Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study.

Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy.

BACKGROUND: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. OBJECTIVE: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. METHODS: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. RESULTS: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. CONCLUSIONS: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction.

Adrenal function recovery after durable oral corticosteroid sparing with benralizumab in the PONENTE study.

BACKGROUND: Oral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day-1 (median (range) 0.0 (0.0-40.0) mg). METHODS: The maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For ∼6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations. Outcomes included changes in daily OCS dosage, Asthma Control Questionnaire (ACQ)-6 and St George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations and adverse events. RESULTS: 598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median (range) OCS dosage was unchanged (0.0 (0.0-40.0) mg), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18 and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (-19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports. CONCLUSIONS: Most patients successfully maintained maximal OCS reduction while achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function.

Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.

BACKGROUND: No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation. METHODS: This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per µL at enrolment or ≥300 cells per µL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1-5 mg every 1-4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307. FINDINGS: Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86-66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62-84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2-3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations. INTERPRETATION: Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm. FUNDING: AstraZeneca.

Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis.

BACKGROUND: Clinically meaningful improvement in the Sino-Nasal Outcome Test-22 (SNOT-22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT-22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP. METHODS: Adults with severe, eosinophilic asthma who had experienced ≥2 prior-year exacerbations despite high-dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician-diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT-22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1 ), and Asthma Control Questionnaire-6 (ACQ-6). All p-values were nominal. RESULTS: Of the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior-year AER = 3.3; mean pre-bronchodilator FEV1  = 55% predicted; and median blood eosinophil count â€‹= 510 cells/µl. For patients with high baseline SNOT-22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT-22 from baseline to Week 24 compared with placebo (Week 24: -10.44 [p = .0176]). Percentage of responders to SNOT-22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT-22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p < .0001) and greater clinically meaningful improvements from baseline in SGRQ total score (-16.7), FEV1 (+0.32 L), and ACQ-6 (-0.88) were observed (p < .0001). Benralizumab was well-tolerated. Frequency of adverse events (AEs) was similar for benralizumab (76.0%) and placebo (73.7%) groups. Most common AEs (frequency ≥5%) reported at a greater frequency in benralizumab vs. placebo included headache, sinusitis, pyrexia, and influenza. CONCLUSIONS: These substudy data from ANDHI demonstrated the efficacy profile of benralizumab for patients with severe, eosinophilic asthma and NP, with improvement in SNOT-22 and asthma outcomes.

Predicting asthma-related crisis events using routine electronic healthcare data: a quantitative database analysis study.

BACKGROUND: There is no published algorithm predicting asthma crisis events (accident and emergency [A&E] attendance, hospitalisation, or death) using routinely available electronic health record (EHR) data. AIM: To develop an algorithm to identify individuals at high risk of an asthma crisis event. DESIGN AND SETTING: Database analysis from primary care EHRs of people with asthma across England and Scotland. METHOD: Multivariable logistic regression was applied to a dataset of 61 861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage Databank of 174 240 patients from Wales. Outcomes were ≥1 hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance, or death (validation dataset) within a 12-month period. RESULTS: Risk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking, and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a receiver operating characteristic of 0.71 (95% confidence interval [CI] = 0.70 to 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI = 5.3% to 6.1%) and a negative predictive value of 98.9% (95% CI = 98.9% to 99.0%), with sensitivity of 28.5% (95% CI = 26.7% to 30.3%) and specificity of 93.3% (95% CI = 93.2% to 93.4%); those individuals had an event risk of 6.0% compared with 1.1% for the remaining population. In total, 18 people would need to be followed to identify one admission. CONCLUSION: This externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding those not at high risk.

Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial.

