a systematic review of Russian studies to assess the effectiveness of measures to increase adherence to AHT, to determine/describe the main directions of the intervention and the methodological level.

Material and methods. The search for full-text articles on adherence to AHT published in Russian in the period from 2000 to 2019 was carried out in the main Russian and international electronic databases eLIBRARY.ru, Embase, Russian Medicine, MEDLINE. Of the 563 publications found, 20 were included in the review.

Results. In 14 studies, adherence was assessed using the 4-item Morisky Medication Adherence Scale (MMAS-4), other studies used bespoke questionnaires or pill counts. Two studies examined factors associated with adherence. The observation period was up 6 weeks to 12 months, the number of participants is 30-2435 people. A higher adherence was noted in women, people over 50 years old, with higher education, working, with concomitant diabetes mellitus and a history of myocardial infarction. Patient education was effective interventions to improve adherence (in particular, in studies, improvement on the MMAS-4 from 1.8 to 3.9 points, p=0.0002 or from 2.80 to 3.79 points, p<0.0001), telephone reminders (p<0.0001), training in self-measurement of blood pressure (p<0.05) and fixed combinations of drugs (p<0.05).

Conclusion. The most effective ways to improve adherence are patient education and the use of drugs fixed combinations. In most studies, subjective methods of adherence assessing were used.

780-786 71
Abstract

Aim. To study the clinical course, treatment, and outcomes in the patients with ST segment elevation acute coronary syndrome (STeACS) in real clinical practice

Material and methods. Our study is based on data of 5694 patients who were sequentially hospitalized in the Regional Vascular Center from 01.01.2009 to 01.01.2019 due to STeACS and included in the Federal Hospital Register. Men prevailed (65.8%); the average age was 68 years old. 14.1% of the patients had the history of myocardial infarction (MI) before this hospitalization. The reperfusion strategy, drug therapy, as well as the risks of complications and outcomes in real clinical practice of the Republic of Karelia were analyzed. Descriptive statistics methods were used to evaluate the results.

Results. In the study group a high frequency of reperfusion interventions (83.5%) with a predominance of percutaneous coronary intervention (PCI; 76.2%) was revealed, as well as optimal drug therapy in most patients. Thus, 99.4% of patients took aspirin, 82.8% – clopidogrel, 91.1% – anticoagulants, 91.6% – beta-blockers, 95.6% – statins, 94.2% – angiotensin-converting-enzyme inhibitors/angiotensin II receptors blockers. A risk assessment of hospital and 6-month mortality was performed using GRACE score. The distribution of the hospital risk mortality were the following: 25.7% of patients had a low (49-125 points), 33.7% an average (126-154 points), and 40.6% of patients had a high risk (more than 154 points). At the same time, the risk of 6-month mortality in a half of the patients (51.6%) was low (27-99 points), the average risk (100-127 points) was determined in 23.0% of patients and the high risk (more than 127 points) – in 25.5% of patients. Life threatening complications developed in 38.1% of patients and the most frequent ones were arrhythmias (31.5%). The outcomes at the discharge from the hospital were as follows: 1432 patients (63.5%) had Q MI, 390 (17.3%) – non Q MI, 76 (3.4%) – unstable angina, 21 (0.9%) – MI of unspecified localization and 317 patients (14.1%) – repeated myocardial infarction.

Conclusion. According to the results of a 10-year hospital registry of patients with STeACS, a high frequency of reperfusion interventions and an optimal drug therapy in most patients was revealed. However, to increase the effectiveness of treatment, it is necessary to minimize temporary losses both at the prehospital treatment and during reperfusion.

787-797 101
Abstract

Aim. To investigate the distribution of the intermittent claudication(IC) and/or angina pectoris (AP) and to evaluate the risk of cardiovascular and allcause mortality in Russian male population with pain syndrome of varying severity during more than 30-year observation period.

