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Along with increased levels of low-density cholesterol, lipid factors of the risk of cardiovascular complications (CVC) include hypertriglyceridemia, particularly increased plasma levels of remnant particles. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are essential for normal functioning of cell membranes, retina, nerve tissue, skeletal muscles, etc. Among the large family of fatty acids (FA), eicosapentaenoic (EPC) and docosahexaenoic (DHX) FA are most studied. The beneficial effect of ω-3 PUFA consumption on the cardiovascular system is related with improvement of blood rheology, antiarrhythmic and anti-inflammatory effects, and a decrease in triglycerides. Large randomized studies of ω-3 PUFA (mixed EPC and DHX or only EPC) have demonstrated their efficiency and safety and a capability for reducing the incidence of CVC and sudden death as well as improvement of the prognosis in various patient populations. In the STRENGTH study (combination of omega-3 and statins), no significant decrease in the risk of CVC was achieved in patients with high triglycerides and low high-density lipoproteins. The ω-3 PUFA treatment is regulated by current international Guidelines and Consensuses as a part of combination therapy with statins for reduction of the risk of CVC and correction of pronounced hypertriglyceridemia.

This Conclusion of the Board of experts is devoted to the analysis of the evidence base, the position in modern clinical guidelines, the efficacy and safety analysis as well as the options of combined therapy with statins and ezetimibe (Otrio, JSC “AKRIKHIN”) in various categories of patients in routine clinical practice in theRussian Federation. Cardiovascular diseases (CVD) continue to lead in the structure of morbidity and mortality inRussia. Hypercholesterolemia is one of the main modifiable risk factors for CVD. Administration of HMGCo-A-reductase inhibitors (statins) remains the basis for the prevention and treatment of the main complications of atherosclerosis, but the achievement of target levels of LDL–C on of statin monotherapy in Russian practice among different categories of risk does not exceed 50%. Proportion of patients (up to 12%) does not tolerate statin therapy, which requires the search for alternative therapies. To optimize the control of the level of LDL–C, combination therapy with statins and ezetimibe is used. Ezetimibe is an effective lipid-lowering drug, an inhibitor of intestinal absorption of cholesterol, which was investigated in many international and Russian studies, the results of which have demonstrated good tolerability, safety and efficacy (reduction of LDL–C levels by 18% in monotherapy). It was noted that the combined therapy with low/medium doses of statins and ezetimibe effectively reduces the level of LDL–C by 44–53%, which is comparable to the effect of high doses of statins and reduces CV risk in patients with CKD and ACS. Otrio (INN Ezetimib) tablets 10 mg ( JSC “AKRIKHIN”,Russia) has demonstrated bioequivalence to the original drug Ezetrol tablets 10 mg (Schering-plough Labo N. V,Belgium). Broad use of a new generic product Otrio in combination with different statins will significantly increase the frequency of achievement of target lipid levels in patients with high and very high CV risk, including patients with chronic renal failure, type 2 diabetes and in patients with high hypercholesterolemia (LDL–C > 5 mmol/l) and, ultimately, reduce the burden of CV disease and mortality in Russia.

Substantial residual risk of development of macro- and microvascular complications is retained in most patients despite contemporary standards of therapy. The search for the solution of actual problem of lowering of residual risk of vascular complications is the aim of multiple current scientific studies conducted in medical practice of the world. The program Residual Vascular Risk Reduction Initiative (R3i) was called upon to join efforts of medical professionals and patients from different countries for solution of the global problem of residual risk of development of vascular complications. In the review we describe objective and main directions of activity of this project. We also give characteristics of individual component factors of residual risk of development of vascular complications investigated in the framework of the R3i program as well as possible methods of improvement of their correction.

To elucidate effect of two doses of atorvastatin (10 and 20 mg/day) on endothelial function, distensibility and stiffness of vascular wall.Patients (n=50) with documented ischemic heart disease and hyperlipidemia were randomized to 10 or 20 mg/day of atorvastatin (Atoris, KRKA). Endothelial function and common carotid artery wall distensibility and stiffness were assessed at baseline and after 12 and 24 weeks of treatment.Administration of both 10 and 20 mg/day doses of atorvastatin for 6 weeks was associated with significant lowering of total cholesterol (CH), triglycerides (TG) and low density lipoprotein (LDL) CH (24.5, 18.4, 34.9% and 29.1, 28.2, 40.9%, respectively). After 24 weeks LDL CH lowering from baseline reached 34.9 and 43.9% (p0.001) and that of TG - 22 and 15%, in 10 and 20 mg/day groups, respectively. There were no significant differences between 10 and 20 mg/day groups in baseline values of endothelium dependent vasodilation (EDV), carotid artery distensibility and stiffness (7.28 and 6.64%, 21.60 and 20.15, 8.04 and 9.19 U, in 10 and 20 mg/day groups, respectively). After 3 months of treatment there occurred significant 38.4% (10 mg/day) and 45.4% (20 mg/day) increases of EDV. Significant 27.6% (10 mg/day) and 28.8% (20 mg/day) enhancement of vascular distensibility was noted after 24 weeks. Vascular wall stiffness decreased 33.4% (p=0.008) and 31.3% (p=0.002) in 10 and 20 mg/day groups, respectively.