BACKGROUND: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. METHODS: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18-75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per µL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. FINDINGS: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39-0·65; p<0·0001) over the 24-week treatment period and provided clinically meaningful and statistically significant improvement from baseline to week 24 in SGRQ total score versus placebo (least squares mean change from baseline -8·11 (95% CI -11·41 to -4·82; p<0·0001), with similar differences at earlier timepoints. Benralizumab improved FEV1, PEF, ACQ-6, CGI-C, PGI-C, PSIA, and SNOT-22 at week 24 versus placebo, with differences observed early (within weeks 1 to 4). Adverse events were reported for 271 (63%) of 427 patients on benralizumab versus 143 (62%) of 229 patients on placebo. The most commonly reported adverse events for the 427 patients receiving benralizumab (frequency >5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. INTERPRETATION: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. FUNDING: AstraZeneca.

Performance of database-derived severe exacerbations and asthma control measures in asthma: responsiveness and predictive utility in a UK primary care database with linked questionnaire data.

BACKGROUND: Observational research is essential to evaluate the real-life effectiveness of asthma treatments and can now make use of outcomes derived from electronic medical records. AIM: The aim of this study was to investigate the utility of several database outcome measures in asthma. METHODS: This study identified cohorts of patients with active asthma from a UK primary care database - Optimum Patient Care Research Database - approximately 10% of which was prospectively supplemented with questionnaire data. The "Questionnaire cohort" included patients aged 18-60 years with valid questionnaire data and 1 year of continuous primary care data. Separate "ICS initiation" and "ICS step-up" cohorts included patients aged 5-60 years initiated on inhaled corticosteroids (ICSs), who had 1 year of continuous primary care data before, and after, this index visit. Database measures of asthma symptom control and exacerbations were identified in the Optimum Patient Care Research Database and cross-tabulated with corresponding patient-reported (questionnaire) data. Responsiveness of the database outcomes was analyzed, using McNemar's and Wilcoxon's signed rank tests, and Poisson regression was used to estimate the association between database outcomes and future risk of database exacerbations, in the ICS initiation cohort. RESULTS: The final study included 2,366 Questionnaire cohort patients and 51,404 ICS initiation patients. Agreement between patient-reported and database-recorded exacerbations was fair (kappa 0.35). Following the initiation of ICS, database risk domain asthma control (based on exacerbations) improved (proportion of patients with uncontrolled asthma decreased from 24.9% to 18.6%; P<0.001) and mean number of database exacerbations decreased from 0.09 to 0.08 per patient per year (P=0.001). However, another measure of asthma control which includes short-acting beta-agonist prescription as part of the definition did not show this improvement. Patients with prior exacerbations had a higher risk of future exacerbation (rate ratio [95% confidence interval], 3.23 [3.03-3.57]). CONCLUSION: Asthma control and exacerbations derived from primary care databases were responsive, with the exception of short-acting beta-agonist prescriptions, and useful for risk prediction.

Applying UK real-world primary care data to predict asthma attacks in 3776 well-characterised children: a retrospective cohort study.

Current understanding of risk factors for asthma attacks in children is based on studies of small but well-characterised populations or pharmaco-epidemiology studies of large but poorly characterised populations. We describe an observational study of factors linked to future asthma attacks in large number of well-characterised children. From two UK primary care databases (Clinical Practice Research Datalink and Optimum Patient Care research Database), a cohort of children was identified with asthma aged 5-12 years and where data were available for ≥2 consecutive years. In the "baseline" year, predictors included treatment step, number of attacks, blood eosinophil count, peak flow and obesity. In the "outcome" year the number of attacks was determined and related to predictors. There were 3776 children, of whom 525 (14%) had ≥1 attack in the outcome year. The odds ratio (OR) for one attack was 3.7 (95% Confidence Interval (CI) 2.9, 4.8) for children with 1 attack in the baseline year and increased to 7.7 (95% CI 5.6, 10.7) for those with ≥2 attacks, relative to no attacks. Higher treatment step, younger age, lower respiratory tract infections, reduced peak flow and eosinophil count >400/µL were also associated with small increases in OR for an asthma attack during the outcome year. In this large population, several factors were associated with a future asthma attack, but a past history of attacks was most strongly associated with future attacks. Interventions aimed at reducing the risk for asthma attacks could use primary care records to identify children at risk for asthma attacks.