Material and methods. The data were obtained from representative samples observed in Moscow and Saint-Petersburg (former Leningrad) from 1975 to 1986 with 75% response. Men (n=10953) aged 35-71 years (mean age 48.8±6.6 years) were examined by the same protocol which includes standard questionnaire, blood biochemistry, blood pressure (BP) and heart rate measurements, anthropometry and electrocardiography (ECG) in 12 leads. The original Rose questionnaire to determine the IC and AP was used. There were defined five risk groups with different pain features. The first group – no pain; the second group – mixed pain in legs and/or in chest including the pain connected with the effort, but without typical IC and AP features; the third group – only IC without AP; the fourth group – only AP without IC; finally, the fifth group – both IC and AP. The median follow-up period was 21.9 years with interquartile range of 13.4-33.5 years. During the follow-up 7893 all-cause deaths including 4220 cardiovascular deaths were found. The Kaplan-Meier method was applied to find out the associations between risk groups and survival. Mortality risk, including cardiovascular mortality, was evaluated by the Cox proportional hazard model.

Results. There were 38.7% men with any pain. The prevalence of IC without AP was 0.7% and the prevalence of AP without IC was 5.8%. Only 0.3% of the population had both IC and AP. The prevalence of both parameters increased with age. As expected, men with no pain live longer than others. Median of the survival time in this group, which means the point when half of the population dies, was 24.9 years. Only in this group the value when 75% of population dies was not reached. Compared to no pain group, loss of the life expectancy of only IC group was 10.9 years, only AP group – 9.2 years, IC and AP group – 17.9 years. Both IC and AP had statistically significant contribution to mortality adjusted for high blood pressure, smoking, presence of ECG disturbances, history of myocardial infarction. Survival curves of isolated IC and AP groups did not have statistically significant difference which means that both diseases have the same contribution to mortality. Similar results were obtained for cardiovascular mortality.

Conclusion. The prevalence of IC without AP was 0.7% and the prevalence of AP without IC was 5.8%. IC and AP are independent factors of all-cause and cardiovascular mortality among the Russian male population aged 35-71 years. However, no statistically significant difference was found between groups only with IC and only with AP for cardiovascular and all-cause deaths. The presence of both conditions in combination reduces the median survival time by 17.9 years compared to the group with no pain.

PAGES OF RUSSIAN NATIONAL SOCIETY OF EVIDENCE-BASED PHARMACOTHERAPY

798-803 53
Abstract

Aim. To evaluate the practice of prescribing antianginal/antiischemic therapy in patients who, after acute myocardial infarction (AMI), retained typical clinical manifestations of stable angina.

Material and methods. The registry includes 160 patients who applied to the polyclinic from March 01, 2014 to June 30, 2015 after suffering an AMI. Anti-ischemic therapy was evaluated in patients with typical angina pectoris.

Results. Based on the survey, typical angina attacks were detected in almost a quarter of patients (38 patients – 23.8%). According to the main indicators, patients with typical angina pectoris practically did not differ from the rest of the group of patients, with the exception of a significantly larger proportion of patients with diagnosed ischemic heart disease before AMI and patients under dispensary supervision. Almost all patients received beta-blockers (97.4%), about a third of patients received calcium antagonists (28.9%) or long-acting nitrates (34,2%). During the first year after AMI, second-line drugs were practically not prescribed to enhance antianginal therapy. According to international non-proprietary names, the choice of doctors tended to prescribe bisoprolol, amlodipine, and isosorbide dinitrate. Exacerbation of the disease course with hospitalization for unstable angina pectoris was recorded in 9 (23.7%) patients from the group with typical angina pectoris and in 5 (4.1%) patients in the rest of the group (p<0.001).

Conclusion. In real clinical practice, only a small part of patients with typical angina pectoris receive drug therapy that corresponds to evidence-based medicine; therefore, the unique possibilities of antianginal (anti-ischemic) therapy often remain unrealized.

