Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

[A prospective study of bone loss in early stage postmenopausal breast cancer treated with aromatase inhibitors].

Objective: To investigate the occurrence and development of aromatase inhibitors (AIs) related bone loss in Chinese patients with postmenopausal early-stage breast cancer. Methods: Patients with estrogen receptor (ER) and (or) progesterone receptor(PR) positive postmenopausal early-stage breast cancer who received Letrozole, Anastrozole, or Exemestane as adjuvant therapy were enrolled. Before treatment, baseline bone mineral density (BMD), bone metabolism markers were examined and a lifestyle questionnaire was completed; BMD was examined annually during the treatment; Outpatient visits were conducted to record recurrent and fatal events. Results: From November 2013 to August 2016, 131 patients with breast cancer eligible for enrollment were enrolled. A total of 65 patients had normal baseline bone mass, and 68 patients had reduced bone mass. Letrozole was taken in 69 patients, anastrozole in 52 patients, and exemestane in 10 patients. With a median follow-up of 43.7 months, 100 patients could be evaluated for changes in bone mineral density. Bone mineral density of femoral neck, total hip, and lumbar spine L1 to 4 decreased year by year, and the decrease was the most significant in the first year, which decreased by 2.3%, 2.4%, and 3.9% respectively. Ten new cases of osteoporosis occurred in two years, eight of them occurred in the lumbar spine, all of whom had reduced bone mass at baseline. Among the 131 patients who completed the lifestyle questionnaire, the proportions of daily calcium supplementation and vitamin D were 28.2% and 7.6%, respectively; more than half (52.7%) of them lacked regular exercise. Conclusion: BMD was declining steadily in patients treated with AIs, especially in the first year. Lumbar spine is the most common osteoporosis site, early prevention and health education should be strengthened.

Breast Cancer Chemoprevention: A Practical Guide for the Primary Care Provider.

Several organizations, including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the United States Preventive Services Task Force, recommend incorporation of breast cancer risk-based counseling and chemoprevention into routine well-woman care. However, primary care providers report both discomfort with and a lack of medical knowledge on this topic. In this review we present a practical, evidence-based guide for incorporating breast cancer risk assessment and chemoprevention into routine care. We advocate a stepwise approach consisting of: (1) risk assessment and communication, (2) selection of appropriate chemoprevention based on risk-benefit analysis, (3) shared decision-making regarding chemoprevention, and (4) management of chemoprevention side effects. We encourage providers to identify high-risk women and refer them to genetic counseling or a high-risk breast cancer clinic. For women who are not considered high risk, we suggest using the Gail model to estimate a woman's 5-year risk of invasive breast cancer. Usually, the benefits of chemoprevention outweigh the risks of chemoprevention once a woman's 5-year risk of invasive breast cancer reaches 3%. For these women there are several factors that need to be considered when selecting a chemoprevention agent, including patient preference, thrombotic history, menopausal status, absence or presence of a uterus, and bone mineral density. We advocate an evidence-based shared decision-making approach that reflects the woman's individual preferences when communicating risk and counseling about chemoprevention. After starting a chemoprevention agent, close follow-up is important as side effects of chemoprevention are common, including vasomotor symptoms and arthralgias. We also review evidence-based management of chemoprevention side effects.

Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer.

CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single-cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian-based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5-Fluorouracil (5-FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar-targeting compounds were tested, and the results showed that exemestane exhibited superior cancer-suppressing efficacy to other ARIs. In addition, exemestane down-regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5-FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose-dependent manner. Combining subminimal doses of 5-FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5-FU and exemestane for GCa therapy is recommended.

Phase 2 placebo-controlled, single-blind trial to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: 5-year results of the single-centre BONADIUV trial.

