Gokul Gopalan

Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study

BACKGROUND Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood eosinophil count and prospective annual asthma outcomes for a large UK cohort. METHODS This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541. FINDINGS Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio [RR] 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less. INTERPRETATION Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment. FUNDING Teva Pharmaceuticals.

Effect of inhalation profile and throat geometry on predicted lung deposition of budesonide and formoterol (BF) in COPD: An in-vitro comparison of Spiromax with Turbuhaler.

Successful delivery of inhalation medication to the lungs can be affected by the inhalation manoeuvre used. Conventional in-vitro testing of the emitted dose from a dry powder inhaler (DPI) uses a vacuum pump to simulate an inhalation. We have adapted this method by replacing the pump with patient inhalation profiles and an anatomical throat. Three anatomical throat sizes and three inhalation profiles were used. The profiles represented the 10th, 50th and 90th percentiles of peak inhalation flow and acceleration of flow from a population of 50 COPD patients inhaling through empty Spiromax and Turbuhaler devices. Combining the dose emission results for the three throat sizes, the mean (SD) budesonide fine-particle dose (FPD) from budesonide-formoterol Spiromax 320/9 μg was 78.91 (20.18), 79.91 (15.36) and 75.10 (19.91)μg and the total emitted dose (TED) of budesonide was 263.69 (40.74), 261.20 (21.65) and 261.61 (45.65)μg. Similarly, the FPD from 320/9 μg Turbuhaler was 22.45 (3.24), 52.20 (12.57) and 69.11 (75.10)μg with a TED of 143.80 (14.90), 149.50 (26.61) and 158.61 (43.04)μg. Spiromax showed greater consistency than Turbuhaler over a range of inspiratory flow profiles. The results demonstrate the value of this new method to assess the doses that patients receive during real-life use of their DPI.

Randomized controlled trial of desloratadine for persistent allergic rhinitis: correlations between symptom improvement and quality of life

Allergic rhinitis (AR) symptoms can impart emotional, quality of life (QOL), and work productivity burdens, especially in persistent AR (PER). Desloratadine, an H1-receptor antagonist, has been shown to be effective against nasal and nonnasal AR symptoms and to improve QOL. Exploratory analyses were conducted to evaluate whether desloratadine-mediated symptom improvement correlated with improvements in QOL and productivity. The Aerius Control: Clinical and Evaluative Profile of Treatment 2 (NCT00405964) study was a 12-week, multinational, randomized, placebo-controlled prospective study of once-daily desloratadine at 5 mg in subjects with moderate-to-severe PER. Assessments included twice-daily symptom severity ratings (0 = none to 3 = severe; total and individual symptoms), sleep interference (morning [A.M.]), interference with activities of daily living (ADL; evening [P.M.]), the Rhinoconjunctivitis Quality of Life Questionnaire-Standardized version (baseline and days 29 and 85), and the Work Productivity and Activity Impairment-Allergy-Specific questionnaire (baseline and weekly). Pearson product-moment correlation statistics (r) were determined to assess correlations between symptom score improvements and QOL factors. All desloratadine-treated patients (n = 360) were included in this exploratory analysis. In the desloratadine-treated patients, all correlations tested were positive (all p < 0.0001). The highest coefficients were seen for the correlations between A.M./P.M. PRIOR total five-symptom score and interference with ADL (r = 0.72) and between A.M. NOW congestion and ADL interference (r = 0.69). Continuous daily treatment of moderate-to-severe PER with desloratadine at 5 mg/day significantly improved symptoms, which correlated positively, albeit moderately, with QOL benefits and reversal of functional impairments caused by PER.

Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD.

Purpose Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2–4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD. Patients and methods Smokers and ex-smokers with COPD ≥40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection. Results Mean patient age was 67 years, 57%–60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32–4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 μg/day versus 436 μg/day for initiation, 438 μg/day versus 534 μg/day for step-up patients). Conclusion We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years’ follow-up.

Observational study comparing intranasal mometasone furoate with oral antihistamines for rhinitis and asthma

AIMS Retrospective database study comparing upper and lower airway-related outcomes for patients with rhinitis and co-morbid asthma receiving mometasone furoate--an intranasal corticosteroid with low systemic bioavailability--or an oral antihistamine. METHODS 395 patients prescribed intranasal mometasone were matched on 10 demographic and respiratory-related criteria in a 1:2 ratio to 790 patients prescribed oral antihistamine. Asthma and rhinitis control were assessed over one year using predefined composite proxy measures. RESULTS Asthma control was achieved by 309/395 (78.2%) versus 580/790 (73.4%; p=0.071) patients in the mometasone and antihistamine cohorts, respectively. Rhinitis control was achieved by 293 (74.2%) versus 539 (68.2%; p=0.035), respectively. The adjusted odds ratios for antihistamines, relative to mometasone, were 0.71 (95% CI, 0.52-0.98) for achieving asthma control and 0.74 (95% CI, 0.56-0.97) for achieving rhinitis control. CONCLUSIONS Patients with rhinitis and co-morbid asthma initiating rhinitis therapy achieved significantly better upper as well as lower airway outcomes with intranasal mometasone than with oral antihistamine.