Fatigue independently predicts different work disability dimensions in etanercept-treated rheumatoid arthritis and ankylosing spondylitis patients.

BACKGROUND: Work disability remains a significant problem in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), despite biological therapy. This study aimed to test the hypothesis that the prevalent symptom of fatigue longitudinally predicts work disability among RA and AS patients commencing etanercept. METHODS: Two observational studies, comprising RA and AS etanercept commencers, respectively, were analysed. Both provided data on work disability over 1 year and a comprehensive set of putative predictors, including fatigue. A series of repeated measures models were conducted, including baseline variables, visit (6/12 months), and the interaction between visit and each of the explanatory variables. RESULTS: A total of 1003 AS and 1747 RA patients were assessed. For AS, fatigue was significantly associated with presenteeism (linear mixed model coefficient 3.75, 95% confidence interval (CI) 2.14 to 5.36) and activity impairment (2.62, 1.26 to 3.98), but not with work productivity loss (1.81, -0.40 to 4.02) or absenteeism (generalised linear mixed model odds ratio (OR) 1.18, 95% CI 0.92 to 1.51). In RA, fatigue was associated with presenteeism (coefficient 3.44, 95% CI 2.17 to 4.70), activity impairment (1.52, 0.79 to 2.26), work productivity loss (4.16, 2.47 to 5.85), and absenteeism (OR 1.23, 95% CI 1.02 to 1.49). The lack of significant interactions between fatigue and visit supported a consistent effect of baseline fatigue over time. CONCLUSIONS: Among patients beginning etanercept therapy, fatigue has a significant and independent effect on absenteeism, presenteeism, productivity loss, and activity impairment for RA patients and a significant but dimension-selective effect on work disability among AS patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00544557 . Registered on 16 October 2007. ClinicalTrials.gov, NCT00488475 . Registered on 20 June 2006.

Bosentan-based, treat-to-target therapy in patients with pulmonary arterial hypertension: results from the COMPASS-3 study.

The phase 4 COMPASS-3 study evaluated whether a singular endpoint produces clinically meaningful outcomes in patients with pulmonary arterial hypertension (PAH). The relationship between cardiac magnetic resonance imaging (cMRI)-derived parameters and right heart catheterization (RHC) measurements was also examined. In COMPASS-3 (ClinicalTrials.gov NCT00433329), 100 patients with PAH received bosentan monotherapy for 16 weeks. Patients continued monotherapy if their 6-min walk distance (6MWD) was ≥380 m, or otherwise received add-on sildenafil for an additional 12 weeks. 6MWD, RHC, and cMRI were performed at baseline, week 16, and week 28 (6MWD and cMRI). Baseline median 6MWD was 274 m and 82% of patients had WHO Functional Class III/IV. At week 16, 17% (n = 16) of remaining patients achieved the 6MWD threshold and 78 (83%) did not. In the intention-to-treat population, median 6MWD increased significantly relative to baseline (week 16 = 308 m; week 28 = 327 m; P < 0.001). At week 28, 9/16 (monotherapy) and 15/76 (20%; add-on sildenafil) patients met the target threshold. Baseline cMRI-derived and RHC-derived parameters showed moderate-to-strong correlations (e.g. right to left ventricular end-diastolic ratio [RVEDV:LVEDV] correlated strongly with pulmonary vascular resistance [r = +0.729, P < 0.0001]). cMRI-derived parameters predicted clinical worsening/decline (e.g. week 16 RVEDV:LVDEV [ P = 0.0172]). Time to clinical worsening/decline did not differ between patients based on 6MWD threshold achievement. No unexpected safety events were reported. A substantial proportion of patients failed to achieve the goal of 380 m, regardless of treatment. Several cMRI parameters predicted clinical worsening/decline and its non-invasive nature further supports its use in future clinical trials.

Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids.

