ORIGINAL STUDIES 
Aim. To analyze health care resource utilization and temporary disability in people of pre-retirement age in the Russian population.
Material and methods. The analysis was carried out on the basis of the ESSE-RF study materials (13 regions of the RF). Standard epidemiological survey methods and evaluation criteria were used. The analysis included results of a survey of the ESSE-RF study participants about health care resource utilization and temporary disability (TD) during 12 months before the survey. The following characteristics were ascertained: a number and reasons of outpatient visits for medical assistance, hospital admissions (including duration of in-hospital treatment), emergency calls and temporary disability (a number of days and cases), their mean number per one study participant, mean number of cases and days of TD per 100 working participants, associations with social-demographic parameters, risk factors, chronic non-communicable diseases, stress and anxiety levels by the Hospital Anxiety and Depression Scale (HADS).
Results. A total of 8334 people aged 50-64 years were examined: men – 2784 (33%) and women – 5550 (67%). A share of the hospitalized (at least one time) was 11% in the age group of 50-54 years, 12% – in the age group of 55-59 years and by the age of 60-64 this indicator increased to 15%. 20% of the participants at least one time were admitted to hospital and/or called an ambulance. A share of people who had utilized health care resources at least one time was increasing with age. Unemployed people were hospitalized more frequently than employed ones. Number of chronic non-communicable diseases correlated with the probability of hospitalization and/or emergency call. Categories 2 and 3 of disability, presence of diabetes mellitus, ischemic heart disease and hypertension were statistically significantly associated with the probability of hospitalization and/or emergency call. Smoking did not increase the probability of hospitalization and/or emergency call in comparison with absence of this risk factor, at that, people who had given up smoking were 1.3 times more likely to be hospitalized than non-smokers. People with low and moderate alcohol consumption were hospitalized and called an ambulance significantly less often than those who abstained from alcohol. Clinically significant anxiety increased the probability of hospital admission and/or emergency call as compared to people without this factor by the HADS. Subclinical and clinically significant anxiety, mean and high levels of stress were associated with the probability of hospitalization and/or emergency call. Number of TD days turned out to be rather low - 0.3 day per 1 working man and 0.4 day - per 1 working woman, this index did not significantly differ with age.
Conclusion. So, pre-retirement age (50-64 years) is characterized by increase in health care resource utilization due to health state worsening. At the same time significant share of people of this age (40%) did not seek medical help. These 40% of pre-retirement age people can be possible reserve for health state improvement by means of their active involvement in preventive activity of primary health care system (the study had been conducted before the preventive medical examination program starting).
Aim. To study the characteristics of the daily profile of blood pressure (BP) and heart damage in patients with essential hypertension (HT), depending on the presence of obesity as well as the antihypertensive and organoprotective effects of fixed-dose combinations of amlodipine/lisinopril and bisoprolol/hydrochlorothiazide in hypertensive patients with obesity or overweight.
Material and methods. 60 patients with untreated HT, stage II, degree 1-2 (51.7% of men, aged 53.6±0.8 years) were examined. 24-hour BP monitoring and transthoracic echocardiography with calculation of myocardial stiffness parameters were performed in all patients. Hypertensive patients with obesity and overweight were randomized into groups treated with fixed-dose combinations amlodipine/lisinopril (n=25) or bisoprolol/hydrochlorothiazide (n=30). Doses of drugs were titrated until the target BP was achieved. The follow-up was 12 weeks.