Association between blood eosinophil count and risk of readmission for patients with asthma : Historical cohort study

Background Recent studies have demonstrated an association between high blood eosinophil counts and greater risk of asthma exacerbations. We sought to determine whether patients hospitalized for an asthma exacerbation were at greater risk of readmission if they had a high blood eosinophil count documented before the first hospitalization. Methods This historical cohort study drew on 2 years of medical record data (Clinical Practice Research Datalink with Hospital Episode Statistics linkage) of patients (aged ≥5 years) admitted to hospital in England for asthma, with recorded blood eosinophil count within 1 baseline year before admission. We analyzed the association between high blood eosinophil count (≥0.35x109 cells/L) and readmission risk during 1 year of follow-up after hospital discharge, with adjustment for predefined, relevant confounders using forward selection. Results We identified 2,613 eligible patients with asthma-related admission, of median age 51 years (interquartile range, 36–69) and 76% women (1,997/2,613). Overall, 835/2,613 (32.0%) had a preadmission high blood eosinophil count. During the follow-up year, 130/2,613 patients (5.0%) were readmitted for asthma, including 55/835 (6.6%) with vs. 75/1,778 (4.2%) without high blood eosinophil count at baseline (adjusted hazard ratio [HR] 1.49; 95% CI 1.04–2.13, p = 0.029). The association was strongest in never-smokers (n = 1,296; HR 2.16, 95% CI 1.27–3.68, p = 0.005) and absent in current smokers (n = 547; HR 1.00, 95% CI 0.49–2.04, p = 0.997). Conclusions A high blood eosinophil count in the year before an asthma-related hospitalization is associated with increased risk of readmission within the following year. These findings suggest that patients with asthma and preadmission high blood eosinophil count require careful follow-up, with treatment optimization, after discharge.

Development of the International Severe Asthma Registry (ISAR): A Modified Delphi Study

BACKGROUND The lack of centralized data on severe asthma has resulted in a scarcity of information about the disease and its management. The development of a common data collection tool for the International Severe Asthma Registry (ISAR) will enable standardized data collection, subsequently enabling data interoperability. OBJECTIVES To create a standardized list of variables for the first international registry for severe asthma via expert consensus. METHODS A modified Delphi process was used to reach consensus on a minimum set of variables to capture in ISAR: the core variables. The Delphi panel brought together 27 international experts in the field of severe asthma research. The process consisted of 3 iterative rounds. In each round, all Delphi panel members were issued an electronic ISAR Delphi workbook to complete and return to the ISAR Delphi administrator. Workbooks and result summaries were anonymously distributed by the Delphi administrator to all panel members at subsequent rounds. Finalization of the core variable list was facilitated by 2 face-to-face meetings. RESULTS Of the initial 747 selected variables, the Delphi panel reached a consensus on 95. The chosen variables will allow severe asthma to be assessed against patient demographics and medical history, patient-reported outcomes, diagnostic information, and clinical characteristics. Physician-reported outcomes such as nonadherence and information about treatment and management strategies will also be recorded. CONCLUSIONS This is the first global attempt to generate an ISAR using a common set of core variables to ensure that data collected across all participating countries are standardized.

Real-life effectiveness and safety of salbutamol Steri-Neb™ vs. Ventolin Nebules® for exacerbations in patients with COPD : Historical cohort study

Introduction Ventolin Nebules® (reference product; GlaxoSmithKline) was the first licensed nebulizer solution containing the rapid-onset, short-acting β2-agonist salbutamol. Salbutamol Steri-Neb™ (comparator; Teva Pharmaceuticals, Inc.) has the same chemical composition as the reference product. This study evaluated whether the effectiveness of the comparator is non-inferior to the reference product alongside concomitant medications during real-life clinical management of COPD exacerbations. Safety in terms of adverse events (AEs) was also examined. Methods This matched (1:1) historical cohort study evaluated data from 2 UK primary care databases on patients prescribed the salbutamol comparator or reference. The study included a 1-year baseline period, starting 1 year before the index prescription date, and 1-year outcome period. Cohorts were matched for baseline COPD respiratory medications. The primary outcome was analysis of non-inferiority for the comparator versus reference product for the rate of moderate and severe COPD exacerbations. Non-inferiority was satisfied if the 95% confidence interval (CI) upper limit for mean differences in proportions between treatments was <15%. Secondary outcomes were examined through rate ratios (RR) of severe exacerbations and AEs. Results After matching, 1191 patients were included in each cohort. Adjusted upper 95% CI for the difference in proportion of patients experiencing moderate or severe exacerbations between comparator and reference groups was 0.032 (3.2%), demonstrating non-inferiority. No significant differences were observed in rates of moderate and severe exacerbations (RR: 1.00; 95% CI: 0.91, 1.10), severe exacerbations (RR: 0.76; 95% CI: 0.49, 1.17), or AEs (RR: 0.98; 95% CI: 0.78, 1.22) after adjusting for baseline confounders. No significant differences across cohorts were observed for rates of any AE or death. Conclusion This matched cohort study of real-life management of COPD patients supports the salbutamol comparator as non-inferior to the reference product, providing an effective treatment alternative for COPD exacerbations. Comparator and reference safety profiles were similar.

