Rational Pharmacotherapy in Cardiology

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Vol 12, No 5 (2016)
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494-502 674

Aim. To evaluate treatment adherence and prevalence of CYP2C9 and VKORC1 gene mutations in patients with atrial fibrillation (AF) and provide rationale of choice for oral anticoagulation therapy.

Material and methods. Treatment adherence was evaluated in 137 AF patients (aged 35-85 years) with quantitative estimation of drug therapy adherence along with compliance to medical support and lifestyle modifications. Among them 82 patients underwent polymerase chain reaction (PCR) analysis of CYP2C9 and VKORC1 gene polymorphisms.

Results. Patients receiving anticoagulation therapy are characterized by lower level of adherence compared to patients without anticoagulants (65.2±19.3% vs 68.5±19.1%; Wald-Wolfowitz; p<0.05). Considering all studied parameters men are less adherent than women (54.7±18.6% vs 60.6±16.7%; Kolmogorov-Smirnov; p<0.05). Patients receiving new oral anticoagulants (NOAC) have better compliance compared with patients of warfarin group. Mutations in CYP2C9 gene were detected in 32.9%, VKORC1 – in 68.3%, and their combination – in 21.9% of study participants. Warfarin therapy may be potentially dangerous in such patients due to low adherence.

Conclusion. Considering high prevalence of CYP2C9 and VKORC1 gene mutations treatment adherence should be estimated to optimize choice of anticoagulation therapy. NOAC treatment should be considered in patients with low adherence for prevention of thromboembolic complications.

503-508 661

Aim. To study the relationship between serum endothelin levels and lipid-lowering therapy in patients with confirmed coronary atherosclerosis.

Material and methods. Patients (n=447; 320 men and 127 women; mean age 62.7±8.8 years) with coronary atherosclerosis, confirmed by coronary angiography, were included into the study. Serum endothelin levels were assessed by enzyme immunoassay (ELISA).

Results. Negative correlation between the statins receiving and serum endothelin level was found in men (r=-0.11; p=0.04). Serum endothelin level was 1.8 times lower in men who received statins, compared with men without statin therapy. The relationship between statins receiving and serum endothelin level was not found in women with coronary atherosclerosis.

Conclusion. The statins receiving in men with coronary atherosclerosis, in contrast to women, negatively correlated with serum endothelin level and is associated with its almost twofold reduction. Relationship between serum endothelin level and receiving other drugs was not found.

509-516 612

Aim. To study the features of the state of hemostasis and platelet enzymes activity in acetylsalicylic acid (ASA) sensitive and resistant patients with acute coronary syndrome (ACS).

Material and methods. The study included 53 patients (25 men and 28 women) with ACS during the first 24 hours and after 10 days. The control group included 50 healthy volunteers. Before treatment the patients were tested on the sensitivity and resistance to ASA. The indicators of vascularplatelet and plasma hemostasis were evaluated as well as the NAD(P)- dependent dehydrogenases activity in platelets was assessed by the bioluminescent method in the first day of ACS before antiplatelet therapy and on day 10.

Results. Increase in spontaneous [1.72 U (1.28-2.72 U) and 1.60 U (1.49-2.78 U), respectively] and ADP-induced [24.4% (21.1-29.8%) and 19.2% (16.1-22.9%), respectively] platelet aggregation, von Willebrand factor activity [159.0% (108.0-190.0%) and 155.0% (149.0-185.1%), respectively] was found in ASA-resistant patients with ACS in 1 and 10 day. Besides the ASA-resistant patients with ACS had very low pentose phosphate cycle and lactate dehydrogenase aerobic activity. They also demonstrated, compared with ASA-sensitive patients, higher intensity of aerobic respiration and the level of NADP-dependent substrate exchange between the tricarboxylic acid cycle and reactions of amino acid metabolism.