Results. Patients with HT and obesity (n=28) compared with hypertensive patients without obesity (n=32) had greater systolic BP (SBP) variability at night (p<0.05) and a morning surge in SBP (p<0.01), end systolic volume (p<0.05), systolic volume (p<0.01),right ventricle anterior-posterior dimension (p<0.001), right atrium volume (p<0.01), the thickness of the interventricular septum (p<0.01) and the posterior wall (p<0.001) of the left ventricle (LV), significantly lower LV global longitudinal systolic 2D-strain (p<0.001), coefficient of diastolic and end-systolic LV elastance (p<0.05 for both). At the end of the follow-up period patients in the amlodipine/lisinopril group compared to patients in the bisoprolol/hydrochlorothiazide group had a greater decrease in the mean daily pulse BP (-10.8 vs -5.4 mm Hg, respectively; p<0.05) and variability of SBP in daytime (-2.8±0.8 vs -0.9±0.3 mm Hg, respectively; p<0.05). Only patients in the amlodipine/lisinopril group had a significant decrease in the variability of SBP (from 12.2±0.8 to 10.9±0.5 mm Hg; p<0.05) and diastolic BP (from 9.3±0.5 to 8.4±0.4 mm Hg; p<0.001) at night. Patients in the amlodipine/lisinopril group compared to patients in the bisoprolol/hydrochlorothiazide group had a greater increase in the left atrium strain (p<0.01), 2D-strain of LV and a greater decrease in the LV end diastolic stiffness (-21.39±2.45 vs -3.54±1.57 mm Hg/ml, respectively; p<0.001), the LV end systolic elastance (-16.15±2.14 vs -12.85±1.37 mm Hg/ml, respectively; p<0.05), and LV myocardial mass index (-13.2±0.9 vs -8.4±0.7 g/m2, respectively; p<0.01), the thickness of the interventricular septum and the posterior wall of the LV.
Conclusion. Untreated hypertensive obese patients in comparison with hypertensive patients without obesity have higher BP level variability during the night and early morning SBP surge, greater sizes of the heart chambers and LV myocardial wall thickness, higher LV myocardium stiffness. In obese or overweight patients with HT, a fixed-dose combination of amlodipine/lisinopril, compared with the fixed-dose combination of bisoprolol/hydrochlorothiazide, resulted in a more significant decrease in pulse BP and variability of systolic and diastolic BP at night, contributed to a more pronounced improvement in the elastic properties of the left atrium and LV myocardium and decrease in LV hypertrophy.
Aim. To study the antihypertensive and hypolipidemic effect of a group of drugs including perindopril,rosuvastatin and fixed-dose combination of perindopril and indapamide, in ambulatory patients with hypertension and dyslipidemia.
Material and methods. Analysis of the medical data of patients treated with perindopril, indapamide and rosuvastatin in the multicenter, non-interventional study (SYNERGY) was performed. Patients had a diagnosis of hypertension and dyslipidemia, determined in routine clinical practice. Therapy was prescribed to patients in various dosing regimens. The data of anamnesis, physical status, blood pressure measurements, lipid levels were taken from the patient's medical records. The safety assessment was also performed. The duration of follow-up was 8 weeks.
Results. A total of 1383 patients were included into the analysis, 53.5% (n=740) of women and 46.5% (n=643) of men. The average age was 55.8 years. 914 patients (66.1%) had previously received antihypertensive therapy, and 439 (31.7%) had previously received lipid-lowering therapy. A significant reduction in the levels of systolic (SBP), diastolic BP (DBP), and low-density lipoprotein cholesterol (LDL-c) was found at the end of the study in all study groups (p<0.05). This demonstrated an adequate antihypertensive and lipid-lowering effect of all treatment regimens. The mean decrease in SBP in treatment groups ranged from 14.3 to 36.2 mm Hg; the mean decrease in DBP – from 3.3 to 22.2 mm Hg. The maximum decrease in SBP was found in the group of perindopril + indapamide + rosuvastatin (PIR) 8 + 2.5 + 20 mg (36.2±12.3 mm Hg); the maximum decrease in DBP – in the group of perindopril + rosuvastatin 8 + 10 mg. The mean decrease in LDL-c level due to the combined treatment with perindopril, indapamide and rosuvastatin ranged from 0.62 mmol/L in PIR groups 2 + 0.625 + 5 mg and 8 + 2.5 + 5 mg to 1.78 mmol/L in PIR group 8 + 2.5 + 20 mg. Three of 1,383 patients reported adverse events after 4 weeks of treatment, while 13 patients – at the end of the study.
Conclusion. PIR therapy resulted in a significant reduction in blood pressure in all treatment groups compared with baseline levels. A dose-dependent reduction in SBP and LDL-c levels was found in all treatment groups. The tolerability of all treatment regimens was good.
