Free Combination Therapy Research Articles

Choice Between Free Combination of Antihypertensive Agents and Fixed Dosed Combinations in the Treatment of Arterial Hypertension

Most patients with arterial hypertension require more than one antihypertensive drug for blood pressure target achievement. Some patients are recommended for a multi-pill antihypertensive regimen, others — treatment with fixed dosed combinations in one tablet. Analysis of elibrary and PubMed publications in the period mostly from 2014 to 2024 concerning the choice of two-component combined antihypertensive agents containing renin-angiotensin system inhibitor and diuretic or calcium channel blocker, revealed that fixed-dose combinations (FDC) use and taking one tablet once a day improves adherence to treatment and facilitates blood pressure control. Although the cost of FDC containing the renin-angiotensin-aldosterone system inhibitor and a thiazide/thiazide-like diuretic or calcium channel blocker is in most cases higher than the same drugs taken separately, the use of fixed combinations, increasing patient adherence to therapy, has clinical advantage in terms of the effectiveness of lowering blood pressure, which confirms their economic feasibility. On the other hand, the use of free combination therapy in two different tablets, when taken separately during the day, can sometimes provide a more sustained antihypertensive effect over 24 hours. Evidence of the effectiveness of blood pressure control for FDCs is often extrapolated from data on free combinations. In addition, FDCs are characterized by less detection of possible ineffectiveness of one of the components. The range of FDCs and the dosage ratios of the components presented in them is gradually expanding, but the choice among free combinations is still wider. In addition, the list of vital and essential drugs (VED) for 2024 does not contain FDCs for antihypertensive drugs, which excludes the possibility of free receiving them on a preferential basis and gives the opportunity for the manufacturer to set prices for them. Despite the fact that recently the scientific community has recommended the use of FDC antihypertensive drugs as initial therapy due to better compliance with the regimen, and therefore clinical effectiveness and economic feasibility, it cannot be said that there is no space left for free combinations of antihypertensive drugs in the treatment of arterial hypertension. The choice of doctor, frequency of prescription, share of purchases of the FDCs in the Russian Federation, review of their consumption requires further analysis.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD)=0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD=-2.06kg; 95% CI: -3.34 to -0.77), SBP (MD=-1.22mmHg; 95% CI: -2.41 to -0.04), and DBP (MD=-1.09mmHg; 95% CI: -1.94 to -0.24) between the two groups. In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.

Use of Perindopril Arginine/Indapamide/Amlodipine in the Management of Hypertension in Two Sub-Saharan African Island Countries of Madagascar and Mauritius.

IntroductionMost patients with hypertension in sub-Saharan Africa require two or more drugs to control their blood pressure. Triple fixed-dose combination therapy of perindopril arginine/indapamide/amlodipine is more effective in lowering blood pressure, offers better target organ protection and has increased adherence compared to monotherapy and free combination therapy, and is safe to use. This observational study evaluates the effectiveness of perindopril arginine/indapamide/amlodipine in controlling blood pressure at least 1 month after treatment initiation and assesses patient- and physician- reported drug tolerance over a 3-month period in Madagascar and Mauritius.MethodsA total of 198 patients with hypertension in ambulatory care who had been on fixed-dose combination of perindopril arginine, indapamide, and amlodipine for at least 4 weeks were included. The main outcome measures were changes in systolic and diastolic blood pressure, attainment of blood pressure control under 140/90 mmHg and 130/80 mmHg, self-reported drug tolerance by the patient, and perceived drug tolerance by the treating physician. Data was collected at 1 month and 3 months.ResultsMean systolic blood pressure was significantly lower at the 1-month (− 3.4 mmHg, p = 0.002) and 3-month (− 8.5 mmHg, p < 0.0001) visits. Diastolic blood pressure also decreased significantly (− 2.4 mmHg at 1-month, p = 0.017 and − 5.4 mmHg at the 3-month visits, p < 0.0001). At 3 months, 80.4% of the patients attained blood pressure targets less than 140/90 mmHg and 42.7% attained targets less than 130/80 mmHg on the basis of their baseline blood pressure. Excellent drug tolerance was reported by more than 90% of patients and physicians at the 1-month visit and by more than 95% at the 3-month visit.ConclusionTriple fixed-dose therapy of perindopril arginine/indapamide/amlodipine continues to show additional blood pressure-lowering capacity even months after initiating the treatment in patients with hypertension in Madagascar and Mauritius. It is also well tolerated by patients with hypertension and assessed as safe to use by physicians.