AIM: We present the final results of the BONADIUV trial, a single-blind, randomised, placebo-controlled phase 2 study to evaluate the impact of ibandronate treatment on bone mineral density (BMD) in osteopenic women taking aromatase inhibitors (AI). PATIENTS AND METHODS: Between 2011 and 2014, 171 osteopenic patients were randomised in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-month evaluation. Primary end-point was the 2-year lumbar spine (LS) and total hip (TH) T-score mean differences as measure of BMD variation. Secondary analyses of survival outcomes have been performed at a 5-year median follow-up. CLINICALTRIALS. GOV IDENTIFIER: NCT02616744. RESULTS: Median age of study population was 60.2 years (range 44-75). At the database cut-off time, the median follow-up was 63.3 months (range 2.7-87.3). No difference in terms of T-score was shown at baseline between arms both for TH (P = 0.61) and LS (P = 0.96). At 2-year follow up, the mean change was statistically significant in favour of ibandronate arm both at TH (P = 0.0002) and LS (P < 0.0001). No significant difference in terms of adverse events was observed between arms. At a median follow-up of 63.3 months (range 2.7-87.3), the overall survival (OS) rate was 97.5% in the placebo group and 93.0% in the ibandronate arm (P = 0.19). The invasive disease-free survival (iDFS) rates did not differ between groups (P = 0.42). CONCLUSIONS: Ibandronate compared to placebo improved BMD change in osteopenic women treated with adjuvant AI. Five-year survival analyses showed no difference between arms in terms of OS and iDFS rates.

Fluticasone furoate, umeclidinium bromide, and vilanterol as a combination therapy for chronic obstructive pulmonary disease.

Introduction: Triple therapy with two bronchodilators (LABA plus LAMA) and an inhaled corticosteroid (ICS) is recommended for patients suffering from severe chronic obstructive pulmonary disease (COPD). Areas covered: All 12-52 week-long studies comparing triple therapy with umeclidinium (UM) added to either fluticasone furoate/vilanterol (FF/VI) or fluticasone propionate/salmeterol (FP/SAL) vs. other comparators in COPD patients of group B or D (2011 GOLD classification) were considered. When UM was added to ICS/LABA with separate devices or within a single device, triple combination was more effective than comparators (usually, ICS/LABA combinations) regarding improvements to pulmonary function, symptoms, quality of life and, in the longer studies, rate of moderate-severe exacerbations. The IMPACT study (a large trial comparing UM/FF/VI with both FF/VI and UM/VI combinations) showed that triple therapy had a greater effect compared to dual therapies in reducing the rate of moderate-severe exacerbations, improving trough FEV1 and improving quality of life. The safety profile was good, without excess cardiovascular effects or pneumonia, however, the presence of comorbidities was frequent. Expert commentary: UM/FF/VI combination represents a good option for severe COPD patients who remain symptomatic and/or with frequent exacerbations despite dual therapies. Once daily administration with a simple and effective device may increase adherence and efficacy of the treatment.

Once-daily triple therapy inhaler for COPD.

▼Trelegy Ellipta (GSK) is a dry powder inhaler containing fluticasone furoate (inhaled corticosteroid [ICS]), vilanterol trifenatate (long-acting beta2 agonist [LABA]) and umeclidinium bromide (long-acting muscarinic antagonist [LAMA]).1 It is licensed for once-daily use as maintenance treatment for adults with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an ICS and a LABA. Here, we consider the evidence for this combination product and discuss how it fits with current management strategies.

Nasal rinsing with an atomized spray improves mucociliary clearance and clinical symptoms during peak grass pollen season.

BACKGROUND: Nasal rinsing with an atomizer spray was found to be effective in the treatment of allergic rhinitis. Two parameters express the nasal functions: (1) mucociliary clearance (MCC), and (2) the pH and its stability. MCC is the main factor that defines the time of pollen transition on the nasal mucosa and, therefore, the amount of the allergen glycoprotein elution. OBJECTIVE: We hypothesized that the nasal wash efficacy could be due to the reduction of contact time of the grass pollen on the nasal mucosa (improving MCC). METHODS: Forty patients with seasonal grass pollen oculorhinitis were randomized in two groups: 20 received three times daily nasal rinsing with hypertonic solution buffered to pH 6.1, before and during the peak pollen season in 2015 (active group), and another 20 patients were allocated to the control group and received no nasal treatment. The daily symptoms score and the use of oral antihistamines when required were evaluated during the grass pollen peak season. All the patients completed the study. RESULTS: In comparison with the control group, in the active group, a significant decrease of both nasal symptoms (p = 0.01) and consumption of antihistamines (p = 0.035) was found. Furthermore, the MCC was significantly worse (p = 0.011) only in the control group. CONCLUSION: The nasal treatment maintained the efficiency of the MCC in the patients in the active group, who showed a significant reduction of symptoms and medication score. The MCC decreased the transit time of the pollen on the nasal mucosa, which favored an elution of the allergenic proteins.

Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study.

