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Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UKResearch in Real Life, 5a Coles Lane, Oakington, Cambridge CB24 3BA, UK
Beclometasone dipropionate is an inhaled corticosteroid (ICS) available in both extrafine and larger-particle hydrofluoroalkane formulations. Extrafine beclometasone has greater small airway distribution and inhalation technique tolerance than larger-particle beclometasone; therefore, its use may be associated with improved asthma outcomes at population levels. The study objective was to compare real-life effectiveness of extrafine and larger-particle beclometasone.
Methods
Retrospective matched cohort study including primary care patients with asthma (ages 12–60 and non-smokers 61–80 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n = 11,289) or switched from another ICS without dose change (switch population, n = 19,065). The extrafine and larger-particle beclometasone cohorts were matched in each population for demographic and database measures of asthma control during a baseline year; and endpoints assessed during 1 outcome year were adjusted for residual confounding factors.
Results
The odds of no loss of asthma control (no asthma-related hospital attendance, consultation for lower respiratory tract infection, or oral corticosteroids) were significantly higher in the extrafine beclometasone cohorts of both initiation population (adjusted odds ratio [aOR] 1.12; 95% CI 1.02–1.23) and switch population (aOR 1.10; 95% CI 1.01–1.19). The odds of better adherence to ICS therapy were also significantly higher in both extrafine beclometasone cohorts (initiation population, aOR 1.64; 95% CI 1.52–1.75 and switch population, aOR 1.35; 95% CI 1.27–1.43).
Conclusions
These findings are consistent with the hypothesis that delivery of beclometasone in extrafine particle size produces real-life asthma treatment benefits.
Beclometasone dipropionate is an inhaled corticosteroid (ICS) that is available in both extrafine and larger-particle formulations for administration by pressurised metered-dose inhaler containing hydrofluoroalkane (HFA) propellant. The mass median aerodynamic diameter particle size of extrafine beclometasone is 1.1 microns, and that of larger-particle beclometasone is 2.9 microns.
Both are formulated with beclometasone in solution, rather than in a suspension as for the now discontinued chlorofluorocarbon (CFC)-beclometasone.
Larger-particle beclometasone was deliberately engineered by addition of glycerol to the formulation to enable a “dose for dose” exchange when transferring from CFC to HFA inhaler propellant. In 6- and 12-week clinical trials, larger-particle beclometasone was equivalent in efficacy on a microgram-for-microgram basis to CFC-beclometasone with regard to asthma-related endpoints, with similar safety and tolerability profiles.
Dose-ranging study results indicate that extrafine beclometasone has significantly greater effects on lung function than CFC-beclometasone on a microgram-for-microgram comparison.
The lung deposition of extrafine beclometasone is much greater than that of CFC-beclometasone (55–60% compared with 4–7% for CFC-beclometasone in healthy volunteers) and oropharyngeal deposition is lower (29–30% versus 90–94%).
Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers.
When switched from CFC-beclometasone to extrafine beclometasone at half the dose, patients in short-term randomised controlled trials maintained similar degrees of asthma control, with comparable safety profile, while those in a 12-month pragmatic trial experienced significantly greater improvement in health-related quality of life and a significantly higher percentage of symptom-free days than patients maintained on CFC-beclometasone.
Hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose.
Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma.
Clinically important improvements in asthma-specific quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropionate.
The cost effectiveness of chlorofluorocarbon-free beclomethasone dipropionate in the treatment of chronic asthma: a cost model based on a 1-year pragmatic, randomised clinical study.
Efficacy in randomised controlled trials, which study tightly defined populations outside the normal ecology of care, does not necessarily translate to effectiveness in a real-life clinical setting, where factors that can influence and interact with asthma-related outcomes include co-morbidities, polypharmacy, smoking habits, poor inhaler technique, and suboptimal adherence.
Rawlins MD. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. In: Harveian Oration. Oct-2008 ed. London: Royal College of Physicians. Available from: http://bookshop.rcplondon.ac.uk/details.aspx?e=262.