RP-HPLC method development and validation for simultaneous estimation of telmisartan, rosuvastatin calcium, and amlodipine besylate in combination.

Dyslipidemia-hypertension proves to be a major risk factor for cardiovascular diseases. In order to achieve better adherence and cost-effectiveness than free equivalent combination therapies, a fixed-dose combination therapy with telmisartan (TEL), rosuvastatin calcium (ROS) and amlodipine besylate (AML) is required in this type of patients.

The Effects of Single Pill Combinations on Adherence and Blood Pressure Control in Hypertensive Patients.

Background:Hypertension is the most important risk factor for cardiovascular morbidity and mortality. Blood pressure control rates are as low as 17% to 31% in patients diagnosed with hypertension in high-income countries; control rates are likely poorer in low- to middle- and low-income countries. Blood pressure control rates are as low as 17% to 31% in patients diagnosed with hypertension in high-income countries; control rates are likely poorer in low- to middle- and low- income countries. Overall, 43% to 66% of patients fail to adhere to their prescribed antihypertensive medications, and after 1 year, ≈40% of patients with hypertension may stop their initial drug treatment.Objective:The aim of the study was to evaluate the effects of single pill combination antihypertensive drugs on the adherence to treatment, blood pressure control and cardiovascular events vs. free-combination therapy.Methods:We enrolled 192 adult hypertensive patients not older than 79 years, with untreated or uncontrolled hypertension despite previously receiving free combination antihypertensive therapy, between November 2020 and March 2022. Patients treated with single pill combination (SPC) were compared with an arm of the same size (n = 96) and matched by age and gender who received a standard free combination (FC) antihypertensive therapy.Results:There were significant reductions from baseline to month 6 of follow-up in office SBP in the SPC group vs. reduction in FC group (21.9 vs. 13.1 mmHg; p < 0.0001). There were significant reductions from baseline to month 6 of follow-up in office DBP in the SPC group vs. group with free-combination therapy (13.7 vs. 8.0 mmHg; p < 0.0001). At 6 months, 94 participants (98%) were still prescribed the SPC therapy. At the final 6-month study visit, 84.2% of patients in the SPC therapy group were adherent to the prescribed antihypertensive therapy vs. 52% of patients in the FC group. Target BP values (mean 24h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of SPC than free-combination therapy (78.2% vs. 46.3%, p < 0.05) at month 6 of follow-up.Conclusion:Treatment with single pill combinations (SPC), is the emerging best practice for safe, effective, rapid, and convenient hypertension control. It improves the affordability, adherence and control of arterial hypertension.

Free combination of dutasteride plus tamsulosin for the treatment of benign prostatic hyperplasia in South Korea: analysis of drug utilization and adverse events using the National Health Insurance Review and Assessment Service database

ObjectiveTo assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH).MethodsThis non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing.ResultsOf 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for ‘frequent’ use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low.ConclusionCombination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy.

Antibody-drug conjugate and free geldanamycin combination therapy enhances anti-cancer efficacy

Antibody drug-conjugates (ADCs) targeting human epidermal growth factor (HER2) are a rapidly expanding class of cancer therapeutics. Such ADCs are known to suffer from inefficient trafficking to the lysosome due to HER2 endosomal recycling, leaving most bound ADCs at the cell surface or in early endosomes. This study aims to increase the maximum cytotoxicity of ADC treatment by co-delivering a small molecule inhibitor targeting the primary chaperone of HER2, heat shock protein 90 (HSP90). We hypothesized that inhibiting HSP90 could aid ADC cytotoxicity by overcoming HER2 endosomal recycling. Flow cytometric studies tracking HER2 surface expression revealed ∼ 10 nM geldanamycin (GA) as the threshold for inhibiting HSP90 mediated HER2 recycling. Cytotoxicity studies in HER2 overexpressing cancer cell lines NCI-N87, MDA-MB-453, and SKOV3 demonstrated that co-administration of ADC alongside 100 nM GA significantly increased cytotoxicity compared to ADC alone. In all cases, baseline cytotoxicity was observed even in low HER2 expressing line MDA-MB-231 cells, indicating possible off-target effects. To mitigate this baseline cytotoxicity, a “pulse treatment” regime was adopted where cells are pre-loaded with T-DM1 or T-MMAE ADCs for 4 h, followed by a 4-hour pulse treatment with ADC and 100 nM GA to initiate trafficking of HER2 bound ADC to the lysosome. Afterwards, GA is removed, and ADC treatment is continued. GA pulse co-treatment decreased the amount of ADC required to achieve maximum cytotoxicity while minimizing baseline cytotoxicity. No such co-treatment regime featuring a pulse sequence has been explored before. Such co-treatments could offer a viable solution to increase ADC efficacy in hard to treat or resistant HER2-positive cancers.