POINT OF VIEW

804-814 56
Abstract

The purpose of this review was to present modern studies that examine the relationship of physical activity and risk of atrial fibrillation (AF) development and the impact of cardiac rehabilitation programs in patients with all forms of AF. Data of 52 Russian and foreign scientific sources published in 1998- 2020 were presented. In our study, 48 patients with paroxysmal AF after radiofrequency ablation (RFA) were randomly assigned to a physical rehabilitation/standard therapy or control (standard therapy) group. Aerobic physical training was conducted for 6 months 3 times a week. AF is one of the most common cardiac arrhythmias. Despite modern advances, results of treatment of this disease are far from optimal. Many problems of patients with AF can be addressed through enrolment in multidisciplinary cardiac rehabilitation programs. But this question remains open. This is mainly due to the complexity of selection of physical rehabilitation program for patients with AF. It is known that physical activity can trigger an episode of AF. In the following review article, the approaches to functional capacity assessment of patient with AF are described, recommendations for prescribing safe exercise training to achieve a therapeutic effect are presented. Various aspects of the effects of physical rehabilitation are discussed, including its impact on cardiovascular risk factors, influence on atrial remodeling processes and associated biomarkers, prevention of AF progression and occurrence of cardiovascular complications. Results of our own research indicate effectiveness of physical training in patients with AF after RFA: increase in exercise duration by 18.6% (p<0.001) and load by 24.8% (p<0.01) during exercise test, increase in level of everyday physical activity by 23.8% (p=0.001); left atrium dimensions remain stable comparing with control group. That was combined with a decrease of post ablation atrial arrhythmias: after 6 months, they were registered in 4.5% of trained patients vs 17.4% of control group patients (p<0.01). Steady growth in the number of patients with AF and catheter ablation procedures around the world dictates the need for organization of multi-purpose medical rehabilitation.

815-821 66
Abstract

Episodes of rapid increase in blood pressure due to uncontrolled arterial hypertension, previously known as a hypertensive urgency, is common clinical condition which many of practicing physicians are encountered daily. As a rule, these conditions are not life-threatening, however they could lead to target-organs damage if not promptly relieved. Therefore, clear evidence-based recommendations of optimal antihypertensive drug administration in these situations would provide more safe and effective therapy. Despite that, definite expert consensus regarding optimal choice of antihypertensive drugs to manage these patients have not been reached so far. The aim of the current review was to assess the results obtained from clinical trials regarding the safety and efficacy of moxonidine for urgent hypertensive therapy in patients with uncontrolled arterial hypertension admitted to emergency healthcare units as well as in those at the prehospital stage. Performed literature-based analysis revealed enough evidences proving that moxonidine can be administered in a single dose of 0.4 mg as a drug of choice in situations where prompt and stable hypotensive effect is desired. Results of comparative studies designed to closely match real clinical settings indicate that more adequate and sustainable therapeutic effect is achieved after moxonidine administration in comparison to other frequently used antihypertensive drugs.

822-830 94
Abstract

The authors present up-to-date review of clinical pathophysiology of aortic stenosis (AS) based on differentiation of its haemodynamic patterns, and some actual issues of instrumental diagnostics and classification of AS. The variety of clinical presentations of AS is based on diverse combination of pathological changes of haemodynamics. In Russian cardiology, there is no clear pathophysiological classification of AS despite of its relevance under the progress of surgical and transcatheter treatment of AS. The authors suggest the pilot haemodynamic classification of AS which includes 6 types (0-5) based on different combination of the following variables: left ventricle ejection fraction, stroke volume, mean aortic systolic pressure gradient. Severe AS with low transaortic pressure gradient in patients with depressed systolic function of the left ventricle (so called «low flow-low» gradient phenomenon) is referred to as the most frequent, classical haemodynamic pattern of low-gradient AS. The prevalence of this variant is about 10% among European population of patients with severe AS. The inconsistence between aortic valve area and mean pressure gradient is as common as in 35-40% of patients with AS, however, in 30-50% of these cases, AS is not severe. Severe AS is a surgical disease that should be treated in a surgical way in all patients but those in whom predicted risk overbalances potential benefits of the procedure. The use of integrated clinical and instrumental approach for identification of a true sever AS is the matter of great concern, as both overestimation and underestimation can misguide the clinical decision-making process. Verification of severe AS in patients with classical and paradoxical low flow-low gradient AS with specific indications for surgical treatment regarded is further emphasized in the paper. Since transcatheter aortic valve implantation has become a commonly recognized alternative to surgical aortic valve replacement, its role in the treatment of severe AS with different haemodynamic patterns is also discussed. The authors stress on the necessity of using tailored approach for treatment of AS regarding different clinical and pathophysiological scenarios: high gradient AS with preserved ejection fraction, classical and paradoxical low flow-low gradient AS.