Aim. To compare the efficacy and safety of thrombolytic therapy with recombinant non-immunogenic staphylokinase and tenecteplase in ST elevation myocardial infarction (STEMI) in real clinical practice.
Material and methods. 84 patients with onset of STEMI symptoms up to 12 hours ago were included into the non-experimental study with mixed design. Recombinant non-immunogenic staphylokinase and tenecteplase were used in 38 and 46 patients, respectively. The dynamics of the ST segment on the ECG, angiographic reperfusion criteria were evaluated as well as clinical outcomes – mortality, reinfarction, stroke, bleeding and allergic reactions.
Results. The ST-segment resolution by 70% after 180 min was achieved in 66% and 66% of patients in recombinant non-immunogenic staphylokinase group and in tenecteplase group, respectively (p=0.66) as well as antegrade coronary blood flow through the infarct-related artery TIMI II-III in 61% and 67% of patients, respectively (p=0.63). Mortality and the rate of reinfarction, intracranial bleeding, stroke, cardiogenic shock, left ventricle aneurism and thrombosis were similar in both groups. Large bleeding (otherwise intracranial one) and allergic reactions were not registered.
Conclusion. In real clinical practice the efficacy and safety of recombinant non-immunogenic staphylokinase and tenecteplase in STEMI are similar.
Aim. To assess the practice of using beta-adrenoblockers (β-AB) in patients with cardiovascular diseases (CVD) in the presence of limitations (chronic obstructive pulmonary disease – COPD) and contraindications (bronchial asthma – BA) in two outpatient registries PROFILE and RECVASA.
Material and methods. The data of the PROFILE registry organized in the specialized cardiological unit of the medical research center in Moscow from 2011 to 2015 (n=1531) were analyzed as well as data of the RECVASA registry included patients who applied to 3 city outpatient clinics in Ryazan from 2012 to 2013 (n=3690).
Results. In the RECVASA registry 279 patients had COPD (mean age 73 years; 59.4% males); in the PROFILE registry 286 patients had COPD (mean age 66 years; 50.2% males). In the presence of COPD in the PROFILE registry, β-AB were prescribed more often (51.1%) than in the RECVASA registry (31.5%, p<0.01), primarily to patients with high cardiovascular risk [after myocardial infarction (MI) and in patients with chronic heart failure (CHF)]. In the PROFILE registry 28 patients had BA (mean age 67 years; 46.4% males); in the RECVASA registry – 188 patients (mean age 64 years; 16.5% males). In patients with BA the frequency of β-AB prescription decreased in both registries: 28.6% in the PROFILE registry and 19.1% in the RECVASA registry (p<0.01). In the PROFILE registry the presence of COPD did not influence β-AB administration is patients with ischemic heart disease and MI history; in the RECVASA registry in the presence of COPD the probability of β-AB administration decreased in patients with ischemic heart disease, MI and CHF. In the presence of BA the probability of β-AB administration decreased in both registries in all patients except hypertensive ones.
Conclusion. Physicians of a specialized institution are more active than physicians of outpatient clinics in prescribing β-AB in COPD when direct indications to β-AB are present (previous MI, CHF) except uncomplicated hypertension. In patients with CVD and BA, doctors in both registries try not to prescribe β-AB. However, in uncomplicated hypertension, BA was often not taken into account, while prescribing β-AB.
Aim. To study the prevalence of metabolic syndrome (MS) and total risk of cardiovascular diseases (CVD) in patients with gout depending on the presence of MS.
Material and methods. 56 patients (aged 53.3±10.9 years; men 82%) with verified primary chronic gout [median disease duration 5.7 (2.0-8.5) years] and MS (the main group) were included into the study. The control group included 30 patients (aged 55.3±12.5 years; men 73.3%) with MS without gout and other inflammatory diseases. The following parameters were evaluated in all patients: MS characteristics, serum uric acid, creatinine, fasting glucose, total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL cholesterol), low density lipoprotein cholesterol (LDL cholesterol), and high-sensitivity C-reactive protein. The total risk of CVD was calculated by the SCORE and PROCAM scales.