BACKGROUND: Regular use of inhaled corticosteroids (ICS) in patients with obstructive lung diseases has been associated with a higher risk of pneumonia, particularly in COPD. The risk of pneumonia has not been previously evaluated in relation to ICS particle size and dose used. METHODS: Historical cohort, UK database study of 23,013 patients with obstructive lung disease aged 12-80 years prescribed extra-fine or fine-particle ICS. The endpoints assessed during the outcome year were diagnosis of pneumonia, acute exacerbations and acute respiratory events in relation to ICS dose. To determine the association between ICS particle size, dose and risk of pneumonia in unmatched and matched treatment groups, logistic and conditional logistic regression models were used. RESULTS: 14788 patients were stepped-up to fine-particle ICS and 8225 to extra-fine ICS. On unmatched analysis, patients stepping-up to extra-fine ICS were significantly less likely to be coded for pneumonia (adjusted odds ratio [aOR] 0.60; 95% CI 0.37, 0.97]); experience acute exacerbations (adjusted risk ratio [aRR] 0.91; 95%CI 0.85, 0.97); and acute respiratory events (aRR 0.90; 95%CI 0.86, 0.94) compared with patients stepping-up to fine-particle ICS. Patients prescribed daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) had a significantly higher risk of pneumonia (OR [95%CI] 2.38 [1.17, 4.83]) compared with patients prescribed lower doses, irrespective of particle size. CONCLUSIONS: These findings suggest that patients with obstructive lung disease on extra-fine particle ICS have a lower risk of pneumonia than those on fine-particle ICS, with those receiving higher ICS doses being at a greater risk.

Initial step-up treatment changes in asthmatic children already prescribed inhaled corticosteroids: a historical cohort study.

BACKGROUND: When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children aged >4 years, guidelines recommend the addition of a long-acting ß2-agonist (LABA), with other treatment options being available if symptoms persist. AIMS: To determine the proportion of initial 'step-up' episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA. METHODS: Between 1999 and 2011, initial step-up episodes from ICS monotherapy were identified in children aged 5-12 years with asthma and in receipt of ICS. Data sources were the Clinical Practice Research Datalink and Optimum Patient Care Research Database. RESULTS: Initial step-up episodes were identified in 10,793 children. ICS dose was increased in 6,252 children (58%), LABA was introduced in 3,436 (32%; including 1,107 where fixed dose combination inhaler (FDC) replaced the ICS inhaler), and leukotriene receptor antagonist (LTRA) was added in 1,105 (10%). Compared with children stepped up to any LABA, others were younger and prescribed lower doses of ICS and reliever medication. ICS dose increase was more likely in obese children and LTRA prescribing was more likely in children with rhinitis and in receipt of antibiotics. Compared with FDC, step-up to separate LABA inhaler was more likely in younger, obese children who were using less oral steroids. CONCLUSIONS: One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings.

Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response. AIM: To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management. METHODS: Eligible patients (n = 678) were those in the Optimum Patient Care Research Database (OPCRD) aged 4-80 years who, at an index date, had their first FeNO assessment via NIOX MINO® or Flex®. Eligible practices were those using FeNO measurement in at least ten patients during the study period. Patients were characterized over a one-year baseline period immediately before the index date. Outcomes were evaluated in the year immediately following index date for two patient cohorts: (i) those in whom FeNO measurement was being used to identify steroid-responsive disease and (ii) those in whom FeNO monitoring was being used to guide on-going asthma management. Outcomes for cohort (i) were incidence of new ICS initiation at, or within the one-month following, their first FeNO measurement, and ICS dose during the outcome year. Outcomes for cohort (ii) were adherence, change in adherence (from baseline) and ICS dose. OUTCOMES: In cohort (i) (n = 304) the higher the FeNO category, the higher the percentage of patients that initiated ICS at, or in the one month immediately following, their first FeNO measurement: 82%, 46% and 26% of patients with high, intermediate and low FeNO, respectively. In cohort (ii) (n = 374) high FeNO levels were associated with poorer baseline adherence (p = 0.005) but greater improvement in adherence in the outcome year (p = 0.017). Across both cohorts, patients with high FeNO levels were associated with significantly higher ICS dosing (p < 0.001). CONCLUSIONS: In the UK, FeNO is being used in primary practice to guide ICS initiation and dosing decisions and to identify poor ICS adherence. Simple algorithms to guide clinicians in the practical use of FeNO could improved diagnostic accuracy and better tailored asthma regimens.