Accumulating evidence indicates that cholesterol oxygenation products, also known as oxysterols (OS), are involved in breast cancer (BC) promotion. The impact of Tam, as well as aromatase inhibitors (AI), an alternative BC endocrine therapy (ET), on OS metabolism in patients is currently unknown. We conducted a prospective clinical study in BC patients receiving Tam (n=15) or AI (n=14) in adjuvant or in metastatic settings. The primary end point was the feasibility of detecting and quantifying 11 different OS in the circulation of patients before and after 28days of treatment with Tam or AI. Key secondary end points were the measurements of variations in the concentrations of OS according to differences between patients and treatments. OS profiling in the serum of patients was determined by gas chromatography coupled to mass spectrometry. OS profiling was conducted in all patients both at baseline and during treatment regimens. An important inter-individual variability was observed for each OS. Interestingly 5,6ß-epoxycholesterol relative concentrations significantly increased in the entire population (p=0.0109), while no increase in Cholestane-triol (CT) levels was measured. Interestingly, we found that, in contrast to AI, Tam therapy significantly decreased blood levels of 24-hydroxycholesterol (24-HC), 7α-HC and 25-HC (a tumor promoter) (p=0.0007, p=0.0231 and p=0.0231, respectively), whereas 4ß-HC levels increased (p=0.0010). Interestingly, levels of 27-HC (a tumor promoter) significantly increased in response to AI (p=0.0342), but not Tam treatment. According to these results, specific OS are promising candidate markers of Tam and AI efficacy. Thus, further clinical investigations are needed to confirm the use of oxysterols as biomarkers of both prognosis and/or the efficacy of ET.

Hepatoprotective Effects of Corilagin Following Hemorrhagic Shock are Through Akt-Dependent Pathway.

Corilagin, a component of Phyllanthus urinaria extract, possesses antioxidant, thrombolytic, antiatherogenic, and hepatoprotective properties, but the mechanism underlying these effects remains unclear. Previous studies showed that the Akt (protein kinase B) signaling pathway exerts anti-inflammatory and organ protective effects. The aim of this study was to investigate the mechanism of action of corilagin and determine whether these effects are mediated through the Akt-dependent pathway in a trauma-hemorrhagic shock-induced liver injury rodent model. Hemorrhagic shock was induced in male Sprague-Dawley rats; mean blood pressure was maintained at 35 mm Hg to 40 mm Hg for 90 min, followed by fluid resuscitation. During resuscitation, three doses of corilagin alone (1 mg/kg, 5 mg/kg, or 10 mg/kg, intravenously) were administered. Furthermore, a single dose of corilagin (5 mg/kg) with and without Wortmannin (1 mg/kg, PI3K inhibitor), Wortmannin alone, or vehicle was administered. Twenty-four hours after resuscitation, plasma alanine aminotransferase and aspartate aminotransferase concentration and hepatic parameters were measured. One-way ANOVA was used for statistical analysis. Hepatic myeloperoxidase activity and the concentrations of plasma alanine aminotransferase and aspartate aminotransferase, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) and CINC-3 increased following hemorrhagic shock. These parameters were significantly attenuated in corilagin-treated rats following hemorrhagic shock. Hepatic phospho-Akt expression was also higher in corilagin-treated rats than in vehicle-treated rats. The elevation of phospho-Akt was abolished by combined treatment with Wortmannin and corilagin. Our results suggest that corilagin exerts its protective effects on hemorrhagic shock-induced liver injury, at least, via the Akt-dependent pathway.

Network Meta-Analysis Comparing Overall Survival for Fulvestrant 500 mg Versus Alternative Therapies for Treatment of Postmenopausal, Estrogen Receptor-Positive Advanced Breast Cancer Following Failure on Prior Endocrine Therapy.