Results. The incidence of arterial hypertension and hypertriglyceridemia was similar in the compared groups of patients with MS regardless of the presence of gout (p<0.001). Reduction in HDL cholesterol level was more typical for patients in the main group compared to patients with isolated MS (50% vs 23.3%; p<0.01). The total CVD risk was significantly higher in the patients of the main group compared to the patients with isolated MS [SCORE: 7.05 (3.84-9.03) vs 2.73 (1.71-4.97), p<0.01; PROCAM: 13.2 (6.55-23.0) vs 11.75 (7.0-17.5), p<0.05]. The strongest positive associations were found between the risk values on the PROCAM scale and the uric acid levels in the patients of both compared groups: correlation coefficients 0.13 and 0.25 in the patients of the main group and in patients with isolated MS, respectively.
Conclusion. A high prevalence of the main risk factors in patients with gout was revealed. Serum levels of total cholesterol, LDL-C cholesterol and triglycerides made the main contribution to the increase in CVD risk according to SCORE and PROCAM scales. A higher CVD risk on the SCORE scale was found in patients with gout in combination with MS compared to patients with isolated MS (p<0.01). This fact indicates that namely a complex of metabolic disorders, developing both in gout and in MS, provides increase in the total CVD risk.
NOTES FROM PRACTICE 
PREVENTIVE CARDIOLOGY AND PUBLIC HEALTH 
Aim. To determine the proportion of patients with atrial fibrillation (AF) among hospitalized patients in the departments of the multidisciplinary hospital and to study the structure of the associated cardiovascular diseases (CVD) and drug therapy within the RECVAZA AF-Tula hospital registry.
Material and methods. All patients with a diagnosis of AF in the patient's chart (n=1225) were included into the RECVAZA AF-Tula registry; that is 4.2% of 29018 patients hospitalized to the Tula Regional Clinical Hospital in 2013. The structure of the associated cardiovascular diseases, as well as drug therapy, was evaluated on the basis of data in the medical documentation.
Results. The mean age of patients with AF was 69.6±9.9 years, men was 47.8%. 87.5% of patients had a combination of AF with hypertension, 75.1% – with ischemic heart disease, and 81.4% – with chronic heart failure. The average number of diagnoses was 3.4 per patient. The proportion of patients with permanent, persistent and paroxysmal forms of AF was 46.4%, 20%, and 29%, respectively. The risk score according to the CHA2DS2-VASc and HAS-BLED scales was higher in patients of therapeutic profile (4.27±1.66 and 1.48±0.95) than this in patients of surgical profile (3.57±1.70 and 1.06±0.74, p<0.05). Average number of medicines for the treatment of cardiovascular diseases was 4.8. The frequency of prognostically significant drug prescriptions for CVD increased in hospital, in comparison with the outpatient stage, by an average of 1.2 times. Frequency of prescribing prognostically significant medications at discharge was higher in the therapeutic departments than this in the surgical departments (77.0% vs 57.1%, p<0.0001), including anticoagulants (65.8% vs 48.3%, p<0.0001). The frequency of compliance of drug prescriptions with clinical guidelines in the hospital was insufficient (on average 67.6%); whereas in the cardiology group of departments it was significantly higher than this in departments of other profiles.
Conclusion. Patients with AF accounted for 4.2% of all hospitalized patients in a multidisciplinary hospital. The proportion of patients with AF in the therapeutical departments was 4 times more than that in the surgical departments. Most patients enrolled in the registry had associated CVD. The compliance of drug therapy of CVD to clinical guidelines was insufficient, especially at the outpatient stage, as well as in the surgical departments of the hospital.
ASSOCIATED PROBLEMS OF CARDIOLOGY 
Aim. To study the features of the parameters of cerebral hemodynamics in extra and intracranial regions in viral hepatic cirrhosis A, B, C classes according to Child-Pugh with different serum levels of interleukin-2, interleukin-6 and tumor necrosis factor alpha and preserved left ventricular ejection fraction for improvement of diagnostics of stages of chronic hepatic encephalopathy.