Conclusion. Despite the dual antiplatelet therapy with ASA and clopidogrel, risk of thrombotic events is saved in ASA resistant patients with ACS. The metabolic changes in platelet influence their aggregation activity and cause an inadequate response to the antiplatelet therapy in ACS patients.

517-521 722

Aim. To study the effect of atorvastatin on the progression of the arrhythmia in hypertensive patients with paroxysmal atrial fibrillation (AF) in the longterm follow-up.

Material and methods. Patients with paroxysmal AF (n=65) were included into the study. The patients were divided into two groups depending on the level of lipid metabolism: group I (n=33) received atorvastatin (10-40 mg/day), and control group II (n=32) did not take statins. The duration of follow-up was 4 years. The evolution of the AF clinical course was evaluated by the number of arrhythmia episodes for 3 months. Increase in the frequency of paroxysms of AF over the past 3 months, the appearance of the long-standing persistent AF or permanent AF considered as the arrhythmia progression.

Results. The increase in rate and duration of AF episodes was found in 14 (42%) patients of group I and in 13 (41%) patients of group II. Progression of AF was observed with equal frequency in groups I and II. The average value of arrhythmia progression was 10.5% per year in patients of group I and 10.3% in group II. Significant differences between groups in the progression of AF were not found (p=0.2).

Conclusion. Atorvastatin in hypertensive patients with paroxysmal AF did not lead to a change in rate and duration of arrhythmia paroxysms. The average value of paroxysmal AF progression was comparable regardless of atorvastatin use.

522-527 1030

Aim. To study the structure of co-morbidities, especially connective tissue undifferentiated dysplasia syndrome (CTDS), in patients with hypertrophic cardiomyopathy (HCM) to develop an algorithm of complex examination of patients.

Material and methods. Patients with HCM (n=186; 88 men and 78 women) were examined. The diagnosis of HCM was based on current guidelines; molecular genetic study was performed in the absence of phenotypic manifestations. Echocardiography and standard examination of cardiac patient were performed in all patients to identify comorbidities. Genotyping of polymorphisms of 12 modifying genes was performed in 61 patients and 61 people in the control group.

Results. HCM was most often associated with uterine myoma (52%), cardiac and extracardiac congenital malformations (50%), and thyroid diseases (37%). Combination of HCM with different variants of connective tissue dysplasia was found in 17% of patients (mitral valve prolapse – 6.3%, tricuspid valve prolapse – 2.7%, supplemental chords – 4.5%, bivalve aortic disease – 1.8%, increased left ventricular trabeculation – 3.6%, atrial septal aneurysm – 3.6%, membranous ventricular septal defect – 1.8%).

Conclusion. CTDS is one of the most often associated disorders in patients with HCM. The study of the association of CTDS and HCM, the nature of their genetic structure and similarity of pathogenesis require further study.

528-535 646

Background. Despite recent advances in stent design and constantly improving protective pharmacological strategies, complications and adverse events following percutaneous coronary interventions (PCI) are still major factors influencing morbidity and mortality. Therefore, predicting secondary vascular occlusions represents an unmet medical need.

Aim. To triage clinical and laboratory predictors of major adverse clinical events (MACE) following coronary stenting.

Material and methods. This was a prospective, case-controlled, single-center study, which included 94 consecutive patients with documented ischemic heart disease (IHD) who underwent PCI with drug-eluting stent implantation. All patients received dual antiplatelet therapy with acetyl salicylic acid and clopidogrel. Numerous clinical characteristics and laboratory biomarkers were assessed before stenting, as well as CYP2C19 genotyping after patient’s discharge and were correlated with poststenting MACE over the mean follow-up of 28 months. MACE included death, nonfatal myocardial infarction, target vessel revascularisation, stroke, stent thrombosis, angina recurrence and in-stent restenosis.

