Fixed-dose Combination In Patients Research Articles

Clinical effectiveness of amlodipine/indapamide/perindopril fixed-dose combination in patients with metabolic disorders: results of post hoc analyzes of the TRICOLOR study

Aim. To describe antihypertensive effectiveness of triple fixed-dose combination of am lo dipine/indapamide/perindopril and assess predictors of its clinical effectiveness in pati ents depending on body mass index (BMI) and presence of type 2 diabetes (T2D).Material and methods. This observational prospective study TRICOLOR (NCT03722524) (n=1247) demonstrated high antihypertensive effectiveness and good tolerability of amlodipine/indapamide/perindopril fixed-dose combination. Subgroup analyzes based on BMI included data from 1144 patients. In a second subgroup analysis, 1128 patients were stratified according to concomitant T2D.Results. In patients with overweight/obesity and diabetes, good antihypertensive effectiveness of amlodipine/indapamide/perindopril was observed, comparable in blood pressure (BP) reduction with the comparison groups (patients with normal BMI and patients without diabetes). At the same time, patients with normal BMI, compared with patients with overweight and obesity, had significantly lower systolic BP (SBP) (after 4 and 12 weeks) and diastolic BP (DBP) (after 2 and 12 weeks). In the subgroups, depending on the diabetes status, there were no significant differences in the decrease in SBP and DBP levels at all follow-up points. By the 12th week, BP decrease in the group of patients with normal BMI was 32,9 (10,5)/15,3 (8,6) mm Hg, in the group with overweight — 33,2 (11,3)/14,2 (8,5) mm Hg, in the obesity group — 33,9 (12,3)/14,1 (8,8) mm Hg (p>0,05 for intergroup comparison). Target BP <140/90 mm Hg already after 2 weeks of therapy achieved a higher number of patients with a normal BMI compared to overweight group (50,8% vs 37,2%, p=0,009). By the 12th week, the vast majority of patients, regardless of BMI and diabetes status, achieved a target BP <140/90 mm Hg, which demonstrates a good and rapid response to triple fixed-dose therapy.Conclusion. Thus, additional analyzes of the TRICOLOR study demonstrate the high antihypertensive effectiveness of amlodipine/indapamide/perindopril in hypertensive patients, regardless of the presence of diabetes, overweight or obesity.

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study.

Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25mg t.i.d. for 8weeks, Trazo/Gaba 5/50mg t.i.d. for 8weeks, Trazo/Gaba 10/100mg t.i.d. for 8weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25mg, 38 in Trazo/Gaba 5/50mg, 37 in Trazo/Gaba 10/100mg, 83 in PLB, and 43 in Gaba. After 8weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8weeks of treatment: Trazo/Gaba 2.5/25mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25mg showed a statistically significant difference to PLB after 6weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25mg t.i.d. showed statistically significant improvement of pain and other scores after 6weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. NCT03749642.

Comparative cardiovascular safety of LABA/LAMA FDC versus LABA/ICS FDC in patients with chronic obstructive pulmonary disease: a population-based cohort study with a target trial emulation framework

BackgroundUse of combinations of long-acting β2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant.AimThe present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies.MethodsWe identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017–2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS).ResultsAmong 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78–1.01) for the composite events, 0.80 (95% CI, 0.61–1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68–3.25) for unstable angina, 1.00 (95% CI, 0.80–1.24) for congestive heart failure, 0.62 (95% CI, 0.37–1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66–1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses.ConclusionOur findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD.

Cost-Effectiveness Analysis of Fixed-Dose Tiotropium/Olodaterol versus Tiotropium for COPD Patients in China.

Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China. A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis. TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by $2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses. Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.

