A Prospective Randomized, Double-Blind, Multi-Center, Phase III Clinical Trial Evaluating the Efficacy and Safety of Olmesartan/Amlodipine plus Rosuvastatin Combination Treatment in Patients with Concomitant Hypertension and Dyslipidemia: A LEISURE Study

Background: This study was a multicenter, randomized, double-blinded, placebo-controlled phase III clinical trial to investigate the efficacy and safety of an olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with concomitant hypertension and dyslipidemia. Methods: Patients with both hypertension and dyslipidemia aged 20–80 were enrolled from 36 tertiary hospitals in Korea from January 2017 to April 2018. Patients were randomized to three groups in a 1:1:0.5 ratio, olmesartan/amlodipine single pill plus rosuvastatin (olme/amlo/rosu) or olmesartan plus rosuvastatin (olme/rosu) or olmesartan/amlodipine single pill (olme/amlo) combination. The primary endpoints were change of sitting systolic blood pressure (sitSBP) from baseline in the olme/amlo/rosu vs. olme/rosu groups and the percentage change of low-density lipoprotein cholesterol (LDL-C) from baseline in the olme/amlo/rosu vs. olme/amlo groups after 8 weeks of treatment. Results: A total of 265 patients were randomized, 106 to olme/amlo/rosu, 106 to olme/rosu and 53 to olme/amlo groups. Baseline characteristics among the three groups did not differ. The mean sitSBP change was significantly larger in the olme/amlo/rosu group with −24.30 ± 12.62 mmHg (from 153.58 ± 10.90 to 129.28 ± 13.58) as compared to the olme/rosu group, −9.72 ± 16.27 mmHg (from 153.71 ± 11.10 to 144.00 ± 18.44 mmHg). The difference in change of sitSBP between the two groups was −14.62± 1.98 mmHg with significance (95% CI −18.51 to −10.73, p < 0.0001). The mean LDL-C reduced significantly in the olme/amlo/rosu group, −52.31 ± 16.63% (from 154.52 ± 30.84 to 72.72 ± 26.08 mg/dL) as compared to the olme/amlo group with no change, −2.98 ± 16.16% (from 160.42 ± 32.05 to 153.81 ± 31.57 mg/dL). Significant difference in change was found in LDL-C between the two groups with −50.10 ± 2.73% (95% CI −55.49 to −44.71, p < 0.0001). Total adverse drug reaction rates were 10.48%, 5.66% and 3.7% in the olme/amlo/rosu, olme/rosu and olme/amlo groups, respectively with no statistical significance among the three groups. Serious adverse drug reactions did not occur. Conclusions: Olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with both hypertension and dyslipidemia is effective and safe as compared to either olmesartan plus rosuvastatin or olmesartan plus amlodipine treatment.

PROSPECTS OF MELDONIUM AND FOLIC ACID USING TO IMPROVE THE CONDITION OF PATIENTS WITH ISCHEMIC HEART DISEASE AND CONCOMITANT HYPERTENSION

Coronary heart disease (CHD) is a leading cause of high mortality, disability and reduced quality of life for patients. At the heart of coronary heart disease - ischemia and activation of oxidative stress. With concomitant hypertension, the condition of patients and the prognosis for the course of their disease deteriorates significantly. The prognosis of coronary heart disease, the occurrence of new hospitalizations or deaths from cardiovascular disease can be further assessed by monitoring ST2 and malonic dialdehyde (MDA). Traditional treatment of coronary heart disease does not always guarantee the achievement of the desired clinical results. That is why it is advisable to use in the complex treatment of patients with coronary heart disease and concomitant hypertension cytoprotectors and drugs that have antioxidant properties, such as meldonium and folic acid. The aim of the research. Detect anti-ischemic activity in meldonium and folic acid and evaluate the effect of these drugs on the level of ST2, MDA in the blood in patients with coronary heart disease and concomitant hypertension. Materials and methods. The research included 80 patients (women - 4, men - 76, aged 57,7 ± 9,8 years) with diagnoses of coronary heart disease: stable angina, functional class II-III (FC), chronic heart failure (CHF) I-IIa, FC II-III ", with concomitant arterial hypertension II-III stages, 2-3 degrees, risk 4 (very high), CHF I-IIa, FC II-III". Patients were divided into 4 groups of 20 patients, respectively: 1) patients who, in addition to basic therapy, were prescribed folic acid at a dose of 0.8 mg / d for six months; 2) patients who, in addition to basic treatment, were prescribed meldonium at a dose of 750.0 mg / d for six months; 3) patients who, in addition to basic treatment, were prescribed folic acid at a dose of 0.8 mg / d and meldonium at a dose of 750.0 mg / d for six months; 4) patients who were prescribed only basic antianginal, disaggregating, hypolipidemic treatment.The number of anginal attacks and doses of nitroglycerin during the day were determined, the results of the test with a 6-minute walk and the plasma concentration of ST2 and MDA before and after 6 months of treatment with meldonium and folic acid were evaluated. Results. Found anti-ischemic activity in meldonium and its combination with folic acid. The combination of these drugs as an adjunct to basic therapy significantly reduced the concentration of ST2. Both drugs alone or in combination reduced the concentration of MDA in the blood of patients. Conclusions. Our research showed the presence of anti-ischemic activity in meldonium, both when added to the basic therapy of patients with coronary heart disease and concomitant hypertension, and when used together with folic acid. In the groups of patients where these drugs and their combinations were used, the frequency of anginal attacks and the number of doses of nitroglycerin used during the day were significantly reduced. The combined use of folic acid and meldonium when added to the basic therapy after 6 months significantly reduced the concentration of ST2 in the blood. Folic acid and meldonium showed pronounced antioxidant properties. At separate adding of these medications to basic therapy or their combined adding significantly decreased the concentration of MDA - a marker of oxidative stress. Therefore, we consider it appropriate to use folic acid and meldonium in the complex treatment of patients with coronary heart disease with stable angina and concomitant hypertension.