Smokers are usually excluded from these trials, as are patients with poor adherence and/or poor inhaler technique, and it would be unethical to maintain a control group of patients at increased risk of exacerbations without increasing their treatment. For these reasons, real-life research is needed to understand whether differences in ICS particle size and the associated difference in airway deposition have an impact on asthma outcomes in routine practice. An observational design can enable the study of large numbers of patients, potentially improving the generalisability of study results.
The objective of this observational database study was to compare the real-life effectiveness of extrafine and larger-particle beclometasone for two populations of primary care patients with asthma: those who were prescribed ICS for the first time and those switched from another ICS with no change in CFC-beclometasone-equivalent dose. Our hypothesis was that the potential benefits of improved total and small airway deposition and lower oropharyngeal deposition with extrafine beclometasone would translate to better asthma-related outcomes (less unplanned health-care use and fewer oral corticosteroid courses).
Methods
Data sources and patients
This retrospective matched cohort study used patient data contained in two computerised primary care databases in the UK. The General Practice Research Database (GPRD), now incorporated into the Clinical Practice Research Datalink (CPRD) is well-validated and used frequently for pharmaco-epidemiological research,
Use of the General Practice Research Database (GPRD) for respiratory epidemiology: a comparison with the 4th Morbidity Survey in General Practice (MSGP4).
and included about 5 million active patients. The Optimum Patient Care Research Database (OPCRD) contains anonymised, research-quality data for 341,000 patients with respiratory disease at approximately 300 practices that subscribe to OPC for respiratory review services.
Patients eligible for the study were 12–80 years old when they initiated ICS therapy for asthma (initiation population), or were switched with no change in CFC-beclometasone-equivalent dose to new ICS therapy (switch population), with a prescription for either extrafine beclometasone (Qvar, Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel) or larger-particle beclometasone (Clenil Modulite, Chiesi Ltd, Highfield, Cheadle, UK) by pressurised metered-dose inhaler. (Patients who received Qvar by breath-actuated inhaler were not eligible.) CFC-beclometasone dose equivalency was calculated in the ratios of 1:2:1:2:2 for larger-particle beclometasone, extrafine beclometasone, budesonide, fluticasone propionate, and mometasone, respectively. Index prescription dates began in 1998, when extrafine beclometasone became available in the UK, and ended on October 31, 2009. To be eligible for inclusion, patients had to have been registered continuously for at least 2 years (1 baseline year before and 1 outcome year after the index date).
“Asthma” was defined as the presence of a diagnostic code for asthma in the database or two or more prescriptions for asthma (reliever or controller medication) on at least two different dates during the baseline year. In addition, to be eligible for the study, patients had to have evidence of chronic asthma, defined as four or more respiratory prescriptions (namely, for a bronchodilator, ICS, or leukotriene receptor antagonist) recorded in the database at any time. To be eligible for the initiation population, patients had to have ongoing asthma therapy, defined as two or more ICS prescriptions during the outcome year including the index prescription; to be eligible for the switch population, patients had to have received at least one prescription for ICS and at least one other asthma prescription drug during the baseline year.
Smokers or ex-smokers older than 60 years were excluded from the study to minimise the inclusion of patients with chronic obstructive pulmonary disease (COPD) misdiagnosed as asthma. A diagnostic code for COPD or any chronic respiratory disease other than asthma at any time in the database was cause for exclusion from the study. Other exclusion criteria were receipt of maintenance oral corticosteroids during the baseline year or prescriptions on the index date for multiple ICS. In addition, for the switch population, patients were excluded if during the baseline year they had been prescribed ICS via dry powder device or a combination inhaler (ICS plus long-acting beta-agonist [LABA]) in addition to their separate ICS inhaler. Prescriptions for separate LABA inhalers were allowed.