Navafenterol for chronic obstructive pulmonary disease therapy

ABSTRACT Introduction Chronic obstructive pulmonary disease (COPD) is a prevalent disease of the airways in which inhaled bronchodilators can be given as monotherapy or fixed dose combination, in order to better control disease symptoms and to reduce its morbidity. A novel bronchodilator approach is represented by bifunctional molecules such as navafenterol, which exert dual synergic bronchodilator effects as a monotherapy. Navafenterol is currently being investigated for COPD. Areas covered This review summarizes the preclinical data regarding navafenterol synthesis and in vitro and in vivo testing. Clinical data coming from phase I and II studies are also discussed. Navafenterol was found to improve lung function, dyspnea, and cough severity and was well tolerated, and its effect was comparable with that of fixed-dose combinations in patients with moderate-to-severe COPD. Expert opinion Despite clinical evidence of efficacy for navafenterol is still limited, the existing data prompts further clinical evaluation and also consideration of other inhalation approaches such as pressure metered-dose inhalers (pMDIs) or nebulization. Other interesting approach would be combination with another bifunctional molecule such as ensifentrine.

Metformin Sustained-Release and Vildagliptin Fixed-Dose Combination for Optimizing Glycemic Control: A Review with Real-World Case Reports

(1) Background: There is a high burden of poor glycemic control in the Indian population with type 2 diabetes mellitus (T2DM). Currently, the use of metformin sustained-release (SR)–vildagliptin fixed-dose combination (FDC) is very low as compared to metformin immediate-release (IR)–vildagliptin FDC which is associated with higher adverse events (AEs). Here, we present real-world effectiveness of metformin SR–vildagliptin FDC treatment in patients with T2DM; (2) Methods: This retrospective analysis was carried out from the medical records of adult T2DM patients visiting a single study center in India (December 2020–February 2021). A total of 10 patients (aged ≥20 years) were treated with vildagliptin 50 mg and metformin SR 500 mg FDC for 15 days. The treatment response was assessed by the percentage of time spent in the target glucose range (TIR at baseline and 15 days after treatment); (3) Results: The glycated hemoglobin (HbA1c) levels at baseline varied between 6.5% to 12%. The glycemic control improved in 70% of patients (mean increase in TIR: 18.9%). Treatment adherence was 100%. No gastrointestinal symptoms or AEs were reported; (4) Conclusions: Early intervention with metformin SR–vildagliptin FDC in patients with T2DM can ensure therapy compliance in terms of superior efficacy along with safety and tolerability. Key summary points: Early initiation of combination therapy helps in early achievement of glycemic goals; Early initiation of metformin and vildagliptin FDC results in significant glycemic control with good tolerability and compliance; Metformin SR–vildagliptin FDC has lower adverse events, compared to metformin IR–vildagliptin FDC; A case series of ten patients with T2DM treated with metformin SR–vildagliptin FDC is presented to assess the real-world effectiveness of this combination.

Differences in Pulmonary Function Improvement after Once-Daily LABA/LAMA Fixed-Dose Combinations in Patients with COPD.

This real-world study evaluated the efficacy of once-daily long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for improving lung function in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD who were treated with once-daily LABA/LAMA FDCs for 12 months were included. We evaluated their lung function improvement after 12 months of treatment with different LABA/LAMA FDCs. A total of 198 patients with COPD who were treated with once-daily LABA/LAMA FDCs were analyzed. A total of 114 patients were treated with umeclidinium/vilanterol (UMEC/VIL); 34 patients were treated with indacaterol/glycopyrronium (IND/GLY); and 50 patients were treated with tiotropium/olodaterol (TIO/OLO). The forced expiratory volume in 1 s (FEV1) was significantly increased in the patients treated with all three once-daily FDCs (55.2% to 60.9%, p = 0.012 for UMEC/VIL, 58.2% to 63.6%, p = 0.023 for IND/GLY, and 54.1% to 57.7%, p = 0.009 for TIO/OLO). The treatment of COPD patients with TIO/OLO resulted in a significant improvement in both forced vital capacity (FVC%) (71.7% to 77.9%, p = 0.009) and residual volume (RV%) (180.1% to 152.5%, p < 0.01) compared with those treated with UMEC/VIL (FVC%: 75.1% to 81.5%, p < 0.001; RV%:173.8% to 165.2%, p = 0.231) or IND/GLY (FVC%: 73.9% to 79.3%, p = 0.08; RV%:176.8% to 168.3%, p = 0.589). Patients treated with UMEC/VIL or TIO/OLO showed significant improvement in FVC. In addition, those receiving TIO/OLO also showed significant improvement in RV reduction.

Hyperuricemia as a risk factor for cardiovascular events in hypertensive patients

Hypertension (HTN) remains one of the most important risk factors for cardiovascular events. Modification of additional risk factors, along with a blood pressure decrease, significantly affects the risk of cardiovascular events. Hyperuricemia is one of the new factors that has a high prevalence in the population and affects the risk for cardiovascular events in hypertensive patients. In the treatment with fixed-dose combinations in patients with hypertension and hyperuricemia, metabolic neutrality is of particular importance. When prescribing diuretics, the practitioner faces additional difficulties. These drugs are highly synergistic when added to other major antihypertensives’ classes, but, in some cases, may worsen the metabolic profile. The use of the thiazide-like diuretic indapamide largely avoids a negative effect on the metabolic profile, making it the preferred choice for patients with hyperuricemia.

Effectiveness of triple fixed-dose combination in patients with inadequate blood pressure control

Aim. In routine clinical practice, to evaluate the antihypertensive efficacy, 24-hour blood pressure (BP) control, tolerability and effect on arterial stiffness of the triple fixed-dose combination (FDC) of amlodipine/indapamide/perindopril according to office and 24-hour ambulatory BP monitoring (ABPM) in patients with uncontrolled hypertension (HTN) using previous therapy.Material and methods. The study included 78 both sex outpatients over 18 years of age with essential HTN. The main inclusion criterion was HTN with inadequate BP control against the background of previous combination therapy including amlodipine, indapamide and perindopril as part of free- or fixed-dose combinations of antihypertensive drugs. All patients were prescribed triple FDC of amlodipine/ indapamide/perindopril (Triplixam) in accordance with the medication instruc tions. The patient’s condition was assessed during four follow-up visits: visit 1 — inclu- sion visit, visit 2 — after 4 weeks, visit 3 — after 12 weeks, visit 4 — after 24 weeks. At each visit, achievement of the target BP levels &lt;140/90 mm Hg and &lt;130/80 mm Hg was assessed, as well as the 24-hour BP profile. The dynamics of BP decrease, achievement of target BP values, 24-hour BP profile, and the effect of therapy on arterial stiffness according to ABPM were also assessed.Results. In the analyzed group of patients, the initial office BP was 160,8± 10,3/91,5±8,1 mm Hg. After 24 weeks, there was a significant BP decrease to 121,3±3,5/73,6±4,2 mm Hg (p&lt;0,001). According to ABPM, an average daytime BP significantly (p&lt;0,001) decreased from 153,9±9,04/8,38±9,18 to 120,3±4,7/73,4±4,7 mm Hg after 24 weeks of amlodipine/indapamide/perindopril FDC therapy. Similar patterns were also found for the average values of nighttime BP. Target BP &lt;140/90 mm Hg after 4 weeks reached the majority (87,2%) of patients, and after 12 weeks, the proportion of pa tients who reached the target BP was 100%.Conclusion. In hypertensive patients with previous ineffective multiagent therapy, the triple FDC of amlodipine/indapamide/perindopril (Triplixam) provided high antihypertensive efficacy, good tolerability and adherence to therapy, and also demonstrated additional organ protection.