Influence of Meldonium on Blood Lipid Spectrum and Echocardiography Parameters in Patients with Coronary Heart Disease and or Withoutconcomitant Arterial Hypertension

Introduction. Coronary heart disease (CHD) is one of the main causes of high mortality, disability and reduced quality of life for patients in both Europe and Ukraine. Modern drug therapy of coronary heart disease in combination with arterial hypertension (AH) does not always achieve a satisfactory therapeutic effect. The use of meldonium, which has antioxidant properties, has a positive effect on NO release and has a lipid-lowering effect is promising for patients with AH. The aim of the study. To evaluate the influence of meldonium on lipid metabolism and echocardiography parameters in combination therapy in patients with CHD with stable angina and concomitant AH. Materials and methods. We examined 66 patients with CHD, stable angina pectoris II-III functional class, 40 of them with concomitant AH stage II-III. Patients were divided into 2 groups of 40 and 26 patients, respectively. The first group included patients with CHD and concomitant AH, the second - without pre-existing hypertension. Each of the groups was further divided into 2 subgroups: 1) Patients who were prescribed meldonium at a dose of 750.0 mg/d for 6 months in addition to the basic therapy of the underlying disease (n = 20 for CHD + AH and n = 14 for CHD without hypertension). 2) Patients who continued basic antianginal, disaggregating, hypolipidemic therapy (n = 20 for CHD + AH and n = 12 for CHD without hypertension). Serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol were assessed. Indicators of cardiac hemodynamics were determined by echocardiography with assessment of left ventricular end systolic and diastolic volumes and diameters (LVESV, LVEDV, LVESD, LVEDD respectively), the thickness of the interventricular septum and posterior wall of the left ventricle (IVST, LVPWT respectively), pulmonary artery pressure (PAP), LV myocardial mass (LVM) and LV myocardial mass index (LVMI). Results. The use of meldonium for 6 months in patients with CHD and concomitant AH led to a decrease in the concentration of total cholesterol from 5.07 to 4.34 mmol/l and LDL from 2.07 to 1.70 mmol/l. In the group of patients without concomitant hypertension there was a decrease in the concentration of total cholesterol from 4.80 to 3.93 mmol/l, LDL from 1.62 to 1.18 mmol/l and an increase in HDL from 1.18 to 1.37 mmol/l. At 6-month administration of meldonium as a part of combination therapy of patients with CHD with concomitant AH, there is a decrease in LVM from 216.90 g to 181.50 g and LVMI from 109.10 g/m2 up to 91.20 g/m2. In patients without concomitant hypertension, a decrease in LVM from 232,20 g to 183.90 g and LVMI from 121.50 g/m2 to 96.40 g/m2 was observed. Conclusions. Our study showed that meldonium has a positive effect on lipid metabolism and echocardiography. In the group of patients with coronary heart disease and concomitant hypertension on the background of additional use of meldonium for six months, we registered a decrease in TC, LDL and AI. LVPWT, PAP, LVM and LVMI also significantly decreased. In the group of patients with coronary heart disease without concomitant hypertension, we registered a decrease in TC, LDL, AI and an increase in HDL. LVM and LVMI also decreased significantly. Therefore, we consider it appropriate to use meldonium in the complex treatment of patients with coronary heart disease with stable angina and concomitant hypertension. Keywords: coronary heart disease, arterial hypertension, meldonium, echocardiography, blood lipid spectrum.