Clinical and cost effectiveness of switching asthma patients from fluticasone-salmeterol to extra-fine particle beclometasone-formoterol: a retrospective matched observational study of real-world patients.

BACKGROUND: Efficacy trials suggest that extra-fine particle beclometasone dipropionate-formoterol (efBDP-FOR) is comparable to fluticasone propionate-salmeterol (FP-SAL) in preventing asthma exacerbations at a clinically equivalent dosage. However, switching from FP-SAL to efBDP-FOR has not been evaluated in real-world asthma patients. AIMS: The REACH (Real-world Effectiveness in Asthma therapy of Combination inHalers) study investigated the clinical and cost effectiveness of switching typical asthma patients from FP-SAL to efBDP-FOR. METHODS: A retrospective matched (1:3) observational study of 1,528 asthma patients aged 18-80 years from clinical practice databases was performed. Patients remaining on FP-SAL (n=1,146) were compared with those switched to efBDP-FOR at an equivalent or lower inhaled corticosteroid (ICS) dosage (n=382). Clinical and economic outcomes were compared between groups for the year before and after the switch. Non-inferiority (at least equivalence) of efBDP-FOR was tested against FP-SAL by comparing exacerbation rates during the outcome year. RESULTS: efBDP-FOR was non-inferior to FP-SAL (adjusted exacerbation rate ratio 1.01 (95% CI 0.74 to 1.37)). Switching to efBDP-FOR resulted in significantly better (p<0.05) odds of achieving overall asthma control (no asthma-related hospitalisations, bronchial infections, or acute oral steroids; salbutamol ≤200µg/day) and lower daily short-acting ß2-agonist usage at a lower daily ICS dosage (mean -130µg/day FP equivalents; p<0.001). It also reduced mean asthma-related healthcare costs by £93.63/patient/year (p<0.001). CONCLUSIONS: Asthma patients may be switched from FP-SAL to efBDP-FOR at an equivalent or lower ICS dosage with no reduction in clinical effectiveness but a significant reduction in cost.

Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care.

PURPOSE: Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy. METHODS: This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler [pMDI] for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma). RESULTS: Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval [CI], 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452). CONCLUSIONS: These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.

Device type and real-world effectiveness of asthma combination therapy: an observational study.

BACKGROUND: Selection of inhaler device type appears to influence real-world effectiveness of inhaled corticosteroids (ICS), but data are lacking on the role of inhaler device in ICS and long-acting ß2-agonist (LABA) combination therapy for asthma. METHODS: This retrospective matched cohort study compared 1-year asthma outcomes for UK patients initiating fixed-dose combination (FDC) fluticasone-salmeterol delivered by pressurised metered-dose inhaler (pMDI) versus dry powder inhaler (DPI). Patients with asthma aged 4-80 years receiving a first prescription for FDC fluticasone-salmeterol by pMDI or DPI were matched on baseline demographic and asthma severity measures. Co-primary outcomes were asthma control (a composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate. RESULTS: Compared with the DPI cohort (n = 1567), patients in the pMDI cohort (n = 1567) had significantly greater odds of achieving asthma control during the outcome year (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.01 to 1.40). Exacerbation rate was lower but not significantly in the pMDI cohort (adjusted rate ratio for pMDI cohort, 0.82; 95% CI 0.66 to 1.00). The odds of treatment success (defined as no exacerbations and no change in asthma therapy) was significantly greater in the pMDI cohort (OR 1.23; 95% CI, 1.07 to 1.42). CONCLUSIONS: For UK primary care patients, pMDIs appear to achieve better asthma control outcomes than DPIs for delivery of FDC fluticasone-salmeterol. Pragmatic trials are needed to further investigate real-world outcomes with different inhaler devices for combination therapy.