Approval was given for use of the GPRD data by the GPRD Independent Scientific Advisory Committee. The OPCRD has been approved by Trent Multi Centre Research Ethics Committee for clinical research use, and the study protocol was approved by ADEPT (Anonymised Data Ethics Protocols and Transparency Committee), OPC's independent scientific advisory committee.
Study endpoints
We used several composite database measures designed to capture asthma-related outcomes during the outcome year, listed and defined in Table 1. In addition to the co-primary endpoint of no loss of asthma control, we evaluated the more stringent measure of no loss of asthma control plus limited short-acting β-agonist (SABA) use, defined as no loss of asthma control plus SABA use limited to salbutamol ≤200 μg/day or terbutaline ≤500 μg/day. The definition for the co-primary endpoint of severe exacerbations was based on the European Respiratory Society/American Thoracic Society (ERS/ATS) Task Force definition (see Table 1).
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
Asthma-related events in the database included all events with a lower respiratory code, including all asthma codes and lower respiratory tract infection codes.
hospital attendance or admission, A&E attendance, out-of-hours attendance, or OPD attendance, and 2. No GP consultation for lower respiratory tract infection, and 3. No prescription for acute course of oral corticosteroids.
Number of severe exacerbations, defined as any of the following:
1. Acute course of oral corticosteroids, or 2. Asthma-related hospital attendance or admission or A&E attendance
Secondary endpoints
No loss of asthma control plus limited SABA use, includes all of the following:
1. No asthma-related hospital attendance or admission, A&E attendance, out-of-hours attendance, or OPD attendance, and 2. No GP consultation for lower respiratory tract infection, and 3. No prescription for acute course of oral corticosteroids, and 4. Average daily prescribed dose of ≤200 μg salbutamol or ≤500 μg terbutaline.
Number of lower respiratory episodes requiring medical resource use, defined as any of the following:
1. Acute course of oral corticosteroids, or 2. Asthma-related hospital attendance or admission, or A&E attendance, or 3. Asthma-related out-of-hours hospital attendance, or 4. GP consultation for lower respiratory tract infection.
Number of respiratory-related hospitalisations, defined as any of the following:
1. Inpatient admission for asthma, or 2. Inpatient admission with lower respiratory code.
Adherence to inhaled corticosteroid, defined as:
1. Number of days' supply of inhaled corticosteroid/365 × 100%.
Controller-to-total asthma medication ratio, defined as:
1. Units of controllers/[units of controllers + relievers]
One unit of controller was defined as one inhaled corticosteroid inhaler or one prescription for leukotriene receptor antagonist; one unit of reliever was defined as one SABA inhaler.
A&E = Accident & Emergency; GP = general practice; OPD = Outpatient Department; SABA = short-acting β-agonist.
a Asthma-related events in the database included all events with a lower respiratory code, including all asthma codes and lower respiratory tract infection codes.
b One unit of controller was defined as one inhaled corticosteroid inhaler or one prescription for leukotriene receptor antagonist; one unit of reliever was defined as one SABA inhaler.
Adherence to ICS was defined as the percentage of a year's supply taken by the patient, calculated using prescriptions (Table 1) and categorised as <50%; 50–69%, 70–99%, and ≥100%.
In addition, we calculated the controller-to-total asthma medication ratio, dichotomised as <0.5 versus ≥0.5 (a ratio of ≥0.5 has been associated with better disease control).
Analyses were conducted using SPSS version 18 (SPSS Statistics, IBM, Somers, NY, USA), SAS version 9.2 (SAS Institute, Marlow, Buckinghamshire, UK), and Microsoft Office Excel 2007 (Microsoft, Bellevue, WA, USA). Statistical significance was defined as p < 0.05.