Beneficial Effects of Fixed-Dose Combination of Amlodipine and Atorvastatin in Patients with Concomitant Hypertension and Hypercholesterolemia: A Multi-Institutional Cohort Study

Background Blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) are important risk factors for cardiovascular (CV) diseases and treating these factors simultaneously is recommended by current guidelines but only short-term clinical results were available. The objective of this study was to examine the longer-term efficacy and safety of fixed-dose combination (FDC) versus free combination of amlodipine and atorvastatin in patients with concomitant hypertension and hypercholesterolemia. Methods Patients with hypertension and hypercholesterolemia were stratified into three groups (FDC of amlodipine 5 mg/atorvastatin 10 mg [Fixed 5/10], FDC of amlodipine 5 mg/atorvastatin 20 mg [Fixed 5/20], and free combination of amlodipine 5 mg/atorvastatin 10 mg [Free 5/10]). After inverse probability of treatment weighting, the composite CV outcome, liver function, BP, LDL-C and glycated hemoglobin (HbA1c) changes were compared. Results A total of 1,788 patients were eligible for analysis and the mean follow-up period was 1.7 year. There was no significant difference in the composite CV outcome among the three groups during the 30-month follow-up period (Fixed 5/10 6.1%, Fixed 5/20 6.3% and Free 5/10 6.0%). The LDL-C level was significantly reduced in the Fixed 5/20 group (-35.7 mg/dL) compared to the Fixed 5/10 (-23.6 mg/dL) and Free 5/10 (-10.3 mg/dL) groups (P=0.001 and <0.001, respectively). The changes in HbA1c were similar among the three groups. Conclusions FDC of amlodipine and atorvastatin, especially the regimen with higher dosage of statin, significantly reduced the mid-term LDL-C level compared to free combination in patients with concomitant hypertension and hypercholesterolemia. Blood sugar level during the follow-up period was not significantly changed by this aggressive treatment strategy.

Approaches to the treatment of exacerbation of chronic obstructive pulmonary disease with comorbid hypertension

Aim. Аnalysis of the efficacy and safety of complex therapy including fixed-dose combinations of long-acting bronchodilators (FCLB) in comorbid patients with an exacerbation of chronic obstructive pulmonary disease (COPD) of the spirometry grades III – IV and hypertension.Methods. A total of 232 patients with an exacerbation of COPD of the spirometry grades III – IV were examined. 174 (75%) patients were diagnosed with the third grade (GOLD III), 58 (25%) – with the fourth spirometry grade (GOLD IV). In the GOLD III group, a moderate exacerbation was diagnosed in 22 (12.6%), severe — in 152 (87.4%). In the GOLD IV group, a moderate exacerbation was diagnosed in 5 (8.5%), severe — in 53 (91.5%), respectively. The patients were divided into 4 groups. Group 1 included 50 patients with an exacerbation of COPD of the spirometry grades III – IV without hypertension; Group 2 – 56 patients with an exacerbation of COPD and concomitant hypertension; Group 3 – 64 patients with an exacerbation of COPD without hypertension, who received FCLB in addition to standard therapy from the 3rd day of hospitalization; Group 4 – 62 patients with an exacerbation of COPD of the spirometry grades III – IV and concomitant hypertension who received FCLB in addition to standard therapy from the 3rd day of hospitalization. The examination included clinical and instrumental methods: the changes in the clinical signs and symptoms, the dyspnea index (according to the mМRS scale), the saturation of hemoglobin with oxygen (SaO2), spirometry, heart rate variability, the frequency and nature of arrhythmias, and systolic and diastolic blood pressure (BP).Results. A sympathicotonic disorder of the autonomic balance was revealed in patients with exacerbation of COPD of the spirometry grades III – IV. This tendency intensified in the patients with concomitant hypertension, which indicated an additional negative effect of comorbid hypertension on the studied parameters. Aggravation of sympathicotonia could be a trigger for an increase in ectopic rhythm disturbances, including high-grade ventricular extrasystoles. In the groups with concomitant hypertension, rhythm disturbances were more frequent (p < 0.05). The inclusion of FCLB in the complex therapy of exacerbation of COPD of the spirometry grades III – IV made it possible to improve the condition of patients significantly: to reduce the dyspnea index on the mМRS scale, increase SaО2 and FEV1 (p < 0.05), achieve clinical improvement in COPD faster and shorten the hospitalization period. As a result of the rapid and effective relief of exacerbation of COPD, the influence of pathogenic factors on the cardiovascular system in the examined patients decreased. The addition of FCLB to the treatment COPD with and without comorbid hypertension did not have a negative effect on heart rate variability, did not aggravate rhythm disturbances, and did not destabilize the BP.Conclusion. The positive clinical effects of the inclusion of FCLB in the complex therapy of exacerbation of COPD of the spirometry grades III – IV in patients with comorbid hypertension led to a decrease in shortness of breath, an improvement in respiratory functions, a decrease in tissue hypoxia and eliminated possible adverse events of this group of drugs.

