Rational Pharmacotherapy in Cardiology

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Vol 11, No 4 (2015)
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344-354 848

Aim. Carriership of CYP2C19*2 allelic variant and reduced CYP3A4 activity can affect the formation of clopidogrel’s active metabolite and, respectively, its antiplatelet effect. We sought to determine the impact of CYP3A4 isoenzyme activity and CYP2C19 polymorphisms on platelet aggregation.

Material and methods. The study included 81 patients with acute coronary syndrome (ACS) and subsequent percutaneous coronary intervention (PCI): 64 males and 17 females, mean age 63.9±10.9 years. CYP2C19 allelic variants were detected by the method of real-time polymerase chain reaction. CYP3A4 isoenzyme activity was estimated by urinary 6-β-hydroxycortisol/free cortisol ratio (6-OHC/FC) using the method of high-performance liquid chromatography. Platelet functional activity was evaluated by a portative aggregometer - the VerifyNow P2Y12 assay.

Results. Logistic regression analysis has demonstrated significantly increased risk of clopidogrel resistance in patients-carriers of the CYP2C19*2 polymorphism (p=0.022). CYP2C19*2 non-carriers had significantly higher mean platelet inhibition percentage as compared with the carriers of this allele: 30.7±20.1 in the CYP2C19*1/*1 group vs 18.2±16.4 in the CYP2C19*1/*2 one (р=0.03). Clopidogrel laboratory resistance (P2Y12 Reaction Units (PRU)>208) was found out to be higher in the CYP2C19*2-carriers as compared with non-carriers: 53.8% in the patients with the CYP2C19*1/*2 genotype and 16.2% in subjects with the CYP2C19*1/*1 genotype (odds ratio [OR]=1.8; 95% confidence interval [95% CI]: 1.0–3.2; р=0.0067). Linear regression analysis has revealed that smaller mean diameter of stent slightly reduces the risk of clopidogrel resistance development. No significant distinctions in urinary 6-OHC/FC ratios (the marker of CYP3A4 activity) were observed: 3.4±2.8 in the PRU>208 group and 3.2±3.0 in the PRU<208 group (p=0.8). Besides, no significant correlation between platelet activity and the 6-OHC/FC ratio was found (р=0.84).

Conclusion. CYP2C19*2-carriership in ACS patients undergoing PCI significantly increases the risk of clopidogrel laboratory resistance. The urinary 6-OHC/FC ratio (as a marker of CYP3A4 isoenzyme activity) does not correlate with platelett functional activity.

355-358 535

Aspects of comorbidity in patients with chronic heart failure are discussed. A focus on hyperuricemia, its effect on the course and prognosis in patients with heart failure, as well as the possibility of its medical correction are maintained.

359-364 1004

Dual antiplatelet therapy, including clopidogrel and aspirin, in a significant share of patients after acute coronary syndrome (ACS) is characterized by high level of platelet reactivity, which is associated with an increased incidence of cardiovascular events. Perhaps it will make reasonable the prescription of new antiplatelet drugs, particularly the combination of ticagrelor with aspirin.

Aim. To assess the cost-effectiveness of VerifyNow P2Y12 platelet reactivity testing in patients after ACS.

Material and methods. The analysis was performed for patients aged 55 years after ACS by modeling based on the results of the PLATO trial considering Russian epidemiological data. The time horizon of simulation was 5 years. It was assumed that the patients were receiving either generic clopidogrel or ticagrelor for 1 year, or before maintenance treatment VerifyNow P2Y12 assay had been performed, and the patients with platelet reactivity index >230 24-48 hours after ACS were receiving ticagrelor and the remaining patients - generic clopidogrel. It was expected that after 1 year the patients would discontinue treatment with clopidogrel or ticagrelor, and hereafter additional therapeutic effect of their use would be absent. The costs of antiplatelet agents in the reference case corresponded to the weighted average price of public procurement in 2013 in Russia. The costs of treatment of complications corresponded to the compulsory health insurance rates for St. Petersburg in 2014. The cost and life expectancy were discounted at 3.5% per year.