In the unmatched initiation population the extrafine beclometasone cohort was larger whereas in the switch population the reverse was the case (Fig. S1 in the Online Supplement); consequently we matched patients in extrafine:larger-particle beclometasone ratios of 2:1 in the initiation population and 1:2 in the switch population to maximise both the cohort sizes and the number of matched groupings, and thus the power of statistical tests. We matched on clinically and demographically significant characteristics, namely, sex, age, and baseline asthma-related factors, including acute courses of oral corticosteroids, average daily SABA dose, non-emergency asthma consultations (namely, those not resulting in a course of oral corticosteroids), and, for patients in the switch population, average baseline daily ICS dose.
Summary statistics were used to describe baseline and outcome variables, and heavily skewed data were categorised. Differences between matched cohorts at baseline were determined using conditional logistic regression. Statistical comparisons of ICS doses prescribed at the index date and during the outcome year were made by doubling extrafine beclometasone doses in line with the recommended 1:2 prescribing dose ratio with larger-particle beclometasone.
The adjusted odds of no loss of asthma control during the outcome year was compared between cohorts, with larger-particle beclometasone as the reference treatment, using conditional logistic regression to adjust for any residual confounding. The dichotomous outcome for no loss of asthma control was used as the dependent variable, with treatment and potential residual confounding factors as explanatory variables. This approach was used also for comparisons between cohorts of the no loss of asthma control plus limited SABA use endpoint. The total numbers of severe exacerbations recorded during the outcome year were compared between treatment cohorts using a conditional Poisson regression model to obtain estimates of exacerbation rates in the extrafine beclometasone cohort relative to the larger-particle beclometasone cohort. The model used empirical standard errors for more robust confidence intervals (CIs), and adjustments were made for residual baseline confounders. A similar approach was used for comparison of other rates.
Conditional ordinal regression models were used to compare cohorts for adjusted odds of higher SABA use and greater adherence to ICS therapy. The categorised outcomes for average daily SABA dose and ICS adherence, respectively, were used as the dependent variable, with treatment and residual confounding factors as explanatory variables.
For all outcome models, we assessed as potential confounding factors those baseline variables that were significantly different or showed a trend towards a difference (p < 0.10, conditional logistic regression) between the two treatment cohorts; in addition, baseline variables that were predictive (p < 0.05) of outcomes through multivariate analysis were also considered as potential confounders (please see full list considered in Supplemental Table S1). We then adjusted each primary and secondary outcome for the appropriate non-collinear baseline confounders. As all primary outcome results were likely correlated, no corrections were made for type I errors for multiple comparisons.
In an exploratory analysis to better understand the difference in outcomes, we drew on patient data contained in the OPCRD to extrapolate the impact of ICS choice by scaling our results to a population size of 340,900 patients, the mean size of a UK Primary Care Trust (PCT).
We applied study inclusion criteria and results to annualised data in the database in 2007 and compared the rates of hospitalisations and oral corticosteroid courses that would result from treatment with extrafine or larger-particle beclometasone.
Results
Patients
A total of 11,289 patients were identified and matched in extrafine:larger-particle beclometasone ratio of 2:1 in the initiation population; and 19,065 were identified and matched in ratio of 1:2 in the switch population (see Fig. S1 in the Online Supplement). Baseline characteristics of the matched cohorts of both study populations are summarised in Table 2 and baseline asthma-related parameters in Table 3.
Table 2Baseline demographic and clinical characteristics of patients with asthma receiving their first ICS prescription as extrafine or larger-particle beclometasone by pMDI or switching ICS therapy to extrafine or larger-particle beclometasone by pMDI.
Not all patients had recorded weight and height data. In the initiation population, BMI n = 6801 (90%) and 3359 (89%) for extrafine and larger-particle beclometasone cohorts, respectively; in the switch population, BMI n = 5858 (92%) and 11,411 (90%), respectively.
The Charlson comorbidity index is a weighted index that accounts for number and severity of co-morbidities, each assigned a score depending on the associated risk of dying.
Patients with rhinitis, cardiac disease, and GERD included those with a recorded diagnosis or recorded therapy for same.