Comparison of medication adherence between fixed-dose combination of angiotensin receptor blockers and statin and free-combination therapy

Abstract Background Non-adherence to angiotensin receptor blockers (ARB) or statin is one of major reasons of insufficient treatment for patients with hyperlipidemia and hypertension. We investigated whether fixed-dose combination (FDC) of ARB and statin improved adherence compared to traditional free combination (FC). Methods In this retrospective nationwide cohort study, adherence of 128,369 patients who started ARB and stain including atorvastatin or rosuvastatin between July 2014 and June 2015 was investigated. Primary endpoint was proportion of days covered (PDC) per 180 days up to day 540. Good compliance defined by PDC≥80% and persistency rate defined by patients remaining on medication were also investigated. Results Patients were 62.9 years of mean age with 48.2% female gender. Compared to FC (N=90,759, 70.7%), FDC (N=37,610, 29.3%) showed higher PDC at day 180 (86% vs 70%), 360 (77% vs 62%), and 540 (74% vs 55%, p&amp;lt;0.001, all). Frequency of patients with PDC≥80% was also higher in FDC compared to FC at day 180 (80.1% vs 51.8%), 360 (71.7% vs 54.2%), and 540 (69.2% vs 49.3%, p&amp;lt;0.001, all). Persistency rate at day 540 was higher in FDC compared to FC (50.4% vs 27.3%, p&amp;lt;0.001). The mean decline in PDC per 180 days were significantly lower in FDC compared to FC per 180 days (6.0% vs. 7.5%, p&amp;lt;0.001). Conclusions In this real-world data analysis, FDC resulted in higher medication adherence and persistence compared to FC among patients who started both ARB and atorvastatin or rosuvastatin. Persistence rate btw FDC and FC Funding Acknowledgement Type of funding source: None

Cost-effectiveness analysis of antihypertensive triple combination therapy among patients enrolled in a Medicare advantage plan

ABSTRACT Objective To assess the cost-effectiveness of single pill fixed dose triple combination therapy vs. free triple combination therapy for the prevention of cardiovascular events among patients with hypertension. Methods A Markov model with a five year cycle was constructed. Two decision models incorporating strict and more relaxed adherence definitions estimated quality adjusted life years (QALYs) and health-care costs for single pill fixed triple combination therapy vs. free-drug combination therapy. Results When the strict adherence measurement criteria were applied, the total QALYs loss and cost/patient were 6.38 QALYs, $486,026.20 for the single pill triple combination therapy and 8.64 QALYs, $406,405.26 for the free combination therapy. ICER for single pill combination therapy compared to free combination therapy was 33,826.46/QALY. When the relaxed adherence measurement criteria were applied, the total QALYs loss and cost/patient were 8.09 QALYs, $493,404.26 for the single pill triple combination therapy and 8.76 QALYs, $436,415.14 for the free combination therapy. ICER for single pill combination compared with free combination therapy was 84,932.26. Conclusion This study suggested that single pill triple combination therapy was cost-effective in comparison with free combination therapy under a willingness to pay threshold of 50,000 when the strict adherence measurement criteria was applied.

Therapy of allergic rhinitis in routine care: evidence-based benefit assessment of freely combined use of various active ingredients