Results. Twenty-three patients experienced MACE. According to univariate regression analysis we found following MACE predictors after PCI: diabetes mellitus (p=0.049), P2Y12 Reaction Units (PRU) according to VerifyNow® (p=0.01), number of stented arteries more than 2 (p=0.01), number of implanted stents more than 2 (p=0.01), baseline levels of plasminogen activator inhibitor-1 (PAI-1) (p=0.03) and von Willebrand activity (vWF) (p=0.01). Using multivariate analysis we demonstrated that concomitant diabetes mellitus, PRU ≥202, PAI-1 level ≥75.95 ng/ml, von Willebrand factor activity ≥155.15% are independent predictors of adverse cardiac events after PCI in stable IHD patients. Other clinical characteristics and laboratory indices, including CYP2C19*2 carriage, showed no significant impact on outcomes after elective PCI.


Conclusions. Background diabetes mellitus, high on-treatment platelet reactivity (according to VerifyNow®), PAI-1 and vWF presenting activity may be useful for MACE prediction over 28 months of follow-up after PCI with drug-eluting stent implantation.

536-541 633

Aim. To study the effect of olmesartan/lercanidipine combination and zofenopril/lercanidipine combination on the level of soluble platelet-endothelial cell adhesion molecule of the first type (sPECAM-1) in plasma in patients with essential hypertension (HT) stage II-III.

Material and methods. We examined 44 people: 16 healthy volunteers (control group) and 28 patients with essential HT aged 40 to 71 years; among them 8 patients with HT II stage and 20 patients with HT III stage. Part of HP patients (subgroup 1A, n=6) received a combination of olmesartan 10- 40 mg/day + lercanidipine 5-10 mg/day; another part of HP patients (subgroup 1B, n=11) received a combination of zofenopril 7.5-30 mg/day + lercanidipine 5-10 mg/day. The examination at baseline and after 7 months included the measurement of office systolic (SBP) and diastolic (DBP) blood pressure, determination of sPECAM-1 levels in blood plasma by quantitative solid-phase enzyme immunoassay, electrocardiography, transthoracic echocardiography, complete clinical blood test, general urine analysis, biochemical blood test with lipid profile.

Results. In patients with HT stage III the level of sPECAM-1 was significantly higher than in the control group (259.10 [145.36; 329.33] vs 133.18 [73.07; 170.99] pg/ml, respectively; p<0.05). These patients had also significantly higher level of low density lipoproteins cholesterol and triglycerides compared with the control group. After 7 months of therapy a significant reduction in office SBP/DBP levels was found both in 1A and in 1B subgroups (19/7 and 37/8 mmHg, respectively). Reduction in sPECAM-1 levels was also observed in both subgroups of treated patients; however, it was significant only in the 1A subgroup (p<0.05).

Conclusion. sPECAM-1 level is increased in patients with essential HT stage III. Despite the reduction in office SBP and DBP in both treated groups, only the subgroup of olmesartan + lercanidipine demonstrated significant decrease in sPECAM-1 level (p<0.05). Thus, olmesartan + lercanidipine combination has more significant effect on endothelial function than zofenopril + lercanidipine combination.

542-546 638

Aim. To study clinical and morphofunctional indicators of respiratory function in patients with dilated cardiomyopathy (DCM) with and without pulmonary hypertension (PH).

Material and methods. 91 patients with idiopathic DCM (34 women and 57 men; mean age of 46.4±13.7 years) were included into the study. 25 (27.4%) patients had right ventricular DCM (RV DCM). 6-minute walking test (6MWT), the standard 12-lead ECG, spirography, echocardiography were performed in all patients. PH occurred in 48 of DCM patients (Group I) and 43 DCM patients had no PH (Group II). A number of patients with RV DCM in Groups I and II was 11 (23%) and 14 (32.5%), respectively.

Results. Pulmonary artery systolic pressure (PASP) in group I was 48.1±10.7 mmHg (in 71% of the patients – degree 1 of PH, and in 29% - degree 2). A significant decrease in the majority of speed indicators of respiratory functions was found in Group I. The inverse relationship between PASP and Tiffno index (p=0.03) and a positive correlation between forced vital capacity (53.17±9.21%) and 6MWT distance (206.7±80.3 m; p=0.017) were found in patients of Group I.