Rhinitis
2276 (30.2)
1175 (31.2)
0.286
2197 (34.6)
4299 (33.8)
0.305
Cardiac disease
2215 (29.4)
1054 (28.0)
0.075
2102 (33.1)
4038 (31.8)
0.032
Gastro-oesophageal reflux
1586 (21.1)
960 (25.5)
<0.001
1222 (19.2)
3053 (24.0)
<0.001
≥1 prescription prior 12 mo, n (%)
NSAID
1666 (22.1)
894 (23.8)
0.047
1381 (21.7)
2906 (22.9)
0.066
Beta blocker
413 (5.5)
204 (5.4)
0.881
146 (2.3)
303 (2.4)
0.706
Paracetamol
1359 (18.1)
787 (20.9)
<0.001
1329 (20.9)
2910 (22.9)
0.001
BDP = beclometasone dipropionate; BMI = body mass index; n/a = not applicable (matching criterion); LP = larger-particle; NSAID = non-steroidal anti-inflammatory drug; pMDI = pressurised metered-dose inhaler.
a Conditional logistic regression.
b Not all patients had recorded weight and height data. In the initiation population, BMI n = 6801 (90%) and 3359 (89%) for extrafine and larger-particle beclometasone cohorts, respectively; in the switch population, BMI n = 5858 (92%) and 11,411 (90%), respectively.
c The Charlson comorbidity index is a weighted index that accounts for number and severity of co-morbidities, each assigned a score depending on the associated risk of dying.
d Patients with rhinitis, cardiac disease, and GERD included those with a recorded diagnosis or recorded therapy for same.
Asthma was identified for all patients as either a database read code for asthma or ≥2 prescriptions for asthma during the baseline year, with no code for another chronic respiratory condition.
Patients with recorded PEF in the extrafine and larger-particle beclometasone cohorts totalled 2047 (27%) and 928 (25%), respectively, in the initiation population and 4098 (65%) and 8939 (70%), respectively, in the switch population.
b Asthma was identified for all patients as either a database read code for asthma or ≥2 prescriptions for asthma during the baseline year, with no code for another chronic respiratory condition.
c Patients with recorded PEF in the extrafine and larger-particle beclometasone cohorts totalled 2047 (27%) and 928 (25%), respectively, in the initiation population and 4098 (65%) and 8939 (70%), respectively, in the switch population.
d The SABA dose is the salbutamol dose equivalent (standard dose in UK is 200 μg).
e Diagnosis of or therapy for oropharyngeal candidiasis (thrush).
In both populations at baseline the proportion of patients meeting the primary measure of no loss of asthma control was similar in the two matched cohorts (Table 3). The date of the index prescription was significantly earlier in the extrafine beclometasone cohort because of the earlier launch date (1998 versus 2006 for larger-particle beclometasone). The proportions of smokers and ex-smokers over 40 years old were similar in the matched cohorts (Table 2). The few significant baseline differences between treatment cohorts were small and not clinically significant; however, all baseline variables that were statistically significantly different between cohorts were considered as potential residual confounders in the adjusted outcomes analyses, as described above.
Outcomes
In the initiation population on the index date, the prescribed mean (SD) CFC-beclometasone-equivalent doses were 465 (229) and 411 (165) μg/d in the extrafine and larger-particle beclometasone cohorts, respectively (p < 0.001), with actual mean dose 232 (115) μg/d of extrafine beclometasone. In the switch population, the index date mean CFC-beclometasone-equivalent doses were 455 (168) and 474 (213) μg/d, respectively (p < 0.001), with actual mean dose 228 (84) μg/d of extrafine beclometasone. Fig. 1 depicts the index date dose distribution in proportion according to the 1:2 dosing recommendations.
Figure 1Inhaled corticosteroid dose (categorised) on the index date for patients with asthma (a) initiating beclometasone or (b) switching to beclometasone. The comparison between treatment cohorts for categorised dose was statistically significant (p < 0.001) for the initiation population but not for the switch population (p = 0.214). The extrafine beclometasone dose is shown in proportion to double the dose of larger-particle beclometasone in accordance with licensing recommendations. BDP = beclometasone dipropionate.