Abstract Background Allergic rhinitis (AR) continues to increase in incidence and is the most common allergic disease. If abstention of the allergen triggering substances is not possible, allergen-specific immunotherapy (AIT) as causal treatment or a drug therapy with mast cell stabilizers, antihistamines (AHs), glucocorticoids (GCs), leukotriene (LT) receptor antagonists and decongestants is indicated. Despite these diverse therapeutic options, studies on the real-life care situation of patients with AR regularly show that a considerable proportion of patients do not feel adequately treated with monotherapy of the usual drugs and therefore use several preparations with different active ingredients simultaneously and in various combinations. However, such parallel applications of several active ingredients are normally not tested in approval studies and therefore carry a potential risk of side effects or lack of efficacy. Methods For the present publication, a focused literature search in PubMed, Livivo and on the World Wide Web for the previous 20 years (period 01/1999 to 01/2020) was carried out. This literature search included original and review articles in German or English. A further analysis of current publications was also conducted for German-language journals that are not available in international literature databases. Results AHs and nasal GCs represent the therapeutic standard in AR. Their efficacy is well documented for several preparations. The evidence for combination therapies is documented very well for a fixed combination of azelastine and fluticasone (MP29-02). For the simultaneous use of non-fixed combined monopreparations, only a few efficacy and safety studies based on modern evidence criteria exist. Conclusion The free combination therapies of mast cell stabilizers, decongestants, AHs and nasal GCs, frequently used in the routine care of patients with AR, cannot be recommended because they are not evidence-based. Due to the fact that over-the-counter antiallergic drugs are not reimbursable in Germany, there is no medical supervision of the therapy. In addition, there are doubts about appropriate treatment, especially of patients with persistent rhinitis with severe symptoms, as these patients often use several preparations at the same time to alleviate their symptoms.

Risk of Cardiovascular Outcomes and Antihypertensive Triple Combination Therapy Among Elderly Patients with Hypertension Enrolled in a Medicare Advantage Plan (MAP).

The aim was to evaluate the risk of cardiovascular-specific hospitalizations with different types of antihypertensive triple combination therapy among patients enrolled in a Medicare Advantage Plan (MAP). A retrospective cohort study was conducted among patients with hypertension enrolled in a Texas MAP between January 2014 and December 2016. Antihypertensive combination therapy users were classified into three treatment groups: single-pill triple combination, fixed-dose dual combination plus a third agent, and free triple combination. Group differences were assessed using Chi-square tests for binary variables and Student's t tests for continuous variables. Cox proportional hazards model was performed to assess the association between type of combination therapy and risk of cardiovascular-specific hospitalization adjusting for potential confounders. A total of 10,836 triple combination users were identified. The risk of cardiovascular disease (CVD) hospitalization for the fixed-dose dual combination plus a third agent group [hazard ratio (HR) 3.82, 95% confidence interval (CI) 1.80-8.12] and for the free triple combination therapy group (HR 3.65, 95% CI 1.43-9.31) was significantly higher than for the single-pill triple combination group. Single-pill triple combination therapy was significantly associated with a lower risk of CVD hospitalizations in comparison to other types of triple combination therapy.

Adherence to Triple-Free-Drug Combination Therapies Among Patients With Cardiovascular Disease

Combination therapies are often needed to modify the concomitant risk factors for cardiovascular disease. Nonadherence to cardiovascular medications is a relevant concern, especially in polytherapy. We conducted a population-based, cohort study with the aim of quantifying the level of adherence and its related determinants in patients exposed to free 3-drug combination therapies, namely concurrent use of angiotensin-converting-enzyme inhibitor (ACEi), calcium channel blocker (CCB), and statin or of ACEi, statin, and low-dose aspirin. Within Health Search Database, we selected a cohort of adult patients concurrently prescribed with ACEi, CCB, and statin, as well as those prescribed with ACEi, statin and low-dose aspirin, from the January 1, 2002 to the December 31, 2014. Adherent patients were concurrent users of triple free pill regimen with a proportion of days covered ≥80% during 1-year follow-up; demographics and clinical determinants of 1-year adherence were identified by multivariate logistic regression. We found that more than half of patients prescribed with triple free drug combination therapy with ACEi plus CCB plus statin or ACEi plus statin plus low-dose aspirin, were found to be nonadherent to these treatments. Males and patients at high/very-high cardiovascular risk were more likely to be adherent, whereas depression and atrial fibrillation were associated with nonadherence. Our findings indicate that sex, cardiovascular risk, presence of atrial fibrillation, and depression can influence adherence to polytherapy. In conclusion, given that patients suffering from multiple cardiovascular risk factors are at higher risk of fatal events, strategies are needed to improve medication adherence to combination therapies.

Persistence and adherence to dutasteride/tamsulosin fixed-dose versus free-combination alpha blocker/5ARI therapy in patients with benign prostate hyperplasia in Germany .