Main aim of the clinical study FARVATER was comparison of effects of 10 and 20 mg/day of atorvastatin on levels of lipids, high-sensitivity C-reactive protein (CRP), fibrinogen (F), and structural-functional state of vascular wall in patients with documented and primary hyperlipidemia (HLP). Fifty patients (mean age 60.8 years) with documented ischemic heart disease and HLP were randomized to continuous administration of 10 and 20 mg/day atorvastatin for 24 weeks. Initial levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDLCH), high density lipoprotein cholesterol (HDL CH), CRP and F were 6.22, 1.86, 4.15, 1.24 mmol/l, 1.46 and 2.93 g/l, respectively. After 6 weeks lowering of TCH, TG and LDLCH was significant both in 10 (24.5, 18.4, and 34.9%, respectively) and 20 mg (29.1, 28.2, and 40.9%, respectively) groups. After 24 weeks TG levels decreased by 22 and 15% in 10 and 20 mg subgroups, respectively. Changes of HDLCH (+11 and +12% in patients treated with 10 and 20 mg, respectively) were not significant. There were no significant changes of CRP and F levels. Seven side effects (4%) were registered during 24 weeks; 2 were related to study drug (allergy and symptomless elevation of creatine kinase).

Efficacy and tolerability of atorvastatin (20 mg/day) were assessed in a 3 month study on 19 patients (5 men, 14 women, mean age 52.3 years) with familial hypercholesterolemia. Average baseline levels of total cholesterol (CH) and low density lipoprotein (LDL) CH were 10.7 and 8.6 mmol/l, respectively. By the end of 3 months levels of CH, LDL CH, triglycerides and atherogeneity index decreased by 32, 41, 16 and 45%, respectively. This was accompanied by 21% increase of high density lipoprotein CH level. There were no cases of AST or ALT activity elevation above 3 upper limits of normal values. However 1 patient had asymptomatic elevation of ALT activity up to 53 U/l which did not cause interruption of therapy. Creatine kinase remained normal throughout the study period. Three patients (16%) stopped taking atorvastatin because of side effects. Thus in patients with familial hypercholesterolemia the dose of atorvastatin 20 mg/day was sufficiently well tolerated and provided effective control of lipid levels.

To study the influence of treatment with HMG-CoA reductase inhibitor atorvastatin on endothelial function in patients with familial hypercholesterolemia type IIa.Sixteen patients (5m/11w, 51-/+3 years) with familial hypercholesterolemia were studied before and after 3 months of therapy with atorvastatin 20 mg/day. EDRF release test (D.Celermajer, 1992) was used to assess flow-mediated endothelium-dependent vasodilatation (FMD) of the brachial artery in response to reactive hyperemia. Plasma nitrite/nitrate (NOx) levels were measured as an indirect index of nitric oxide (NO) production in vivo using HPLC.Atorvastatin treatment resulted in a 32% reduction in total serum cholesterol (CH), 41% reduction in low density lipoprotein (LDL) CH, 16% reduction in triglycerides and a 21% increase in high density lipoprotein CH. Flow mediated dilatation (FMD) was impaired at baseline (5.8-/+0.9%) and significantly improved up to 9.5-/+0.9% after 3 month atorvastatin therapy (p0.002). Change in FMD inversely correlated with baseline FMD (r = -0.58, p0.05). There was no significant correlation between FMD and neither total serum CH nor LDL CH levels at baseline. During atorvastatin therapy significant reduction of plasma NOx levels occurred from 53.4-/+5.1 mcmol/l at baseline (range 42.6-86.2 mcmol/l) to 35.5-/+5.1 mcmol/l (18.4-46.0 mcmol/l) after treatment (p0.02, n=7).In patients with familial hypercholesterolemia atorvastatin produced beneficial effect on endothelial function (increase in flow-mediated dilatation, decrease in NOx).