Real-life effectiveness and safety of the inhalation suspension budesonide comparator vs the originator product for the treatment of patients with asthma: a historical cohort study using a US health claims database

Objective The objective of this study was to determine whether the effectiveness of budesonide comparator is non-inferior to budesonide reference in the prevention of asthma exacerbations. Asthma-related hospitalizations and safety were also examined. Methods This study used a matched, historic cohort design. Data were drawn from the Clinformatics™ Data Mart US claims database and included a 1-year baseline, starting 1 year before the index prescription date, and a 1-year outcome period. Patients received budesonide comparator or reference treatment. The primary outcome was the rate of asthma exacerbations. Non-inferiority for budesonide comparator vs budesonide reference was established if the 95% confidence interval (CI) upper limit of mean difference in proportions between treatments was <15%. Secondary outcomes examined rate of asthma-related hospitalizations and adverse events (AEs). Results The budesonide comparator and reference-matched cohorts each included 3109 patients. The adjusted upper 95% CI for the difference in proportions of patients experiencing asthma exacerbations was 0.035 (3.5%), demonstrating non-inferiority. Cohorts did not significantly differ in the rate of asthma exacerbations (adjusted rate ratio [RR]=1.04, 95% CI: 0.95–1.14) or rate of asthma-related hospitalizations (adjusted RR=1.10, 95% CI: 0.99–1.24) after adjusting for baseline confounders. No asthma exacerbations occurred during the outcome period in 72.9% of budesonide comparator patients and 71.8% of budesonide reference patients. No asthma-related hospitalizations occurred in 77.9% of patients in the budesonide comparator cohort and 79.0% of patients in the budesonide reference cohort. The most frequent AEs were throat irritation (≤0.4% of patients) and hoarseness/dysphonia (0.02% of patients). AEs did not significantly differ between treatment cohorts. Conclusion In this real-life study, non-inferiority of the budesonide comparator vs reference was met for the primary end point of asthma exacerbation rates. Asthma-related hospitalization and AE rates did not differ between the two treatment cohorts. The budesonide comparator is an effective and safe treatment alternative for asthma exacerbations.

Independent Identification of Handling Errors for Dry Powder Inhalers, Spiromax® and Turbuhaler®, Using a Delphi Process Involving Respiratory Device Experts

IntroductionCorrect use of inhalation devices is critical for optimal drug delivery to the lower lung. This Delphi process was conducted to compile lists of potential handling errors when using a Spiromax® or Turbuhaler® inhalation device, as determined by an independent panel.MethodsA Delphi process was used to obtain consensus on potential handling errors for each device from ten independent respiratory device experts. In Round 1, advisors listed potential errors with the devices. In Round 2, a severity rating was assigned to each error based on erroneous device handling negatively affecting functionality and treatment effectiveness (error [score 0–3]; potentially critical [4–7]; critical [8–10]). In Round 3, advisors revised their ratings based on the group scores and voted on whether to accept the median severity score as the consensus in Round 4.ResultsA total of 29 potential errors for Spiromax and 31 for Turbuhaler were identified in Round 1. After Round 4, consensus was reached for 69% of the Spiromax errors and 94% of the Turbuhaler errors. After completion of the Delphi process, some anomalies were identified in the list of handling errors, which were then investigated with the panel via teleconferences. After teleconferences to discuss discrepancies in the results, there were 22 errors for Spiromax (four critical, 12 potentially critical, and six errors) and 27 for Turbuhaler (nine critical, 14 potentially critical, and four errors). Not inhaling through the mouthpiece, exhaling into the device, and incorrect mouth positioning were identified as critical errors for both devices.ConclusionThrough the Delphi process, advisors independently identified and reached consensus on handling errors for Spiromax and Turbuhaler. Fewer Spiromax errors were classified as critical or potentially critical than with Turbuhaler, indicating that there may be less potential for handling errors with Spiromax.FundingTeva Branded Pharmaceutical Products R & D, Inc.