Objective: To evaluate real-world persistence and adherence in patients with benign prostate hyperplasia (BPH) receiving a fixed-dose combination of dutasteride plus tamsulosin (DUT-TAM FDC) versus α-blocker plus 5-α reductase inhibitor (AB/5ARI) free-combination therapy. Materials and methods: This retrospective, observational cohort study utilized the German IMS LRx (IQVIA) database. Patients ≥ 45 years old with BPH receiving DUT-TAM FDC or AB/5ARI free-combination therapy from July 1, 2011 to November 30, 2017 were included. Data were analyzed for 48 months from index date (date of first prescription). Persistence, measured as time to discontinuation (defined as a 90-day gap in therapy), was evaluated using Kaplan-Meier curves (log-rank tests). Adherence, measured as medication possession ratio (MPR), was based on a comparison of mean prescribing duration and expected treatment duration. Results: A total of 141,667 patients were included (DUT-TAM FDC, n = 86,057; free AB/5ARI: n = 55,610). Small differences in persistence were observed between treatment arms. At month 12, 41.8% of DUT-TAM FDC-treated and 41.0% of AB/5ARI free-combination therapy-treated patients were persistent; at month 24, 28.2% and 27.1% were persistent, respectively. A higher proportion of DUT-TAM FDC-treated patients had MPR ≥ 0.80, ≥ 0.75 and ≥ 0.70 compared with AB/5ARI free-combination therapy (p < 0.0001). Conclusion: Small differences observed in persistence between treatment arms may not translate to meaningful clinical relevance. Adherence was significantly better in the FDC arm, which may be clinically relevant as improved adherence is associated with better outcomes. Persistence and adherence to BPH therapy in Germany is low; further studies exploring the reasons behind this are required.

Long-term effect of the perindopril/indapamide/amlodipine single-pill combination on left ventricular hypertrophy in outpatient hypertensive subjects

BackgroundMost antihypertensive drugs used in monotherapy or in combination therapy reduce the left ventricular mass index (LVMI). However, little is known about the effects on LVMI of a triple fixed-dose combination (TFC) therapy, containing in a single pill an angiotensin-converting enzyme inhibitor (ACEI), a diuretic and a calcium channel blocker (CCB). MethodsIn this prospective open-label study, 92 patients with essential hypertension were randomized to treatment with a TFC of perindopril/indapamide/amlodipine at different doses or a triple free combination therapy (FCT) including ACEI/diuretic/CCB. Office blood pressure (BP) measurement, 24 h-ambulatory BP monitoring and echocardiography were performed at baseline and during a 14-month follow-up. The BP variability (BPV) over 24 h was calculated as ± standard deviation of the daytime systolic BP. Differences between office and monitored BP and LVMI were evaluated by ANOVA for repeated measures. ResultsA significant BP-lowering effect was observed for both treatments. At follow-up, BPV was reduced in both the treatment groups vs. the baseline (14.0±1.5 vs. 17.0±1.8 and 16.2±2.1 vs. 17.6±2.3, respectively), but it was lower in the TFC vs. the FCT group (14.0±1.5 vs. 16.1±2.2, P < 0.05). LVMI was lower in both the treatment groups, but the change was greater for TFC vs. FCT (−8.3±4.9% vs. −2.0 ±2.1%, P < 0.0001). Left ventricular hypertrophy (LVH) regression was greater in the TFC vs. the FCT group (43.5% vs. 30.4%, P < 0.05). ConclusionsIndependently of BP values achieved, the antihypertensive TFC therapy was more effective than FCT in LVMI reduction and LVH regression, possibly related to drugs’ intrinsic properties and to BPV modulation.

Treatment with Free Triple Combination Therapy of Atorvastatin, Perindopril, Amlodipine in Hypertensive Patients: A Real-World Population Study in Italy.

Polytherapy is often required to treat the comorbidity of hypertension and hyperlipidemia. Fixed-dose co-formulation, rather than free combinations, simplifies medication taking and also improves adherence to medication, which is the key for a successful management of these conditions. To determine the number of patients potentially eligible for treatment with triple fixed-dose atorvastatin/perindopril/amlodipine (CTAPA), and to estimate if an unmet medical need exists among CTAPA free combination treated patients. This observational retrospective study was based on administrative databases of 3 Italian Local Health Units. The cohort comprised adult patients with at least one prescription of amlodipine and perindopril (either as free combination or co-formulated) and atorvastatin during 2014. Follow-up period started on the date of prescription of the 3 molecules (index date) and lasted 1year. Adherence to CTAPA was analyzed during follow-up, by using the proportion of days covered (PDC). 2292 patients (9.1 per 10,000 beneficiaries) had a prescription for CTAPA as free combination. Only 1249 (54.5%) were adherent to the therapy (PDC ≥ 80%); among them, a small percentage required dosage modification. The number of patients with CTAPA increased during the study period. Discontinuation of drugs prescribed the year before interested 582 patients in 2014, and 522 in 2015. Considering the Italian national population (n = 60,782,668), it was estimated that 69,542 hypertensive patients could be eligible for fixed-dose CTAPA during 2014. Real-world analysis among patients with free combination therapy can be applied to estimate the eligible population for fixed combination, and to evaluate the appropriateness of their prescriptions. Moreover, fixed-dose CTAPA could effectively improve adherence, which was calculated to be low in the free combination cohort.