Results for the primary and secondary outcome measures are depicted in Table 4 and Fig. 2. The percentages of patients meeting the no loss of asthma control measures were greater in both extrafine beclometasone cohorts than the corresponding larger-particle beclometasone cohort (Table 4), and the adjusted ORs for both measures were significantly higher for patients prescribed extrafine beclometasone (Fig. 2). There were no significant differences between cohorts in the rate of severe exacerbations after adjustment for residual baseline confounders (Fig. 2).
Table 4Unadjusted outcomes over 1 year after patients with asthma received their first inhaled corticosteroid prescription as extrafine or larger-particle beclometasone or switched inhaled corticosteroid therapy to extrafine or larger-particle beclometasone.
The SABA dose is the salbutamol dose equivalent. The daily inhaled corticosteroid dose consumed during the outcome year was calculated as the dispensed amount divided by 365. Median (IQR) extrafine BDP doses are doubled (extrafine BDP is prescribed, per licensing, at half the larger-particle BDP dose).
The SABA dose is the salbutamol dose equivalent. The daily inhaled corticosteroid dose consumed during the outcome year was calculated as the dispensed amount divided by 365. Median (IQR) extrafine BDP doses are doubled (extrafine BDP is prescribed, per licensing, at half the larger-particle BDP dose).
The SABA dose is the salbutamol dose equivalent. The daily inhaled corticosteroid dose consumed during the outcome year was calculated as the dispensed amount divided by 365. Median (IQR) extrafine BDP doses are doubled (extrafine BDP is prescribed, per licensing, at half the larger-particle BDP dose).
a Co-primary endpoints. See Table 1 for definitions of study endpoints.
b Conditional logistic regression.
c The SABA dose is the salbutamol dose equivalent. The daily inhaled corticosteroid dose consumed during the outcome year was calculated as the dispensed amount divided by 365. Median (IQR) extrafine BDP doses are doubled (extrafine BDP is prescribed, per licensing, at half the larger-particle BDP dose).
d Diagnosis of or therapy for oropharyngeal candidiasis (thrush).
Figure 2Adjusted outcome measures for study endpoints over 1 year after the first ICS prescription for (a) the initiation population and (b) the switch population. The larger-particle beclometasone cohort is the comparator, with adjusted risk ratio/odds ratio set at 1.0. Adjustments for baseline confounding factors: *Adjusted for smoking status, rhinitis diagnosis/therapy, inpatient admissions, and OPD attendance. †Adjusted for LABA use, number of LRTI consultations, and smoking status. ‡Adjusted for number of asthma consultations and inpatient admissions. §Adjusted for number of prescriptions for asthma or allergy drugs, number of asthma consultations, and time between asthma diagnosis and the index date. ¥OR of a higher categorised mean daily SABA dose, adjusted for time between diagnosis and the index date, smoking status, A&E attendance, and number of SABA prescriptions. #OR of a higher categorised adherence to ICS therapy, adjusted for time between diagnosis and the index date and number of prescriptions for asthma or allergy drugs. ˆAdjusted for age, time between diagnosis and the index date, number of LRTI consultations, and baseline incidence of oral candidiasis. **Adjusted for LABA use and number of LRTI consultations, inpatient admissions, and OPD attendance for asthma. †Adjusted for LABA use, number of SABA prescriptions and LRTI consultations, and smoking status. ‡‡Adjusted for LABA use, adherence to ICS therapy, and number of inpatient admissions. §§Adjusted for number of inpatient admissions. ¥¥OR of a higher categorised mean daily SABA dose, adjusted for time between diagnosis and the index date, and number of SABA prescriptions. ##OR of a higher categorised adherence to ICS therapy, adjusted for time between diagnosis and the index date, LABA use, and baseline adherence to ICS therapy. ˆˆAdjusted for baseline incidence of oral candidiasis. A&E = Accident and Emergency; BDP = beclometasone dipropionate; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LRTI = lower respiratory tract infection; OPD = Outpatient Department; SABA = short-acting β-agonist. Hospital attendance and admission, and OPD and A&E attendance, were for asthma or lower respiratory reasons.