A randomized controlled trial of long-acting muscarinic antagonist and long-acting \u03b22 agonist fixed-dose combinations in patients with chronic obstructive pulmonary disease

BackgroundIn chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs—glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)—in patients with COPD.MethodsWe enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).ResultsNo significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.ConclusionsThe three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported.Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Triple fixed-dose combination in the treatment of hypertension: the results of the Russian observational study TRICOLOR

The article presents the main results of the Russian post-marketing multicenter open-label program TRICOLOR (Triple fixed-dose combination in the treatment of hypertension).Aim.To evaluate the antihypertensive efficacy and tolerability of the triple amlodipine/indapamide/perindopril fixed-dose combination, as well as the adherence of hypertensive (HTN) patients to this therapy in actual clinical practice.Material and methods.The program enrolled 1247 outpatients aged 18 to 79 of both sexes with essential HTN. All patients included in the study receive amlodipine/ indapamide/perindopril fixed-dose combination. The patient’s condition was assessed according to four visits: visit 1 — at inclusion, visit 2 — after 2 weeks, visit 3 — after 4 weeks, visit 4 — after 12 weeks of follow-up. At each visit, the achievement of the target blood pressure (BP) &lt;140/90 mm Hg and &lt;130/80 mm Hg. At enrollment and visit 4, quality of life was analyzed using the SF-36 questionnaire and adherence to therapy using a validated 6-question questionnaire.Results. After 12 weeks, a significant decrease in systolic and diastolic BP was recorded — by 33,5 and 14,3 mm Hg, respectively (p&lt;0,001). Target BP &lt;140/90 mm Hg after 12-week follow-up was achieved by the overwhelming majority (93,4%) of patients. After 12 weeks, the proportion of patients with good medical adherence increased from 18,8% to 49,0%, while the proportion of patients with low adherence, on the contrary, decreased from 46,3% to 5,1%.Conclusion.The results of the TRICOLOR program demonstrate a high antihypertensive efficacy, good tolerance and medical adherence of triple amlodipine/indapamide/perindopril fixed-dose combination in patients with essential HTN in actual clinical practice in Russia.

Antihypertensive polytherapy in Australia: prevalence of inappropriate combinations, 2013-2018.

To estimate the prevalence of inappropriate antihypertensive polytherapy in Australia. We used a nationally representative 10% sample of Pharmaceutical Benefits Scheme (PBS) eligible Australians and their dispensing history to identify people aged 18+ years exposed to at least one PBS-listed antihypertensive between 2012 and 2018. We measured prevalence of antihypertensive polypharmacy (≥40 days concomitant exposure), inappropriate antihypertensive combinations (against guideline recommendations; within-class polytherapy) and combinations to be used with caution. Almost half (47.5%) of people using antihypertensives in 2018 experienced polytherapy. Among these, 2.4% had an inappropriate combination (1.5% against guidelines; 1.0% within-class polytherapy). Inappropriate combinations were more prevalent in people experiencing polytherapy with three (3.7%) or four (16.1%) antihypertensive medicines than people on dual therapy (0.7%). Inappropriate combinations occurred at a lower rate in people using fixed-dose rather than free-drug combinations for dual therapy (0 vs. 0.7%) and in those using three antihypertensives (2.4 vs. 7.3%); this was not the case for people using four or more antihypertensives (15.5 vs. 16.1%). Between 2013 and 2018, the prevalence of antihypertensive polytherapy was relatively stable (49-47%); however, the prevalence of inappropriate combinations among these patients halved (from 5.1 to 2.4%). Antihypertensive polytherapy in Australia is common, but the prevalence of inappropriate combinations is low and decreasing over time, suggesting strong awareness of Australian clinical guidelines. However, in 2018, approximately 49 000 Australian adults experienced inappropriate polytherapy; prescribing of fixed-dose combinations in patients on dual or triple therapy may further reduce this inappropriate care, although increased vigilance treating patients with more than 3 antihypertensives is required.