BACKGROUND: We conducted a review of randomized trials to compare the overall survival (OS) with fulvestrant 500 mg versus alternative treatment for estrogen receptor-positive advanced breast cancer following endocrine therapy failure. MATERIALS AND METHODS: Hazard ratios (HRs) were obtained by modeling OS data with the Weibull distribution. A fixed-effect Bayesian network meta-analysis was conducted. The evidence network included anastrozole 1 mg, letrozole 2.5 mg, fulvestrant 250 mg, exemestane 25 mg, megestrol acetate 40 mg, and everolimus 10 mg plus exemestane 25 mg as comparators. Post-antiestrogen and post-aromatase inhibitor subgroup networks were analyzed. RESULTS: In the overall analysis, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg, and numerically favorable differences with fulvestrant 500 mg versus other comparators. In the antiestrogen subgroup, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg; numerical differences in the HRs were seen versus anastrozole 1 mg and letrozole 2.5 mg. In the aromatase inhibitor subgroup, the HRs for OS numerically favored fulvestrant 500 mg versus fulvestrant 250 mg and exemestane 25 mg. CONCLUSION: Acknowledging the limitations of the present network meta-analysis, these findings suggest that fulvestrant 500 mg might provide improved OS versus fulvestrant 250 mg and megestrol acetate 40 mg for treatment of estrogen receptor-positive ABC following endocrine therapy failure. Although OS efficacy versus everolimus 10 mg plus exemestane 25 mg (for overall evidence network), anastrozole 1 mg, exemestane 25 mg, and letrozole 2.5 mg is numerically favorable, additional studies are required to draw formal conclusions.

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover.

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial.

BACKGROUND: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting ß2 agonist (LABA). METHODS: This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone. RESULTS: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively. CONCLUSIONS: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP. TRIAL REGISTRATION NUMBER: NCT01513460.

A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD.

BACKGROUND: COPD guidelines recommend the combined use of inhaled long-acting ß2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) if symptoms are not improved by a single agent. This systematic review tested the hypothesis that the bronchodilator effect of the LABA/LAMA combination, umeclidinium (UMEC)/vilanterol (VIL), would translate into better outcomes without incurring increased adverse events (AEs). METHODS: This was a systematic review of randomized, placebo-controlled or crossover trials (> 4 weeks) involving UMEC/VIL compared with its monocomponents, tiotropium, or fluticasone/salmeterol. Primary outcomes were trough FEV1, serious adverse events (SAEs), and serious cardiovascular events (SCVEs). RESULTS: Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of AEs, SAEs, SCVEs, and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination. CONCLUSIONS: Once-daily inhaled UMEC/VIL showed superior efficacy compared with its monocomponents, tiotropium, and fluticasone/combination in patients with moderate to severe COPD.

The use of large volume low pressure nasal saline with fluticasone propionate for the treatment of pediatric acute rhinosinusitis.

OBJECTIVES: Fluticasone propionate and nasal saline irrigation have been used in the treatment of sinonasal diseases for a long time. Our study investigates the effect of the combination of large volume low pressure nasal saline irrigation and fluticasone propionate for the treatment of pediatric acute rhinosinusitis. METHODS: Ninety-one pediatric patients with acute rhinosinusitis were included in our study. The patients were randomized into two groups. The first group (n=45) was treated with standard therapy (antibiotherapy+nasal decongestant) for 2 weeks, the second group was treated with the large volume low pressure nasal saline+fluticasone propionate combination for 3 weeks. The clinical scores, radiologic evaluations (X-ray Waters view), peak nasal inspiratory flow (PNIF) measurements, total symptom scores and hematologic parameters (WBC, CRP, ESR) of the patients were evaluated and compared. RESULTS: There were no significant differences in between the two groups regarding age, gender, height and weight. Even though the clinical scores of Group 2 improved more rapidly, there were no significant differences in between groups regarding clinical scores by the 21st day. There were no significant differences in post treatment radiologic evaluations (Waters graphy). Both groups had significant improvement of their post treatment PNIF values, yet the improvement was more marked in Group 2 than in Group 1. The rhinorrhea, nasal congestion, throat itching and cough symptoms improved more rapidly in Group 2 than in Group 1. Post-treatment nose itching and sneezing symptoms were significantly less in Group 2. The values of hematologic parameters were significantly reduced at the end of the 3rd week in both groups. CONCLUSIONS: Our study is a first in investigating the combined use of large volume low pressure nasal saline and fluticasone propionate in acute pediatric rhinosinusitis, and the results reveal that the combination therapy was effective. Low pressure large volume nasal saline+fluticasone propionate combination can be employed as a new line of therapy for the treatment of pediatric acute rhinosinusitis, either by itself or combined with standard therapy.