Material and methods. 107 patients with viral cirrhosis A, B, C classes according to Child-Pugh with different serum levels of interleukin-2, interleukin-6 and tumor necrosis factor alpha were included into the study. The parameters of hemodynamics in common carotid and middle cerebral arteries of the first order of both hemispheres as well as the parameters of echocardiography were studied in all patients. Evaluation of hepatic encephalopathy stages was carried out by the West-Haven symptoms scale and the Reitan test (Number Connection Test) according to the recommendations of the Working group of the XI-th World Gastroenterology Congress.
Results. Reduction in the compensation of hepatic cirrhosis A and C classes was accompanied by a thickening of the intima-media complex in the common carotid arteries from 0.69±0.21 mm to 0.79±0.35 mm, respectively. The hemispheric asymmetry of the mean linear blood flow velocity tended to increase from 25.1±2.42% in cirrhosis A class to 39.5±7.94% in cirrhosis C class. The greatest disorders of the hemodynamics in the middle cerebral arteries were observed in hepatic cirrhosis C class due to changes in the linear blood flow velocity parameters, increase in the hemispheric asymmetry of the average linear flow rate up to 33.9±10.5%, reduction in resistance and pulsatility indices to 0.49±0.22 and 1.02±0.21, respectively.
Conclusion. Chronic hepatic encephalopathy of all stages can occur in the presence of discirculatory disorders with the development of chronic cerebrovascular insufficiency in viral hepatic cirrhosis A, B, C classes with different serum levels of interleukin-2, interleukin-6 and tumor necrosis factor alpha and preserved systolic function of the left ventricle. The duration of the Number Connection Test more than 200 s, blood flow hemispheric asymmetry more than 40%, decrease in blood flow velocity parameters and vascular resistance indices in the middle cerebral artery below the reference values are associated with a poor prognosis of hepatic encephalopathy. The degrees of cognitive and discirculatory disorders are related with the stages of hepatic cirrhosis compensation. An increase in the degree of cognitive impairments (from ability to logical thinking and attention to disorientation in time and space) is observed in discirculatory disorders and decrease in the stage of cirrhosis compensation.
Studies of endothelial dysfunction in patients with respiratory diseases have become relevant in recent years. Perhaps endothelial dysfunction and high arterial stiffness bind bronchopulmonary and cardiovascular diseases.
Aim. To reveal features of disturbances of arterial wall vasoregulatory function in patients with chronic obstructive pulmonary disease (COPD) in the presence and absence of arterial hypertension (HT).
Material and methods. The study included 50 patients with COPD with normal blood pressure (BP) and 85 patients with COPD and HT. Control group was presented by 20 practically healthy men comparable in age with COPD patients. Tests with reactive hyperemia (endothelium-dependent dilation) and nitroglycerin (endothelium-independent dilation) were performed in order to evaluate endothelium function. The number of desquamated endotheliocytes in the blood was determined.
Results. In patients with COPD and HT in comparison with COPD patients without HT and healthy individuals more pronounced damages of the vascular wall, endothelium vasoregulatory function disturbances and a tendency to the reduction in endothelium-dependent vasodilation were determined both during COPD exacerbation and remission. These differences were most pronounced during the COPD exacerbation. In patients with COPD and HT in comparison with COPD patients without HT the damage of the vascular wall was more pronounced during the remission and endothelium-dependent dilatation disorder – during the exacerbation. The revealed disorders in patients with COPD and HT were associated with smoking status (r=0.61, p<0.01), severity of bronchial obstruction (r=-0.49, p<0.05), and hypoxemia (r=-0.76, p<0.01). We noted relationships between the parameters of 24-hour BP monitoring and remodeling of the brachial artery (r=0.34, p<0.05), endothelium lesion (r=0.25, p<0.05), and impairment of its vasoregulating function (r=-0.58, p<0.05). At that, the following parameters were important: the average systolic and diastolic BP levels, the BP load and variability indices, the time and rate of morning surge in systolic BP, and the circadian rhythm of BP.
Conclusion. The obtained data show the aggravation of the severity of the vascular wall damages and the reduction in the endothelium vasoregulating activity in patients with COPD after development systemic HT. This effect is more evident during the exacerbation of bronchopulmonary disease.