Resistant arterial hypertension: clinical and pathogenetic peculiarities and predictors of therapy effectiveness

The aim – to evaluate the features of the target organs damage, neurohumoral and proinflammatory status and to determine the predictors of the effectiveness of antihypertensive therapy in patients with resistant arterial hypertension (RAH).Materials and methods. The study included 257 patients with apparent RAH. The secondary hypertension was revealed in 8.5 % of patients. After 3 months therapy with triple fixed-dose combination (FDC) of antihypertensive drugs in maximum tolerated doses, patients were distributed into two groups – true RAH (n=103) and patients with pseudo resistant AH (PRAH) (n=132). We performed the comparative analysis of clinical characteristics, target organ damage degree, features of neurohumoral (plasma concentration of aldosterone and active renin, 24 – hour urinary metanephrines) and proinflammatory (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor – α (TNF-α) in plasma) status among groups. The predictors of effectiveness of the 4th antihypertensive drug addition (spironolactone, eplerenone, nebivоlol, moxonidine) to triple FDC in patients with RAH were studied.Results and discussion. Higher levels of office and ambulatory blood pressure (BP), frequent (up to 14 %) disturbance of BP rhythm as night-peaker type, high BP morning surge are typical for RAH patients. 95 % of RAH patients had concentric left ventricular hypertrophy and 80 % – carotid atherosclerosis, a lower glomerular filtration rate and higher level of urinary albumin excretion rate (UAER). RAH patients had higher level of CRP – by 17.3 % (p=0.02), IL-6 – by 21.8 % (p=0.01), TNF-α – by 13 % (p=0.003) in comparison with PRAH patients. The predictors of spironolactone and eplerenone efficacy are plasma aldosterone concentration (β=0.653; p=0.002), aldosterone-renin ratio (β=0.542; p=0.003), UAE (β=–0.362; p=0.01) and the level of CRP (β=–0.315; p=0.03).Conclusions. Higher level of BP, target organ damage, more expressed activation of low – grade inflammation, sympathetic and renin-aldosterone-angiotensin systems activity are typical for RAH patients. The most effective drugs in addition to three – component FDC are MRA – spironolactone and eplerenone, which lead to the achievement of target BP at 48.5 % and 46.9 % (according to office and ambulatory testing) RAH patients. Nebivolol application contributed to BP normalization at 39.7 % and moxonidine – at 41.2 % RAH patients.

Efficacy and Safety of Bempedoic Acid + Ezetimibe Fixed-Dose Combination in Patients at High CVD Risk and with Elevated LDL-C Receiving Maximally Tolerated Statin Therapy

Efficacy and Safety of Bempedoic Acid + Ezetimibe Fixed-Dose Combination in Patients at High CVD Risk and with Elevated LDL-C Receiving Maximally Tolerated Statin Therapy

Inhaler Devices for Delivery of LABA/LAMA Fixed-Dose Combinations in Patients with COPD.

Inhaled fixed-dose combinations (FDCs) of a long-acting β-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) have become the cornerstone for the maintenance treatment of symptomatic COPD patients. In this regard, global COPD treatment guidelines have recognized the importance of inhaler devices as integral contributors to the effectiveness of LABA/LAMA FDCs and recommend regular assessment of inhaler device use by the patients in order to improve long-term clinical outcomes. Optimal disease control is also highly dependent upon patient preferences and adherence to inhaler devices. This review objectively examines and compares the major inhaler devices used to deliver different LABA/LAMA FDCs, discusses the inhaler device characteristics that determine drug deposition in the airways, real-life preference for inhaler devices, and handling of inhaler devices that impact the results of the long-term management of COPD. The introduction of new LABA/LAMA FDCs, new inhaler devices, and more clinical studies have created confusion among physicians in choosing the optimal inhaled therapy for COPD patients; in this context, this review attempts to provide an evidence-based framework for informed decision-making with a particular focus on the inhaler devices.Funding. The preparation of this manuscript was funded by Novartis Pharma AG.