Comparison of conventional medicine, TCM treatment, and combination of both conventional medicine and TCM treatment for patients with chronic obstructive pulmonary disease: study protocol of a randomized comparative effectiveness research trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects millions worldwide. Although many therapies exist and are being developed to relieve symptoms and reduce mortality, few data are available to understand which of the therapeutic alternatives is the most cost-effective for COPD patients in everyday clinical practice, especially for traditional Chinese medicine (TCM). Comparative effectiveness research can help patients, clinicians, and decision-makers make best informed treatment decisions where such evidence was previously lacking. This study aims to compare the effectiveness and economic evaluation of three treatments: (1) conventional Western medicine; (2) TCM treatments, which have been evaluated and have certain effect; and (3) a combination of both conventional Western medicine and TCM treatments, and then determine which treatment is the most suitable for COPD patients. METHODS/DESIGN: A multicenter, pragmatic, randomized, controlled trial is adopted. A total of 360 patients will be recruited and randomly assigned to one of the three treatments group, with 120 in each group. Patients in the conventional Western medicine group will be given Salbutamol, Formoterol, Salmeterol/fluticasone, respectively, according to the guidelines. For the TCM group, patients will be given Bufei granule, Bu-Fei Jian-Pi granule, Bu-Fei Yi-Shen granule, and Yi-Qi Zi-Shen granule based on their corresponding TCM syndrome patterns, respectively. For the combination of conventional medicine and TCM treatments group, patients will be given a combination of conventional Western medicine and TCM granules. Treatments in each group are recognized as a whole comprehensive intervention. After the 26-week treatment, another 26 weeks will be followed up. The outcome measures including the frequency and duration of acute exacerbations, lung function, dyspnea, exercise capacity, quality of life, and economic evaluation will be assessed. DISCUSSION: It is hypothesized that each of the three treatments will have beneficial effects in reducing the frequency and duration of acute exacerbations, improving exercise capacity and psychosocial function of COPD patients. In addition, the combination of conventional medicine and TCM treatments may be most suitable for COPD patients with better effectiveness and economic evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01836016.

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.

BACKGROUND: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. METHODS: In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. FINDINGS: Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. INTERPRETATION: Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. FUNDING: Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.

Complementary and alternative medicine use and adherence to asthma medications among Latino and non-Latino white families.

OBJECTIVE: The current study sought to evaluate patterns of complementary and alternative medicine (CAM) use in a sample of Latino and non-Latino white (NLW) children with asthma to determine whether parental beliefs about conventional medications and barriers to obtaining these medications were related to CAM use and to assess whether CAM use was associated with decreased adherence to controller medications. METHODS: Participants included 574 families of children with asthma from NLW, Puerto Rican (PR), and Dominican backgrounds from Rhode Island (RI) and from Island PR. All parents completed a brief checklist of barriers to medication use and an assessment of CAM approaches. A subsample of 259 families had controller medication use monitored objectively for approximately 1 month by MDILog (fluticasone propionate), TrackCap (montelukast), or dosage counter (fluticasone/salmeterol combination). RESULTS: Prevalence of CAM use was high among Latino families. Perceived barriers to obtaining medication were related to increased CAM use in PR families from RI. Elevated medication concerns were positively associated with CAM use among NLW and Island PR families. CAM use was positively related to objective adherence within NLW families, and unrelated in other groups. CONCLUSIONS: CAM use is common among Latino families with asthma. Among some families, CAM use may be initiated as a way to cope with barriers to obtaining medication or when parents have concerns about conventional medications. Families who report CAM use do not appear to be substituting CAM for conventional asthma medication.

New therapies for allergic rhinitis.

Because of its burden on patient's lives and its impact on asthma, allergic rhinitis must be treated properly with more effective and safer treatments. According to guidelines by Allergic Rhinitis and Its Impact on Asthma (ARIA), the classification, pathogenesis, and treatment of allergic rhinitis are well defined. Currently, second-generation antihistamines and inhaled steroids are considered the cornerstone of first-line therapy. However, new formulations of available drugs (e.g., loratadine and rupatadine oral solution, ebastine fast-dissolving tablets, and the combination of intranasal fluticasone propionate and azelastine hydrochloride), recently discovered molecules (e.g., ciclesonide, bilastine, and phosphodiesterase-4 inhibitors), immunologic targets (e.g., omalizumab), and unconventional treatments (e.g., homeopathic treatments) are currently under investigation and represent a new frontier in modern medicine and in allergic rhinitis management. The aim of this review is to provide an update on allergic rhinitis treatment, paying particular attention to clinical trials published within the past 20 months that assessed the efficacy and safety of new formulations of available drugs or new molecules.