To analyze retrospectively data on lipid lowering efficacy, tolerability and safety of different doses of simvastatin in patients with primary hyperlipidemia.Thirty five patients (mean age 54.9-/+8.5 years, 15 men, 20 women) received simvastatin for 3-6 months in doses 10 (n=12), 20 (n=8), 40 (n=10) and 80 (n=5) mg/day. Average lowering of low density lipoprotein cholesterol was 28.9, 37.6, 39.7, and 46.2% on doses 10, 20, 40 and 80 mg/day, respectively. Elevation of activity of transaminases (AST and ALT) above 3 upper limits of normal (ULN) accompanied by right upper quadrant pain occurred in 1 patient and the drug (10 mg/day) was stopped. Symptomless elevation of AST and ALT activities above 2 ULN was registered in 2 other patients receiving 10 and 20 mg/day. The dose of 80 mg/day was well tolerated - none of 5 patients had symptoms of myopathy or elevated creatinekinase activity.

To study effect of simvastatin of the level of high density lipoprotein (HDL) cholesterol (CH).Simvastatin (40 mg/day) was given for 3 months to 15 patients (3 men, 12 women, mean age 56-/+10.3 years) with hereditary type II hypercholesterolemia after washout from lipid lowering therapy. Initial level of HDL CH was below and above 1.0 mmol/l in 7 and 8 patients, respectively. Blood lipids, activity of liver enzymes and creatine kinase were determined after 1 and 3 months of therapy with simvastatin. Safety and tolerability of simvastatin were also studied.Simvastatin was well tolerated. In 1 patient the drug was stopped because of pain in the liver and nausea. In patients with initially low HDL CH levels of total and low density lipoprotein (LDL) CH significantly decreased by 29.6 and 36.8%, respectively, after 3 months, while level of HDL CH increased by 20% after 1 month of therapy. In patients with initially normal HDL CH levels of total and LDL CH significantly decreased by 31.1 and 32.6%, respectively, while those of triglycerides and HDL CH did not change.In patients with hereditary hypercholesterolemia 40 mg/day of simvastatin besides pronounced lowering of LDL CH level caused significant increase of HDL CH (up to 20% in 1 month) in patients with initially low level of this parameter.

The study was undertaken to enhance the effectiveness of a low-density lipoprotein apheresis procedure by using the mathematical approach to choosing an individual sorption regimen for each patient when the cholesterol concentration given by a physician was achieved in the shortest time. The experimental estimation of time course of changes in plasma cholesterol levels at the column inlet and outlet during low-density lipoprotein apheresis allowed the optimal parameters of the procedure to be calculated. The adequacy of the proposed methods to the real data was examined by the paired t-test (p0.0001). The optimal regimen was chosen for 5 patients with familial hypercholesterolemia. It is shown that the optimization of the regime will reduce the time of the procedure to 47 min, by removing the same amount of a substance.

Lipoprotein (a) [L(a)] is an atherogenic lipoprotein, its human plasma concentration correlates with the occurrence of coronary heart disease. The procedure for selectively removing L(a) with an anti-L(a) immunosorbent was performed to treat 3 patients who had high L(a), normal total cholesterol and other lipoprotein levels. All the patients had coronary stenosis as documented by angiography. After L(a)-apheresis, the level of L(a) decreased by 72%, while that of other plasma components, including low density lipoproteins virtually unchanged. Thus, the procedure of L(a)-apheresis is an effective and safe method for lowering human blood L(a) concentrations. In addition, this in vivo model allows information on L(a) metabolism to be obtained.

The serum level of lipoprotein (a) (LP(a] was measured in 117 patients with coronary heart disease (CHD) angiographically documented, 22 patients with unaltered coronary arteries as evidenced by coronary angiography (Control Group 1), and 28 subjects without clinical CHD signs (Control Group 2). Total cholesterol, triglycerides, low and high density lipoprotein cholesterol, and apolipoproteins (apo) AI and B were measured in the patients and healthy subjects. They were found to be higher in CHD patients than in patients with unaltered arteries and healthy subjects. The level of LP(a) was significantly increased in patients with three-vessel disease as compared to the control groups and patients with single-vessel disease. There was no relation of LP(a) to total cholesterol, triglyceride, high density lipoprotein cholesterol, low and very low density lipoprotein cholesterol, apo-AI, apo-B, age, and sex. The findings supports the assumption that LP(a) is associated with coronary atherosclerosis.