Respiratory-related hospitalisations were infrequent overall (Table 4) but occurred at a significantly lower rate in the extrafine beclometasone cohorts (Fig. 2). The median daily dose of SABA was the same in both cohorts of each population (data not shown). In the switch population, after adjustment for baseline confounding factors, patients who received larger-particle beclometasone had significantly higher odds of receiving a higher SABA dose.
Adherence to ICS therapy was significantly higher in both extrafine beclometasone cohorts than the comparable larger-particle beclometasone cohort (Fig. 2). Median ICS doses taken during the outcome year were significantly higher in both extrafine beclometasone cohorts (see Table 4). We further evaluated dose–response relationships in the four study cohorts by examining outcomes (no loss of asthma control and exacerbations) according to 1) actual ICS dose consumed and 2) adherence. The comparative effects of treatment with extrafine beclometasone and larger-particle beclometasone were consistent across ICS dose as well as adherence during the outcome year (Figs. 3 and 4).
Figure 3Proportion of patients in the initiation population, by treatment cohort, who achieved the no loss of asthma control measure during the outcome year, (a) categorised by consumed ICS dose (i.e., prescribed ICS divided by 365, with EF-BDP dose doubled in line with the recommended 1:2 prescribing dose ratio with LP-BDP) and (b) by adherence to ICS therapy during the outcome year. Panel c depicts exacerbation rates by consumed ICS dose (EF-BDP dose doubled), and panel d depicts exacerbation rates by adherence to ICS. Patient count percentages may not equal 100% because of rounding. EF-BDP = extrafine beclometasone dipropionate; ICS = inhaled corticosteroid; LP-BDP = larger-particle beclometasone dipropionate.
Figure 4Proportion of patients in the switch population, by treatment cohort, who achieved the no loss of asthma control measure during the outcome year, (a) categorised by consumed ICS dose (i.e., prescribed ICS divided by 365, with EF-BDP dose doubled in line with the recommended 1:2 prescribing dose ratio with LP-BDP) and (b) by adherence to ICS therapy during the outcome year. Panel c depicts exacerbation rates by consumed ICS dose (EF-BDP dose doubled), and panel d depicts exacerbation rates by adherence to ICS. Patient count percentages may not equal 100% because of rounding. EF-BDP = extrafine beclometasone dipropionate; ICS = inhaled corticosteroid; LP-BDP = larger-particle beclometasone dipropionate.
Spacer device prescribing was significantly less frequent in the extrafine beclometasone cohort of the initiation population and more frequent in the extrafine beclometasone cohort of the switch population (Table 4). Fewer patients in the two extrafine beclometasone cohorts developed oral candidiasis as compared with the corresponding larger-particle beclometasone cohort (Table 4), although after adjustment for confounding factors the differences between cohorts were no longer significant (Fig. 2).
Exploratory analysis
Extrapolating from 2007 data in the OPCRD, we calculated that each year 511 adults would initiate ICS therapy for asthma and 3142 adults would switch from CFC to HFA ICS in the average PCT population size of 340,900 patients. For 511 adults with asthma initiating ICS, we calculated that prescribing extrafine instead of larger-particle beclometasone would result each year in 4 fewer patients being hospitalised for respiratory-related illness and 8 fewer patients receiving a course of oral corticosteroids. For 3142 adults with asthma, switching from CFC to extrafine instead of larger-particle HFA-beclometasone would result each year in 15 fewer patients being hospitalised for respiratory-related illness and 31 fewer patients receiving a course of oral corticosteroids.