Results. The platelet reactivity test and the prescription by its results of the combination of clopidogrel plus aspirin or ticagrelor plus aspirin can prevent 5 myocardial infarction and 6 deaths per 1000 patients additionally as compared with the prescription of clopidogrel plus aspirin combination to all patients. The costs for one additional year of life as compared with the combination of clopidogrel plus aspirin were 376.5 and 373.2 thousand rubles, respectively, the costs for one additional quality adjusted life year (QALY) were 433.8 and 509.8 thousand rubles, respectively. The total predictive value of costs per 1 patient with ACS using the test was 32% lower than in the routine use of ticagrelor in all patients.

Conclusion. Assessment of platelets reactivity using VerifyNow P2Y12 assay in patients with ACS and modification of antithrombotic therapy in accordance with the received data can be considered as a cost-effective intervention which can reduce treatment costs as compared with the routine use of new antithrombotic drugs.

365-370 484

Aim. To study the changes of plasma levels of NT-proBNP and NT-proANP in patients with persistent atrial fibrillation (AF) treated with various antiarrhythmic drugs.

Material and methods. Patients with persistent AF (n=123) aged 39-83 years old were included into the study. The patients were divided into 2 groups: group 1 included patients with arterial hypertension (n=61), group 2 - patients with ischemic heart disease (IHD; n=62). After sinus rhythm restoration the patients were divided into 4 subgroups. Patients of 1A subgroup used propafenone to maintain sinus rhythm during the next 6 months, while patients of 2A subgroup used amiodarone. Patients of 1B and 2B subgroups used bisoprolol to control ventricular rate. Plasma natriuretic peptide levels were evaluated in all patients during the first 3 days after the sinus rhythm restoration and 6 months after.

Results. Increased levels of NT-proBNP and NT-proANP in the first days after the sinus rhythm restoration were found in patients of both groups and were associated with the episode of AF. After 6 months of treatment the reduction of NT-proBNP and NT-proANP levels was found in patients of 1A subgroup (NT-proBNP: from 160.5±15.2 pg/ml to 130.1±12.2 pg/ml; NT-proANP: from 15.3±6.4 nmol/L to 11.5±5.3 nmol/L, p<0.05 for both) and of 2A subgroup (NT-proBNP: from 180.2±12.7 to 120.6±10.9 pg/ml; NT-proANP: from 17.1±7.1 to 11.8±7.2 nmol/L, p<0.05 for both). NT-proBNP and NT-proANP levels were decreasing consistently both in hypertensive patients receiving propafenone and in IHD patients taking amiodarone. No significant changes in NT-proBNP and NT-proANP levels were found in patient of subgroups 1B and 2B during the follow-up.

Conclusion. Increased plasma levels of NT-proBNP and NT-proANP were found in the first days after the restoration of sinus rhythm in patients with persistent AF, and after 6 months of sinus rhythm maintenance these levels reduced significantly.

371-379 525

Aim. To study the possibilities of using multi-channel volume sphygmography (MCVS) in prophylactic medical examination of the population.

Material and methods. Simultaneous examination of 522 individuals older than 18 years was performed. Along with standard procedures provided by the prophylactic medical examination program synchronous registration of blood pressure (BP) on four extremities by MCVS was performed. At that a difference in systolic BP between arms (ΔSBParm) and legs (ΔSBPleg) and ankle-brachial index (ABI) were automatically calculated. Values of │ΔSBParm│ or │ΔSBPleg│≥15 mm Hg or ABI≤0.9 were considered as markers of atherosclerotic vascular disease.

Results. Signs of peripheral arterial atherosclerotic lesions among patients ≥40 years old were found in 14.7% of the cases (95% confidence interval [CI] 11.7-18.4). Relative risks of atherosclerotic lesions in arteries increase 1.71-fold (95% CI 1.06-2.74) in arterial hypertension, 1.70-fold (95% CI 1.08-2.68) – in obesity, 1.91 fold (95% CI 1.17-3.12) – in diabetes, as well as with the increasing levels of cardiovascular risk. In patients with ischemic heart disease and a history of cerebral stroke MCVS can detect signs of multifocal atherosclerosis in 21% (95% CI 14-32) and 22% (95% CI 9-46) of the cases, respectively.

Conclusion. MCVS with the determination of ΔSBParm, ΔSBPleg and ABI may be regarded as the basis for low-cost and efficient system of cardioangiological screening.


380-384 580

Cardiovascular diseases remain the most common cause of death in Russia. In real clinical practice doctors are more focused on the modification of other major risk factors rather than on the correction of dyslipidemia, or pay more attention to secondary prevention of cardiovascular diseases.