Comparative efficacy of spironolactone, eplerenone, nebivolol and moxonidine in patients with resistant arterial hypertension

The aim – to study the effectiveness of spironolactone, eplerenone, nebivolol, moxonidine as the 4th component of therapy in patients with resistant arterial hypertension.Material and methods. The study involved 66 patients with true resistant arterial hypertension (RAH). The average age of patients was 51.9±1.2 years, mostly men (59.1 %). In addition to standard triple-dose fixed combination antihypertensive tharepy, all patients received in turn spironolactone (45.0±3.6 mg/day), eplerenone (47.9±2.1 mg/day), nebivolol (8.9±0.6 mg/day) and moxonidine (0.5±0.1 mg/day). After completion of each stage, after 3 months of therapy, all patients have been assessed an office blood pressure measurements and ABPM.Results. In patients with RAH, the addition standardized therapy with a triple fixed-dose combination of antihypertensive drugs, antagonists of mineralocorticoid showed better effectiveness than nebivolol and moxonidine: the target level of BP with treatment of spironolactone was achieved in 68.2 % patients, eplerenone – 65.2 %, whereas in the groups of nebivolol and moxonidine – in 53.9 % and 56.2 %, respectively. The predictors of the effectiveness of the antagonists of the mineralocorticoid receptors are increasing plasma aldosterone concentrations (β=0.653; Р=0.002) and ARR values (β=0.542; Р=0.003), while the β-blocker and imidazolin receptor agonist were more effective in older patients (β=0.425; Р=0.02) along with increase of average daily pulse (β=0.315; P=0.04) and excretion of urine metanephrines (β=0.382; Р=0.01).Conclusoins. Spironolactone and eplerenone are drugs of choice for adding to triple fixed-dose combination in patients with RAH. They were significantly more effective than beta-blocker (nebivolol) and an imidazolin receptor agonist (moxonidine).

IMPROVING AN EFFICIENCY OF RESISTANT HYPERTENSION TREATMENT WITH FIXED DOSE COMBINATION OF 3-COMPONENTS ANTIHYPERTENSIVE MEDICATION

Objective: Improving an efficiency of resistant hypertension treatment with fixed dose combination of 3-components antihypertensive medicationDesign and method: 180pts with the preliminary diagnosis of RAH,which was confirmed by24-h ambulatory blood pressure monitoring(ABPM),were included in the study. All pts received an average of4.1 ± 0.3 antihypertensive drugs, mainly in free combinations. After ABPM pts were started treatment with 3-component fixed dose combination (FDC) of antihypertensive drugs:the FDC of perindopril10 mg/indapamide2.5 mg/amlodipine10mg(108pts)or the FDC of valsartan320 mg/hydrochlorothiazide25 mg/amlodipine10mg(72pts). The adherence to the treatment was evaluated by the Morisky-Green test (MGT) at the initial examination and after 3 months of treatment with the FDC of antihypertensive drugs. Results: The average level of office systolic BP (SBP) and diastolic BP (DBP)was158.1 ± 1.2 and 91.03 ± 0.9mmHg respectively. After 3 months of treatment with 3-components FDC, according the results of office and ambulatory BP measurements,RAH was confirmed at 78pts and 102pts achieved the target blood pressure level (these pts were classified as pts with controlled arterial hypertension (CAH)). RAH pts were older than CAHpts:52.4 ± 1.2vs49.8 ± 1.6years (p = 0.02). Both groups were dominate by men-60.5%among RAH pts and62.6% among CAH pts. But initial BP levels (office and ambulatory)were higher in RAH group (tab.1). In the CAH group the office SBP decreased by 21%,DBP-by19.5%,the average daytimeSBP and DBP by15.2 and14% respectively,the average nighttime SBP and DBP by16.7 and16.4% respectively. In the RAH group BP lowering was smaller:the office SBP decreased by13.2%,DBP - by9%,the average daytime SBP and DBP by10.3and8.7% respectively,the average nighttime SBP and DBP by11.1and10.2% respectively. All pointed changes of BP were significant (p < 0.001)(tab.1). The results of the Morisky-Green tests show that treatment with FDC of antihypertensive drug leaded to improvement of the adherence to therapy. The initial Morisky-Green rate,which was assessed retrospectively,at RAH pts was1.3 ± 0.1points and at CAH pts1.4 ± 0.1 (p > 0.05),after 3-months of treatment with 3-components FDC it elevated to 2.5 ± 0.2 and 2.6 ± 0.2 points, respectively, in both groups (p < 0.005). Conclusions: Thereby, administration of 3-components FDC (RAAS blocker/diuretic/calcium channel blocker)improves the adherence to treatment, which can probably ameliorate the efficacy of antihypertensive treatment. Perhaps,the use of 3-component FDC in patients with a diagnosis of RAH could help to achieve the effective BP control and reduce the necessity of adding the 4-th antihypertensive drug for achieving of goal BP.