Conclusion. PH syndrome often aggravates the DCM course. Forced expiratory volume in the first second, Tiffno index, and some speed indicators show disorders of respiratory function in DCM patients.


547-552 888

The risk of cardiovascular events in patients with rheumatoid arthritis (RA) is higher than this in population in 3.96 times. Arterial hypertension (HT) is one of the modifiable risk factors. According to published data 10-30% of patients have "masked" HT, detectable by the daily monitoring of blood pressure (BP). According to our own study, the prevalence of "masked" HT among RA patients is 28.2%. Among hypertensive patients with RA 7.5% of patients had resistant HT, 36.8% - do not regularly control BP. During daily monitoring of arterial stiffness in RA patients with HT we revealed that outpatient stiffness index was significantly higher than this in patients with essential hypertension (p<0.05). It is known that the basic anti-inflammatory drugs reduce cardiovascular risk; however, data regarding symptomatic treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids are contradictory. Antihypertensive treatment of HT patients with RA should be selected taking into account concomitant anti-inflammatory therapy. Treatment with calcium channel blockers is the most justified because they do not reduce their efficacy when used simultaneously with NSAIDs.


553-557 681

Aim. To study the effect of rivaroxaban compared with warfarin on the incidence of cardioembolic stroke and systemic thromboembolic complications (TEC), bleeding in patients with non-valvular atrial fibrillation (AF).

Material and methods. Patients (n=126) older than 18 years, appealed to the Cardiology Clinic with non-valvular AF were included into an open non-randomized study. The patients were divided into 2 groups based on their socio-economic status: 77 patients received rivaroxaban and 49 - warfarin. The incidence of acute coronary syndrome, ischemic stroke and other TEC, bleeding as well as (only for patients taking warfarin) international normalized ratio (INR) and time in the therapeutic INR range were evaluated.

Results. The incidence of ischemic stroke was not significantly different between groups, at the same time the incidence of other TEC was significantly higher in the warfarin group (0 vs 8%, p=0.011). The incidence of minor bleedings was significantly prevailed in warfarin group (0 vs 20%; p=0.0004). The time in the target INR range in the warfarin group was only 43%. 93.5% of patients continued to receive rivaroxaban after 9 months, and warfarin – 67.4% of patients.

Conclusion. The results of our own clinical studies of rivaroxaban in patients with non-valvular AF have demonstrated efficacy comparable to that of warfarin. Rivaroxaban was superior to warfarin in safety.


558-566 875

Measures for the prevention of cardiovascular diseases (CVD) are more effective if they are performed taking into account the risk factors of their development. Screening scales, which are helpful in determining the population risk, are used in primary prevention for cardiovascular (CV) risk stratification. The assessment of individual CV risk remains a problem. Biomarkers and instrumental investigations are used for its detailing. Carotid ultrasound is the main noninvasive method of vascular assessment. It allows assessing the intima-media thickness (IMT) and detecting the presence, location and morphology of atherosclerotic plaques (ASP), in other words, subclinical signs of atherosclerosis. Different views on the diagnosis of IMT and ASP in the carotid arteries and their value as predictors of CV and cerebrovascular diseases among individuals without CVD are presented in the article. Opinions about the benefits of IMT assessment for re-classification of patients with signs of subclinical atherosclerosis are also presented. The debate about the value of IMT in the CV risk stratification, and the feasibility of its assessment in clinical practice has not yet been completed. Assessment of IMT for CV risk stratification is most appropriate in patients with intermediate risk or with multiple risk factors of CVD. Consensus on primary CV prevention strategies in patients with intermediate risk of CVD is currently unavailable. Assessment of subclinical atherosclerosis by carotid ultrasound is important in such patients. The finding of increased carotid IMT should have an effect on the choice of hypolipidemic drug and intensity of treatment. However, the diagnosis of subclinical atherosclerosis is not built into the algorithm for determining the CV risk. This causes difficulties in choosing tactic of prophylactic intervention, especially for intermediate risk patients.