Aim. To analyze the incidence of severe dyslipidemia (total cholesterol >9 mmol/l), clinical signs of atherosclerosis at its presence and the adequacy of hypolipidemic treatment according to the data of multi-field medical hospital.

Material and methods. We have analyzed 28225 medical charts of patients undergoing treatment in Therapeutic Departments of Petrozavodsk urgent care hospital for the years from 2001 to 2012.

Results. The incidence of severe dyslipidemia (total cholesterol >9 mmol/l) was 1.59%. The most frequent nonlipid risk factor for ischemic heart disease was arterial hypertension (was diagnosed in 85% of patients). The main clinical manifestation of atherosclerosis was ischemic heart disease (it was diagnosed in 79.3%), 48.9% of patients had a history of acute myocardial infarction, 28.9% - of stroke. In patients with severe dyslipidemia (total cholesterol >9 mmol/l) the frequency of statins prescription in 2009-2012 was 70%. In 28.9% of the patients the target levels of total cholesterol and low-density lipoprotein were obtained. High doses of statins were prescribed rarely.

Conclusion. There is a serious therapeutic problem related to the insufficient attention of doctors to examination and treatment of patients with newly-diagnosed severe dyslipidemia, especially when the primary disease is not a cardiovascular one.

385-390 480

Aim. To study the differences in views on treatment among patients with cardiovascular diseases in state and private outpatient clinics, as well as the motivation for choosing one of these outpatient clinics.

Material and methods. Anonymous and voluntary survey of cardiology patients (n=90) in 2 state (57.7%) and 3 private outpatient clinics (42.2%) was conducted in Saratov.

Results. 33.3% of respondents were men; the median age was 65 years. Patients of state outpatient clinics were more likely to have retirement age (p=0.0008), low income (p=0.0006), history of hypertensive crises (p=0.0129) and chronic heart failure (p=0.0001). Patients of private outpatient clinics were more likely to have mental work (p=0.0001), higher education (p=0.0001), moderate income (p=0.0006). The difference in views on the disease and the attitude towards a doctor among patients of state and private clinics was shown.

Conclusion. Patients of private outpatient clinics were more active, young, aimed at continuation of life. They are more likely to have higher education, mental work and moderate income. Patients of state outpatient clinics are "infatuated with their illness"; it is their “lifestyle”. Paternalistic model of communication with doctors is expressed in all the patients.


391-397 680

Aim. To reveal cognitive deficit after coronary artery bypass, the influence of citicoline, piribedil on the state of higher cerebral functions in the early and late periods after surgery.

Material and methods. The study included 94 patients with ischemic heart disease. All patients were divided into 3 groups. Patients of the first group (n=30) were prescribed citicoline as a cerebral neuroprotective drug. Patients of the second group (n=32) had piribedil in addition to standard therapy. Patients of the control group (n=32) had only a standard treatment without any neuroprotective drugs. All patients underwent coronary artery bypass surgery. The cognitive function was assessed before, 10 days after and six months after coronary artery bypass.

Results. Patients of group 1 and 2 had achieved pre-surgical levels of cognitive tests results 6 months after coronary artery bypass. The control group had achieved initial levels only in three tests: visual memory (immediate simulation; p=0.008), categorical association (p=0.002), clock drawing test (Wilcoxon test; p=0,005), while other indices were reduced in comparison with the initial ones.

Conclusion. The obtained results allow considering the studied drugs as a protectors of cognitive function after surgery. Randomized controlled double-blind studies on large samples are needed to confirm these results.

398-403 548

Aim. To study the effect of «treat-to-target» antirheumatic therapy on diastolic dysfunction of the left (DDLV) and right (DDLV) ventricles in patients with early rheumatoid arthritis (RA) during 18 months of observation.

Material and methods. The study included patients with early RA (n=66; 71% women; age - 56 [46; 61] years) with moderate/high activity (DAS28 5.3 [5.0; 6.2]), seropositive on rheumatoid factor (77%) and/or cyclic citrullinated peptide antibodies (100%), disease modifying anti-rheumatic drugs (DMARD) and glucocorticoids naive. Treatment with methotrexate (MTX) with the escalation of the dose up to 25-30 mg/week subcutaneously was initiated in all the patients. After 3 months in 47 (71%) patients biologics were added to MTX due to its inefficiency. In 18 months remission of RA was achieved in 44% of the patients. 51 (77%) patients had a cardioprotective therapy. The target blood pressure (BP) level was achieved in 38 (58%) patients. Evaluation of traditional cardiovascular risk factors, 24-hour BP monitoring and echocardiography were performed in all patients initially and in 18 months of MTX/MTX + biologics use.