PAGES OF RUSSIAN NATIONAL SOCIETY OF EVIDENCE-BASED PHARMACOTHERAPY 
INNOVATIVE CARDIOLOGY 
Aim. To study the anti-inflammatory effects of intensive lipid-lowering therapy and genetic predictors of its effectiveness in patients with very high cardiovascular risk.
Material and methods. 58 patients with a history of cardiovascular disease and low-density lipoprotein cholesterol (LDL-C)>1.8 mmol/l or non-highdensity lipoprotein cholesterol (non-HDL-C)>2.6 mmol/l (mean age 61.9±8.6 (M±SD) years, 62.1% of men) were included into the study. Polymorphism Phe189Ser of the CYP3A4 (gene encoding cytochrome P4503A4, CYP3A4*17, rs4987161) and APOA1 (gene encoding apolipoprotein A): -75G/A in the promoter region (rs670) and +83C/T in the 5'-untranslated region (rs5069) was determined in all patients. Inflammatory status (high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1) and soluble vascular adhesion molecule (sVCAM-1)) was assessed initially and after 4 weeks of treatment with atorvastatin 80 mg/day. The results were considered statistically significant at p<0.05.
Results. 16 (27.6%) patients achieved LDL-C<1.8 mmol/l, 21 (37.6%) patients – non-HDL-C<2.6 mmol/l. The carriership of the allele -75G of the APOA1 gene was associated with failure to achieve the target level of the non-HDL-C (Fisher's exact test p<0.05 (bilateral), p<0.01 (one-sided)). The levels of hsCRP, MCP-1 and sVCAM-1 significantly decreased by 46.8, 19.2 and 13.2%, respectively (p=0.0001). In the ROC analysis the level of MCP-1<471 pg/ml predicted the achievement of the target level of non-HDL-C with a sensitivity of 53.3% and a specificity of 90%.
Conclusion. Intensive lipid-lowering therapy in patients with a very high cardiovascular risk is accompanied by a pronounced anti-inflammatory effect. The baseline level of MCP-1<471 pg/ml is associated with the achievement of the target values of non-HDL-C. The carriership of the allele (-75)G of the APOA1 gene is associated with the lack of achievement of the target level of non-HDL-C during intensive lipid-lowering therapy and can be considered as a predictor of resistance to statins.
POINT OF VIEW 
The results of prospective randomized clinical trials planned to assess the efficacy of using statins in high doses before percutaneous coronary interventions (PCI) are presented in the review. The effect of this approach on the severity of myocardial damage and clinical outcomes in planned PCI in patients with stable ischemic heart disease (IHD) and early PCI in acute coronary syndrome (ACS) without stable ST-segment elevation was found. The results of the trials planned to study the incidence of contrast-induced nephropathy as well as data from meta-analyzes of conducted clinical trials are demonstrated.
According to the accumulated facts, taking high doses of statins before PCI can contribute to reduce myocardial damage with a decrease in the risk of periprocedural myocardial infarction. This effect was demonstrated in the planned coronary stenting in patients with stable IHD and in PCI in the first days of treatment of ACS without the stable ST-segment elevation. It was found both in patients who had not previously taken statins and in patients permanently treated with statins. The additional expected benefit of using a high dose of statins prior to PCI is the prevention of contrast-induced nephropathy. However, due to the limited evidence base, there is no consensus on the advisability of such an approach in current clinical guidelines.
CURRENT QUESTIONS OF CLINICAL PHARMACOLOGY 
JUBILEE 
4 сентября руководитель отдела профилактической фармакологии Национального медицинского исследовательского центра профилактической медицины, кардиолог, доктор медицинских наук, профессор Марцевич Сергей Юрьевич отмечает 65-летний юбилей.Накануне известный врач и ученый рассказал корреспонденту журнала о новшествах в области кардиологии и барьерах на пути внедрения открытий доказательной медицины в клиническую практику.
Специально для журнала «Рациональная Фармакотерапия в Кардиологии».
ISSN 2225-3653 (Online)