45-50 100

Aim. To study the incidence and structure of sudden cardiac death (SCD) among the working population of the Bryansk region, as well as to determine its share in the structure of total and cardiovascular mortality in this age group.

Material and methods. We analyzed the structure and incidence of SCD in 417740 people of working age (25-64 years) in five major areas of the Bryansk region and the city of Bryansk in 2012. Medical records (outpatient card, patient’s chart, autopsy protocol, a medical certificate of death) of 1447 people of working age who died from diseases of the circulatory system were analyzed.

Results. 106 cases corresponded to the criteria for SCD, which determined the frequency of SCD 25.4 per 100000 working-age population. The predominance of men over women (85% vs 15%) was marked. Only 24% of cases of SCD occurred in hospitals, while 76% - in outpatient settings. A strong association between SCD and age was noted. Chronic (43%) and acute (37%) forms of ischemic heart disease turned out to be the main clinical entities that caused SCD.

Conclusion. The share of SCD in total and cardiovascular mortality was 2.9% and 7.3% respectively. Strong correlation between SCD rate and age was found. Chronic and acute forms of ischemic heart disease turned out to be the main clinical entities that caused SCD.


567-573 811

The role of randomized controlled trials (RCTs) and observational studies in evaluation of the efficacy and safety of cardiology drugs is compared in the article. The clear conclusion is made that RCTs are the basis of modern evidence-based medicine, and that they have no alternative. Observational studies conducted in compliance with the modern rules can be a source of information on the efficacy of drugs only in the absence of data from RCTs.


574-581 1209

The review analyzes new treatment for patients with chronic heart failure (CHF) with low ejection fraction – cardiac contractility modulation (CCM). CCM is carried out by supplying electric signals to an absolutely refractory ventricular myocardium, to elicit a positive inotropic effect without increasing myocardial oxygen consumption. These effects are independent on QRS duration; consequently, the therapy might be beneficial for patients who are not candidates for cardiac resynchronization therapy (CRT). It should be noted that the use of CCM treatment of CHF should begin only with maximum active therapy when its efficacy is not enough. It is not an alternative, but complement to the most active treatment of patients. Clinical studies primarily focused on patients with normal QRS duration because the CPT is optimal treatment of patients with prolonged QRS. The article focuses on the prerequisites for the development of the method and discusses the results obtained when evaluating the clinical efficacy and safety of treatment of patients with CHF in randomized clinical trials FIX-HF-3 (n=25), FIX-HF-4 (n=164), FIX-HF-5 (n=428). The total number of patients included into these studies was 617 people. Baseline patient characteristics were similar for all 3 studies. All participants received optimal medical therapy, had a normal QRS duration. All patients were II and III functional class (by NYHA). The studies analyzed the changes in NYHA class, ejection fraction, peak oxygen consumption (VO2), the precursor of brain natriuretic peptide (NT-proBNP) level. Quality of life was assessed by the Minnesota questionnaire; the mortality rate was compared with that predicted by MAGGIC scale. CCM therapy had beneficial effect on the survival and quality of life in patients with CHF. However, more data is needed to assess long-term effects of the CCM therapy.


582-589 1100

Atrial fibrillation (AF) is one of the most common arrhythmias. It reduces quality of life and its duration due to thromboembolic complications. Obesity contributes to the structural and electrical remodeling of atrial myocardium. This leads to occurrence of ectopic foci in the mouths of the pulmonary veins and the disruption of normal electrical conduction in the atria. Systemic inflammation, myocardial fibrosis, cardiomyocyte overload by Na+ and Ca2+ ions, accumulation in the cells of unoxidized metabolic products, imbalance of the autonomic regulation are considered as the main mechanisms of arrhythmogenic substrate formation. Hypertension, insulin resistance, and obstructive sleep apnea, associated with obesity, increase the risk of development and progression of the arrhythmia. Study of pathogenetic mechanisms of AF in obesity is necessary to develop new strategies for its prevention and the creation of more effective methods of treatment of these patients.