Results. After 18 months DDLV incidence decreased by 7% (from 49% to 42%; p>0.05) and DDRV incidence decreased by 5% (from 24% to 17%; p>0.05). A more significant decrease in DDLV incidence [from 23 (62%) to 18 (49%)] and of DDRV incidence (from 12 (32%) to 6 (16%)] (р=0.05), was found in MTX + biologics group than in MTX only group [DDLV incidence remained unchanged - 7 (28%), and DDRV incidence increased from 3(12%) to 4 (16%); p>0.05]. The normalization of left ventricle (LV) diastolic function in early RA patients depended primarily on the efficacy of antihypertensive treatment, and of right ventricle (RV) diastolic function - on the achievement of target BP level and RA remission. Reduced erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) plasma levels were associated with the improved LV diastolic function [E/A LV and ΔESR (r=-0,3; p<0,04), E/A LV and CRP (r=-0,2; p<0.05), A LV and ESR (r=0.3; p<0.01)] and improved RV diastolic function [ΔA RV and ΔCRP (r=0.4; p<0.003), ΔE RV and ΔCRP (r=0.3; p<0.01), E/A RV and DAS28 (r=-0.5; p<0.001), E/A RV and CRP (r=-0,3; p<0.05)] by the 18th month of the study.

Conclusion. In early RA patients after 18 months the downward trend of DDLV incidence and a significant reduction of DDRV incidence were found, more expressed in patients treated with MTX + biologics. The achievement of RA remission and target BP level is a prerequisite for the normalization of LV and RV diastolic function and slowing the progression of heart failure.


404-412 494

Change of the status of innovative technologies depending on the received evidences is considered. Examples reflecting the initiation of interest in the new technology of treatment, the transition from innovation to standard therapies, as well as the weakening of interest in the previously introduced technology due to disappointing results of clinical trials on evaluation of its effectiveness are presented.


413-419 488

Today the role of disturbances in sleep duration in the development of various chronic diseases, including cardiovascular diseases is known and proven. In addition, the results of many clinical studies demonstrate the relationship between impaired sleep duration and the rate of telomere shortening. In turn, short telomeres are associated with the development of arterial hypertension, chronic heart failure, atherosclerosis and other diseases with high mortality both in Russia and worldwide. This article presents an overview of the clinical studies demonstrating the negative effect of sleep duration disturbances on total and cardiovascular mortality, as well as works that specify in detail the relation between sleep duration and telomere length.

420-425 505

Relationships of pharmaceutical industry with medical science and practice are analyzed. The influence of pharmaceutical industry on clinical trials, journal publications, governmental organizations, physicians and researchers is discussed.

426-430 510

Heart rate variability (HRV) in patients with ischemic heart disease, a life-threatening heart rhythm disorders, as well as diabetes mellitus (DM) is considered. A significant association between the autonomic regulation of the cardiovascular system and death from cardiovascular causes is identified. The reactions of the autonomic nervous system (ANS) can serve as a precipitating factor of arrhythmias in patients with heart disorders. Analysis of HRV at rest is the main and informative method for determination of the ANS disorders. HRV decreases greatly in patients with acute myocardial infarction, cardiac arrhythmia, and DM, predicting a high risk of death. The leading cause of death in diabetic patients is cardiac autonomic neuropathy, with the development of "silent" ischemia and painless myocardial infarction. Autonomic regulation of the heart rate should be assessed for early diagnosis and prevention of complications in the form of sudden death.


431-437 548

Issues of pathogenesis of the calcified aortic stenosis and ischemic heart disease in the elderly are considered. The relevance of early detection of angina, syncope, and dyspnea in view of their non-specific and subclinical course for early detection of heart disease is specified. Current scientific views on the myocardial bioenergy and its role in the genesis of chronic heart failure are presented. Particular attention is paid to the place of cytoprotectors, especially trimetazidine, in the management of patients with cardiac N.Yu. Karpova1diseases.


438-439 274

To sow reasonable, kind, eternal.

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