Dual-Targeted Lactoferrin Shell-Oily Core Nanocapsules for Synergistic Targeted/Herbal Therapy of Hepatocellular Carcinoma.

Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice (P < 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.

PCV13 RISK OF CARDIOVASCULAR OUTCOMES AND ANTIHYPERTENSIVE TRIPLE COMBINATION THERAPY AMONG PATIENTS ENROLLED IN A MEDICARE ADVANTAGE PLAN (MAP)

To evaluate the risk of cardiovascular specific hospitalizations with different types of antihypertensive triple combination therapy among patients enrolled in a MAP. A retrospective cohort study was conducted among older adult patients with hypertension enrolled in Texas MAP between January 2014 and December 2016. Antihypertensive combination therapy users were classified into single pill triple combination group, fixed dose dual combination plus a third agent group, and free triple combination group. The primary outcome of interest was time to first cardiovascular related hospitalization. Descriptive statistics with patient characteristics were examined. Group differences were assessed using chi-square tests for binary variables and student’s t-tests for continuous variables. Cox proportional hazards model was performed to assess the association between type of combination therapy and risk of cardiovascular specific hospitalization adjusting for potential confounders including demographic variables, adherence, CMS risk score and several comorbidities. A total of 10,836 triple combination users were identified with 336 (3.10%) patients in the single pill triple combination group, 470 (4.34%) patients in the fixed dose dual combination plus a third agent group and 10,030 (92.56%) patients in the free triple combination group. The risk of CVD hospitalization for the fixed dose dual combination plus a third agent group was significantly higher than the single pill triple combination group (HR: 3.82, 95%CI: 1.80-8.12). In addition, the risk of CVD hospitalization for the free triple combination therapy group was significantly higher than the single pill triple combination group (HR: 3.65, 95% CI: 1.43-9.31). Male patients, higher CMS risk score, and comorbidities such as depression, diabetes, heart failure, and neuropathy were significantly associated with an increased risk of CVD hospitalization. Single pill triple combination therapy was significantly associated with a lower risk of CVD hospitalizations in comparison to other types of triple combination therapy.

Effectiveness of antimalarial interventions in Nigeria: Evidence from facility-level longitudinal data.

To evaluate the effectiveness of a program of antimalarial interventions implemented in 2010-2013 in Niger State, Nigeria. Utilization reports from 99 intervention and 51 non-intervention health facilities from the Niger State Malaria Elimination Program, supplemented by data on facility-level characteristics from the Niger State Primary Health Care Development Agency and Local Government Malaria Control units. Estimated with mixed-effects negative binomial modeling, a difference-in-differences method was used to quantify the impact of the program on the number of febrile illness cases and confirmed malaria cases. Potential confounding factors, non-stationarity, seasonality, and autocorrelation were explicitly accounted for. Data were retrieved from hard copies of utilization reports and manually inputted to create a panel of 5550 facility-month observations. The program was implemented in two phases. The first phase (August 2010-June 2012) involved the provision of free artemisinin-based combination therapies, long-lasting insecticidal nets, and intermittent preventive treatments. In the second phase (July 2012-March 2013), the program introduced an additional intervention: free parasite-based rapid diagnostic tests. Compared to the pre-intervention period, the average number of monthly febrile illness and malaria cases increased by 20.876 (P<0.01) and 22.835 (P<0.01) in the first phase, and by 19.007 (P<0.05) and 19.681 (P<0.05) in the second phase, respectively. The results are consistent across different evaluation methods. This study suggests that user-fee removal leads to increased utilization of antimalarial services. It motivates future studies to cautiously select their investigative methods.

Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis.

Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis.

PH-activatable polymeric nanodrugs enhanced tumor chemo/antiangiogenic combination therapy through improving targeting drug release

It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells.