Women manifest more severe COPD symptoms across the life course.

BACKGROUND: Previous studies suggest that gender differences exist in COPD diagnosis and symptoms; these differences may be more pronounced in younger adults. Our objective was to explore age-associated gender differences across a range of COPD severities. MATERIALS AND METHODS: A total of 4,484 current and former smokers with COPD from the Genetic Epidemiology of COPD cohort were investigated using regression modeling to explore the association between gender, age, disease severity, and the contributing elements of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system (symptoms, exacerbation risk, airflow limitation). RESULTS: The age-gender interaction was observed across multiple age categories. Compared to men with COPD, younger women with COPD had a greater likelihood of more severe dyspnea, airflow limitation, greater risk for exacerbations, and categorization in GOLD groups B and D. These differences were less pronounced in older women with COPD. However, older women remained more likely to experience severe dyspnea and to manifest more severe COPD (B vs A) than older men, despite lower pack-years of smoking. CONCLUSION: These data demonstrate the significant symptom burden of COPD in women, especially younger women. More research is needed to understand the pathogenesis of increased severity of COPD in women and to develop gender-targeted clinical assessment and management approaches to improve outcomes for women and men with COPD at all ages.

Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies.

PURPOSE: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 µg and once-daily UMEC/VI 62.5/25 µg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

Inhalation of tobramycin using simulated cystic fibrosis patient profiles.

INTRODUCTION: TOBI® Podhaler™ is a capsule-based drug-device combination (tobramycin inhalation powder [TIP] 28 mg capsules via unit-dose dry powder T-326 Inhaler [Podhaler™]) developed for treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF). We explored how inspiratory flow profiles and mouth-throat geometries affect drug delivery with the T-326 Inhaler. METHODS: Inspiratory flow profiles were recorded from 38 subjects aged 6-71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDin vitro ) was measured using four anatomical throat models, ranging from a child to a large adult. RESULTS: Aerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDin vitro ranged from 54.8% to 72.4% of capsule content between the flow profile/throat options tested, and the mean TLDin vitro across the range of flow profiles and anatomical throats tested was 63 ± 5%. CONCLUSIONS: Our findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLDin vitro . Pediatr Pulmonol. 2016;51:1159-1167. © 2016 Wiley Periodicals, Inc.

Randomized study of antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan monotherapy in hypertensive participants with type 2 diabetes mellitus.

In this double-blind study, 1143 hypertensive participants with type 2 diabetes and stage 1 or 2 chronic kidney disease (CKD) were randomized to receive combination aliskiren/valsartan 150/160 mg or valsartan 160 mg monotherapy for 2 weeks, with force-titration to 300/320 mg and 320 mg, respectively, for another 6 weeks. Ambulatory blood pressure (ABP), the primary outcome, was available for 665 participants. Reductions from baseline to week 8 in 24-hour ABP were -14.1/-8.7 mm Hg with aliskiren/valsartan vs -10.2/-6.3 mm Hg with valsartan (P<.001). Adverse events were reported in 202 participants (35.2%) taking aliskiren/valsartan and 182 participants (32.2%) taking valsartan. No participant had blood urea nitrogen values>40 mg/dL or serum creatinine values>2.0 mg/dL. There were no confirmed cases of serum potassium values≥6.0 mEq/L. Combination aliskiren/valsartan has additive effects on blood pressure reduction and tolerability similar to valsartan in hypertensive/diabetic participants with early-stage (stages 1 and 2) CKD.

Economic burden of gouty arthritis attacks for employees with frequent and infrequent attacks.

The objective of this study was to compare episode-related and annual costs and work absence days for employees with <3 versus ≥ 3 annual gout attacks. Human Capital Management Services data (2009-2010) from adult employees with gout (International Classification of Diseases, Ninth Revision code 274.x) and ≥ 12 months of medical and pharmacy benefits were studied. Outcomes of interest included medical and drug costs, number of emergency department and urgent care visits, number of inpatient days, short- and long-term disability, sick leave, workers' compensation costs, and work absence days. An algorithm based on diagnosis code and antigout medication use identified acute gout treatment episodes. Multivariate analysis compared annual and pre-episode vs. during-episode outcomes for employees with ≥ 3 vs. <3 gout annual attacks. Of 3361 employees with gout, 76 had ≥ 3 attacks; these employees had higher short-term disability costs ($1663 vs. $643, P=0.06) and days (11.68 versus 4.61, P<0.05), more emergency room visits (0.55 vs. 0.23, P<0.0001), and urgent care visits (0.07 vs. 0.04, P<0.01), and lower pharmacy costs ($1677 vs. $1108, P<0.0001) than those with <3 attacks. Medical costs both before ($203 higher) and during attacks ($136 higher) were significantly higher for those with ≥ 3 attacks than for those with <3 attacks. Additionally, a quadratic increasing relationship was found between number of attacks and cost. Frequency of acute gout attacks (≥ 3 episodes per year) among employees with gout was associated with greater short-term disability cost, absence days, and emergency department and urgent care visits, and trends toward higher overall costs.

The effect of gout on health-related quality of life, work productivity, resource use and clinical outcomes among patients with hypertension.

Although gout has been found to be associated with health-related quality of life (HRQoL), few studies have examined the burden of gout in the presence of concomitant cardiometabolic conditions. The present study evaluated the effect of gout on HRQoL and work productivity among patients with hypertension. Data from the 2010 National Health and Wellness Survey were obtained for respondents ≥18 years of age who had self-reported, physician-diagnosed hypertension or blood pressure levels ≥140/90 mmHg (≥130/80 mmHg for those with physician-diagnosed diabetes or chronic kidney disease). Bivariate analysis was used to evaluate differences between patients with and without self-reported comorbid gout. Generalized linear models were used to evaluate differences in productivity (using the Work Productivity and Activity Impairment scale) and HRQoL (using the physical component summary [PCS], mental component summary and health utilities from the SF-12v2 health survey). As uric acid levels may influence other organ systems, core modeling did not include comorbidities other than osteoarthritis and depression as covariates. Sensitivity analyses were controlled for the Charlson comorbidity index. A total of 22,686 patients with self-reported hypertension met study eligibility requirements. Of these, 4.51% reported having gout. These patients were older, more likely to be male and have insurance through Veteran Affairs (all p-values < 0.05). Patients with comorbid gout reported lower levels of mental component summary scores (47.25 vs 48.93), PCS scores (39.06 vs 43.78) and health utilities (0.68 vs 0.73; all p-values < 0.05). For both PCS and health utilities, differences between groups exceeded clinically meaningful cutoffs. Sensitivity analyses conducted on PCS and health utilities uncovered slightly smaller, but statistically significant and clinically meaningful, effects (p-values < 0.05). The effect of gout on overall work impairment (23.33 vs 17.40% with and without comorbid gout, respectively) remained after controlling for the Charlson comorbidity index. Significantly greater impairment in daily activities (38.96 vs 28.32%; p < 0.05) was also observed among patients with comorbid gout. Results demonstrate that gout has significant and clinically meaningful impact on work productivity, physical HRQoL and utilities independent of other health conditions.

Comparison of patient characteristics and gout-related health-care resource utilization and costs in patients with frequent versus infrequent gouty arthritis attacks.

OBJECTIVE: To examine the association between frequent gouty arthritis and the presence of absolute/relative contraindications to gout therapies, and health-care expenditure associated with frequent gouty arthritis. METHODS: This retrospective study used administrative claims to identify patients with gouty arthritis between 1 July 2005 and 30 June 2010. Patients with ≥3 yearly gouty arthritis attacks (frequent gout) were matched 1:2 to patients with <3 yearly attacks (infrequent gout). Absolute and relative contraindications to gout medications were evaluated based on product labelling. Negative binomial regression and generalized linear models with logarithmic transformation were used for multivariate analysis of overall and gout-related health-care use and cost. RESULTS: Mean patient age was 58 years (n = 15 669) and 77% were men. Compared with patients with infrequent gout, those with frequent gout had higher rates of absolute/relative contraindications to NSAIDs (91.5% vs 78.7%, P < 0.0001), corticosteroids (96.4% vs 87.3%, P < 0.0001), allopurinol (51.0% vs 41.2%, P < 0.0001) and probenecid (13.4% vs 9.4%, P < 0.0001). Mean gout-related costs were $889 for frequent gout vs $210 for infrequent gout (P < 0.0001) and all-cause direct costs were $10 913 for frequent vs $10 685 for infrequent gout (P = ns). Mean all-cause outpatient visits among patients with comorbidities compared with those without were 25.8 vs 11.8 among frequent and 19.7 vs 9.0 among infrequent (both P < 0.001) groups. Gout-related costs were higher among frequent gout patients with comorbidities than those without comorbidities ($886 vs $513, P = 0.03). CONCLUSION: Patients with frequent gouty arthritis are likely to have absolute and/or relative contraindications to gout medications and higher gout-related treatment costs.

Comparison of the effects of aliskiren/valsartan in combination versus valsartan alone in patients with stage 2 hypertension.

The extent to which the combination of a renin inhibitor with an angiotensin receptor blocker (ARB) lowers clinic and ambulatory blood pressure (BP) versus an ARB alone in stage 2 hypertension is not well known. Hence, we performed an 8-week, randomized, double-blind study in 451 patients with stage 2 hypertension to compare the efficacy of the combination of aliskiren/valsartan 300/320 mg versus valsartan 320 mg. The primary endpoint was change in seated systolic BP from baseline to week 8 analyzed on the intent-to-treat (ITT) population using the last-observation-carried-forward (LOCF) approach; patients completing the entire treatment period (per-protocol completers) were similarly analyzed. For the predefined primary analysis, systolic BP reductions for aliskiren/valsartan (n = 230) and valsartan (n = 217) were -22.1 and -20.5 mm Hg, respectively (P = .295). In per-protocol completers, aliskiren/valsartan (n = 201) lowered BP significantly greater than valsartan (n = 196); -23.7 mm Hg versus -20.3 mm Hg, respectively (P = .028). Although limited by a small sample size (n = 76) using ambulatory BP monitoring, aliskiren/valsartan lowered the 24-hour BP significantly more than valsartan alone (-14.6/-9.0 mm Hg versus -5.9/-4.2 mm Hg; P < .01). Safety and tolerability were similar for the two treatment groups. These data demonstrate the importance of multiple modalities to assess BP changes in clinical trials of antihypertensive therapies, particularly in stage 2 hypertension.

Comparison of aliskiren/hydrochlorothiazide combination therapy and amlodipine monotherapy in patients with stage 2 systolic hypertension and type 2 diabetes mellitus.

Patients with stage 2 hypertension and diabetes are at high cardiovascular risk and require large blood pressure (BP) reductions to reach treatment goals. This randomized double-blind study compared aliskiren/hydrochlorothiazide (HCTZ) combination therapy with amlodipine monotherapy in 860 patients with mean sitting systolic BP (msSBP) ≥160 mm Hg to <200 mm Hg and type 2 diabetes. Patients received either once-daily aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg for 1 week then force-titrated to double the doses for 7 weeks. Baseline BP was 167.7/91.4 mm Hg. At week 8 end point, aliskiren/HCTZ provided significantly greater reductions in msSBP than amlodipine (28.8 mm Hg vs 26.2 mm Hg; P<.05). Mean sitting diastolic BP reductions were similar with aliskiren/HCTZ (9.9 mm Hg) and amlodipine (9.0 mm Hg). Achievement of BP control (<130/80 mm Hg) was significantly greater with aliskiren/HCTZ (23.2%) than amlodipine (13.8%; P<.0001). Aliskiren/HCTZ provides substantial msSBP reductions and greater BP control rates than amlodipine, and offers an attractive treatment option for patients with hypertension and diabetes mellitus.

Central Pressure and Biomarker Responses to Renin Inhibition with Hydrochlorothiazide and Ramipril in Obese Hypertensives: The ATTAIN Study.

BACKGROUND/AIMS: In obese, hypertensive subjects, the renin-angiotensin system (RAS) is enhanced and natriuresis impaired, suggesting a role for combination RAS blockade with diuretics. Data suggest that renin inhibition may attenuate diuretic-induced RAS activation and oxidative stress. METHODS: In this 8-week, double-blind study of 386 obese individuals (mean body mass index: 35.3) with stage 2 hypertension (mean age: 54.9 years; mean sitting systolic blood pressure, SBP: ≧160 but <200 mm Hg), we compared the efficacy of aliskiren + hydrochlorothiazide (HCTZ) in reducing blood pressure (BP), plasma renin activity (PRA), and a urinary marker of oxidative stress to ramipril. Subjects were randomized to aliskiren/HCTZ 150/12.5 mg or ramipril 5 mg for 1 week, and after the 1st week force titrated to aliskiren/HCTZ 300/25 mg or ramipril 10 mg for 7 weeks. RESULTS: After 8 weeks, aliskiren/HCTZ provided greater reductions in office BP than ramipril (-28.1/-10.1 vs. -16.6/-3.6 mm Hg, p < 0.0001) as well as 24-hour ambulatory and central pressure measures. Aliskiren/HCTZ also lowered PRA (-45 vs. +83%) and the urinary F2-isoprostane/creatinine ratio (-18 vs. +7%) to a greater extent than ramipril. Adverse events (AEs) were similar in the two groups (35.8% with aliskiren/HCTZ vs. 37.3% on ramipril reporting at least one AE). CONCLUSIONS: Our findings suggest that the aliskiren/HCTZ combination reduced BP, PRA, and isoprostanes to a greater extent than did ramipril in obese patients with stage 2 hypertension.

Effects of high- and low-sodium diets on ambulatory blood pressure in patients with hypertension receiving aliskiren.

Dietary sodium reduction and, as necessary, pharmacologic treatment are recommended for hypertension management. This prospective, randomized, open-label, blinded-end point, multicenter, crossover study investigated the effect of dietary sodium intake on mean ambulatory systolic blood pressure (maSBP) in patients with hypertension receiving aliskiren 300 mg once daily. Following a 2- to 4-week washout period, patients were randomized to a high- (≥ 200 mmol/d) or low- (≤ 100 mmol/d) sodium diet and were started on aliskiren, 300 mg/d. After 4 weeks, patients were crossed over to the alternate diet for an additional 4 weeks. The primary efficacy variable was change in maSBP between diets. During treatment with aliskiren, maSBP was significantly lower with the low-sodium diet compared with the high-sodium diet (least squares mean difference, 9.4 mm Hg; 95% CI, 7.5-11.4; P < .0001). The percentage of patients achieving a maSBP response to aliskiren (<130 mm Hg or a ≥ 20-mm Hg reduction from baseline) was greater with the low- (76.5%) versus the high-sodium diet (42.6%; P < .0001). Overall, 40.9% patients had ≥ 1 adverse event and the rates were similar between groups. In this study, aliskiren was well tolerated and a low-sodium diet accentuated its antihypertensive effect.