Fixed-dose lercanidipine and enalapril in field practice: a meta-analysis

Objective: This meta-analysis evaluates the efficacy and safety of lercanidipine/enalapril fixed-dose combination in patients with mild to moderate essential hypertension.Methods: Four observational studies on patients with sitting diastolic blood pressure (SDBP) between 95 and 109 mmHg, treated with lercanidipine/enalapril fixed-dose combination, were analyzed. The Random-Effect Model was used to limit heterogeneity across the studies. Weights were applied to determine the influence of each study on the combined results. The efficacy outcome measure was the reduction from baseline to endpoint in systolic and diastolic blood pressure (SBP and DBP, respectively). The incidence of treatment-emergent adverse events (TEAEs) was also investigated.Results: The total number of patients analyzed for efficacy and safety was 9565. No differences between study groups in demographics characteristics were observed. Mean blood pressure in the pooled population of the four studies was 162/94 mmHg at baseline. Overall, the lercanidipine/enalapril fixed-dose combination reduced SBP by 26 mmHg (95% CI, 23–29), and DBP by 13 mmHg (12–15), p < 0.05 for both. No safety concerns were reported.Conclusion: This meta-analysis supports the use of the lercanidipine/enalapril fixed-dose combination for the treatment of mild-to-moderate hypertension.

Safety and efficacy of once daily ledipasvir/sofosbuvir fixed-dose combination in patients with chronic hepatitis C

ABSTRACTIntroduction: During the past couple of years, the regulatory authorities have approved seven new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C (CHC). In 2014, the US FDA approved the fixed dose combination of ledipasvir (LDV) plus sofosbuvir (SOF) for the treatment of genotype (GT) 1 HCV and the European Commission Granted its marketing authorization to treat patients with GT1 and 4. This regimen showed outstanding rates of virologic response along with a favorable safety profile with a very low rate of both virologic failure and treatment discontinuation.Areas covered: In this review, we sought to review the pharmacokinetics, clinical efficacy and safety profile pertaining to LDV/SOF combination in treatment of CHC with special emphasis on phase III clinical trials.Expert opinion: In all phase III trials, the 12-week course of this new interferon (IFN)-sparing regimen has delivered high virologic cure rates among patient with GT1 and 4 both treatment-naïve and – experienced Data about its effectiveness in patients under 18 years of age, end-stage renal disease and patients with significant other organ involvement are eagerly awaited.

Efficacy and safety of aclidinium/formoterol fixed-dose combination in patients with COPD, stratified by ICS use

Background: A secondary analysis of pooled data, stratified by concomitant inhaled corticosteroid (ICS) use, is presented from ACLIFORM (NCT01462942) and AUGMENT (NCT01437397), two Phase III, 24-week, randomised, double-blind studies of twice-daily (BID) aclidinium/formoterol (AB/FF) fixed-dose combination in patients (pts) with moderate to severe airflow obstruction.