AB0224 SUSTAINABLE LOW DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS: REAL-WORLD EXPERIENCE WITH TOCILIZUMAB

Background:Sustainability, the ability of drugs to maintain remission or low disease activity (LDA) in patients with rheumatoid arthritis (RA), plays a crucial role for the prevention of structural damage to joints and thus, preserving patients’ functional capacity, health-related quality of life and general sense of well-being. Therefore, studying the sustainable effectiveness of tocilizumab (TCZ) as a monotherapy or combined with methotrexate (MTX) is important (1).Objectives:We aimed to examine to what extend TCZ, alone or combined with MTX, could achieve and further sustain LDA in patients with long-standing RA in the light of current, strictly index-based definitions of LDA and to compare the two versions of DAS28 in patients in real clinical practiceMethods:85 RA patients treated with TCZ for at least eighteen months were consecutively enrolled in the present single-center, retrospective cohort study. All participants met the 1987 ACR classification criteria and attended the rheumatology department of University Hospital “St. Marina” Varna in an outpatient setting. Patients receiving pre-filled syringe contained 162 mg TCZ once weekly subcutaneously. Real-world data were extracted and analyzed from patient’s full medical file. For each visit, disease activity score 28 with ESR and CRP (DAS28-ESR and DAS28-CRP) and simple disease activity index (SDAI) were calculated simultaneously according to generally adopted formulas. A twelve-month result was determined for sustained LDA at each of the patient’s three visits (at 6-month intervals), according to DAS28 and SDAI. Descriptive statistics, Chi square test, Cochran´s Q test, kappa statistic were used, a binary logistics model was compiled to study the impact. Significance level of p <0.05.Results:Two hundred fifty-five patient visits were analyzed. The mean durations of RA and treatment with TCZ were 12.6 (±9.6) years and 3.64 (±1.8) years, respectively. The mean age of patients was 60.3 years (37-87 years), 80% were women, 24.7% were obese, 65.9% have concomitant hypertension. 61.2% of patients are treated with combination therapy TCZ with MTX.Of all patients, these with a sustained 12-month LDA were 41.2%, 28.2% or 23.5% depending on the studied index (DAS28-CRP, SDAI, or DAS28-ESR, respectively).A 12-month SDAI LDA was found in a significantly small proportion of patients (28.2%, p = 0.001). The DAS28 ESR determined a proportion similar to SDAI (23.5%, p> 0.05), while according to the DAS28 CRP, patients with a sustained 12-month LDA were significantly more (41.2% p = 0.005). A moderate level of agreement was found between the assessments of SDAI and the two variants of DAC28 when determining 12-month results of Tocilizumab treatment (DAS28-ESR k = 0.511, p <0.001 and DAC28-CRP k = 0.618, p <0.001). No relationship was found between the combination of TCZ with MTX and the patients’ chance of a sustained 12-month LDA, regardless of which index the result was measured.Patients with hypertension were significantly less likely to have sustained 12-month LDA according to SDAI and DAS 28 ESR (OR 0.135, 95% CI 0.048-0.386; OR 0.313, 95% CI 0.111-0.882, respectively), but not according to DAS28 CRP.Conclusion:Sustained 12- month LDA with TCZ in patients with long-term RA remains uncommon in daily clinical practice. Co-administration of MTX is not associated with an increased likelihood of achieving a sustained LDA in the analysis of long-term responses. Patients with concomitant hypertension are less likely to be in a sustained 12-month LDA, according to SDAI and DAS28-ESR. The results according to DAS28 ESR, but not according to DAS28CRP are comparable to those of SDAI when measuring long-term results of treatment with TCZ.References:[1]Hamann PDH, Pauling JD, McHugh N, Shaddick G, Hyrich K; BSRBR-RA Contributors Group. Predictors, demographics and frequency of sustained remission and low disease activity in anti-tumour necrosis factor-treated rheumatoid arthritis patients. Rheumatology (Oxford). 2019 Dec 1;58(12):2162-2169.Disclosure of Interests:None declared

Cesarean Section in a COVID-19 Positive Patient with Takayasu Arteritis: A Case Report

Takayasu arteritis is an idiopathic, granulomatous aorto-arteritis that usually affcts young or middle-aged women. The anesthetic management of patients with Takayasu arteritis undergoing cesarean section with COVID-19 is challenging. Patients may have concomitant hypertension, tissue hypoperfusion with the potential for major perioperative cardiovascular complications. The challenges increase considerably in resource-limited settings. We report the case of a 27-year-old primigravida at 39 weeks of gestation with concomitant Takayasu arteritis, chronic hypertension, hypothyroidism, and COVID-19, who underwent an elective cesarean section at our hospital. She incidentally tested positive for SARS-CoV-2 after admission to the hospital. The cesarean section was successfully performed under subarachnoid block. We are not aware of any previous publication describing the anesthetic management in patients with Takayasu arteritis and COVID-19 undergoing cesarean section.