831-841 69
Abstract

In recent years there is a positive trend in the development of preventive medicine, in particular, primary prevention of diseases. However, in most cases, patients seek help from a doctor after the manifestation of the disease, and therefore, early identification of risk factors (RF) remains relevant. Conduction of a large number of studies that are aimed at studying modifiable RF associated with the development of cardiovascular diseases (CVD), allowed the experts of the American Heart Association to develop recommendations “Life's Simple 7”, which makes it possible to structure methods of primary prevention of CVD and minimize the risk of their development. In 2019, experts from the American College of Cardiology presented a simplified version of these recommendations, to improve approaches to primary prevention and their effectiveness not only for doctors but also for patients. Thus, by involving the patient in the decision-making process about follow-up treatment, doctors can achieve a high level of compliance, which is essential for improving the prognosis. The “ABCDE” recommendations, in name of which are reflected the first letters of the leading CVD RF, include such paragraphs as RF assessment, the use of antiaggregating therapy, correction of blood pressure, cholesterol levels, smoking elimination, correction of high glucose levels and diabetes treatment, weight loss, assessment of social and economic factors affecting the morbidity in a particular patient. Despite the undoubted benefit of the “ABCDE” recommendations, some problems of primary prevention currently cannot be solved: the inability to accurately assess social and economic RF; the imperfection of the used CVD risk scales. The updated version of the recommendations allows not only to assess the existing RF of the patient, but also to effectively correct them. In addition, the patient himself can read the recommendations, which improves understanding of the primary prevention importance.

CURRENT QUESTIONS OF CLINICAL PHARMACOLOGY

842-851 67
Abstract

Despite the widespread awareness that hypertension and dyslipidemia are risk factors of prime importance for cardiovascular disease, the prevalence of these risk factors is still high, and the success of their control can hardly be considered satisfactory. The latest European guidelines for the management of hypertension strengthened the position of fixed-dose combinations, the main advantage of which is increased adherence to treatment. The purpose of this review was to discuss the background and the possibility of using fixed-dose combinations containing antihypertensive drugs and a statin in the treatment of patients with hypertension and dyslipidemia. We outlined the theoretical concepts that substantiate the possibility of using such therapy and discussed the results of randomized clinical trials investigating the efficacy of combined administration of antihypertensive and lipidlowering drugs. Illustrated by single pill combination of indapamide, perindopril and rosuvastatin, the requirements for fixed drug combinations are discussed, as well as clinical scenarios when their use is considered justified.

852-860 81
Abstract

Apixaban is oral anticoagulant, it is widely used in prevention of stroke in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Its main mechanism of action is through reversible inhibition of factor Xa. It specifically binds and inhibits both free and bound factor Xa which ultimately results in reduction in the levels of thrombin formation. Apixaban is mainly metabolized by CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 isoenzymes. Some of the major metabolic pathways of apixaban include o-demethylation, hydroxylation, and sulfation, with o-demethylapixabansulphate being the major metabolite. The aim of this review is analysis of associated researches of single nucleotide variants (SNV) of CYP3A5 and SULT1A1 genes and search for new candidate genes reflecting effectiveness and safety of apixaban. The search for full-text publications in Russian and English languages containing key words “apixaban”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of apixaban are considered in this review. The hypothesis about CYP и SULT1A enzymes influence on apixaban metabolism was examined. To date, numerous SNVs of the CYP3A5 and SULT1A1 genes have been identified, but their potential influence on pharmacokinetics apixaban in clinical practice needs to be further studies. The role of SNVs of other genes encoding beta-oxidation enzymes of apixaban (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2) and transporter proteins (ABCB1, ABCG2) in its efficacy and safety are not well understood, and ABCB1 and ABCG2 genes may be potential candidate genes for studies of the drug safety.

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