590-594 721

Atrial fibrillation (AF) is the most common cardiac cause of systemic embolism and cardioembolic stroke. The risk of thromboembolic complications increases significantly when performing for electrical cardioversion. Vitamin K antagonists (warfarin) more often used to prepare for electrical cardioversion. However lately new oral anticoagulants (NOAC) are becoming more common for the prevention of thromboembolic events in patients with AF. Possibility to perform planned cardioversion while receiving dabigatran has been shown in a retrospective analysis of patients from the RE-LY study. The incidence of stroke and systemic embolism within 30 days after cardioversion was low and did not differ significantly in all groups. Thus, the results of the RE-LY study allow performing the planned and emergency cardioversion in patients receiving dabigatran. These results were later confirmed in other retrospective studies and meta-analyzes that are presented in this article. The X-VERT study and sub-analysis of the ARISTOTLE study showed the efficacy and safety of rivaroxaban and apixaban in preparation and performance of electrical cardioversion in patients with non-valvular AF. Long-term preparation courses for the cardioversion were used in the majority of patients in all published papers. By the present time a specially designed study directly aimed at assessing the NOAC effectiveness, in particular, dabigatran, in preparing and performing electrical cardioversion was not carried out in patients with AF. Some questions about the safety and efficacy of dabigatran during short preparation courses before electrical cardioversion remain.

595-602 652

Prevalence of atrial fibrillation (AF) in population is very high and continues to grow. According to the existing statistics its prevalence reaches about 2% so it is twice more, than it was considered in the last decade. Prevalence of AF among patients with chronic kidney disease (CKD) varies from 11 to 22% (according to other data – from 15 to 20%) and increases with age, considerably surpassing that in the general population among all age groups. Vast majority of patients with AF need in treatment with anticoagulants to prevent an ischemic stroke and systemic thromboembolisms. However, in case of combination AF and CKD, in addition to increase in frequency of strokes and the thromboembolic events, also the frequency of major bleedings significantly increases that considerably complicates the choice of adequate anticoagulant therapy in such situation. Many years the vitamin K antagonists were the only representatives of a class of anticoagulants for long-term therapy in patients with AF. Their well-known deficiencies (a narrow therapeutic window, need of frequent laboratory control, numerous drug-drug and dietary interactions, unpredictability of a pharmacodynamics and pharmacokinetics at certain patients) promoted search of new medicines, more convenient in use. Direct oral anticoagulants were easier to use, and by results of the main studies didn't yield or exceeded warfarin concerning balance of efficiency and safety. However, they were not specially studied in patients with the reduced kidney function. Features of modern anticoagulant therapy in patients with the nonvalvular AF and CKD are considered in the review. The possibility of the safest use of anticoagulants for patients with decreased creatinine clearance is analyzed.


603-609 4647

The effectiveness of antiarrhythmic drugs in the elderly is similar to that in younger patients. However data for «the very elderly» are lacking. Elderly patients are more vulnerable to adverse drug reactions (ADRs) because of age-related changes of pharmacokinetics, co-morbidity and drug interactions. Аmioadarone is not considered as the drug of choice in elderly patients because of the high risk of serious ADRs. Other class III drugs should be prescribed to the elderly with great caution under close monitoring of the treatment. Diltiazem and verapamil should not be used in elderly patients with NYHA class III-IV heart failure and should not be combined with β-blockers.


610-613 486

News of the European Society of Cardiology Congress (Rome, 2016) is reviewed. The results of recent randomized controlled trials, observational studies (registers) data, common problems in the presentation and interpretation of the reviewed data are discussed.



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