Discussion
In this matched cohort study evaluating real-life asthma management, primary care patients prescribed beclometasone in an extrafine formulation, as compared with a larger-particle formulation, had significantly greater odds of no loss of asthma control and of the more stringent database measure of no loss of asthma control plus limited SABA use. This difference was recorded both for patients initiating inhaled beclometasone therapy and for those switching to beclometasone therapy at a dose equivalent to that of their prior ICS. In addition, adherence to therapy and cumulative ICS dose received were significantly higher during the outcome year in the extrafine beclometasone cohorts, whilst the odds of respiratory-related hospitalisations were significantly lower. The adjusted risk of severe exacerbations was not significantly different between treatment cohorts.
The fact that the comparative effects of treatment with extrafine beclometasone and larger-particle beclometasone were consistent across ICS dose consumed as well as adherence during the outcome year reassures us that differences in outcomes were due to treatments. The differences in outcomes between the two treatment cohorts suggest greater success when using extrafine beclometasone in attaining key goals of asthma therapy, namely, maintaining asthma control while minimising hospitalisations. Moreover, study results were consistent for both the initiation and switch populations. Whilst we did not record a large effect, one would not expect a large difference when comparing matched cohorts and the same class of therapy for patients with only limited scope to show difference.
We designed the coprimary measure of no loss of asthma control to capture evidence of an exacerbation (oral corticosteroids or hospital visits for asthma) as defined by the ERS/ATS Task Force,
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
The difference in findings for no loss of asthma control versus exacerbation measures could be explained by this difference (inclusion of antibiotic prescribing) as well as the fact that asthma control is a dichotomy (yes versus no), while the exacerbation rate is a continuum and thus distinguishes between 1 versus more than 1 events. We constructed the no loss of asthma control plus limited SABA use measure to capture both impairment as well as risk of future exacerbations, the two accepted components of asthma control.
The Global Initiative for Asthma (GINA) definition of asthma control includes rescue therapy use, symptoms, functional limitation, and pulmonary function
; however, only rescue therapy use can be determined in a database study such as ours. We included a cut-point of ≤200 μg/d salbutamol, which works out to <4 canisters/year, an amount that is on the low end of a validated 4-level long-term control scale using SABA prescriptions from computerised pharmacy data, in which a significant linear relationship was seen between this scale (0–2, 3–6, 7–12, and >12 SABA canisters/year) and impairment as well as subsequent risk of exacerbations.
Results of our exploratory analysis suggest that each year in an average PCT population of 340,900 patients, prescribing extrafine instead of larger-particle beclometasone would prevent 4 hospitalisations amongst 511 adults initiating ICS and 15 hospitalisations amongst 3142 switching ICS; 8 and 31 fewer patients, respectively, would require a course of oral corticosteroids. These differences would be achieved at no additional cost.
The results of the present study are compatible with those of prior observational studies suggesting that better asthma outcomes are achievable with extrafine as compared with larger-particle size ICS delivered by a pressurised metered-dose inhaler.
Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study.
In earlier studies comparing delivery of extrafine beclometasone with delivery from CFC-driven, pressurised metered-dose inhalers, use of the extrafine formulation resulted in lower oropharyngeal deposition in patients with asthma and healthy volunteers, suggesting the possibility of a reduced risk of oropharyngeal candidiasis (thrush).
Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers.
In the present study we did not observe a significant difference between treatment cohorts in the adjusted risk of thrush, although the comparison in this case was not with devices using different propellants.
Our data do not provide information regarding the precise mechanisms behind the better asthma outcomes with extrafine beclometasone therapy. One might speculate that they at least partly reflect previously demonstrated, improved lower airway deposition of the drug when delivered in extrafine particles even in patients with relatively poor coordination of inhalation and actuation of a metered-dose inhaler.
A reason proposed for the relatively stable and better deposition of beclometasone delivered in extrafine particles, as compared with delivery by a CFC-driven device (lung deposition, 4–7%), is that the extrafine particles remain suspended for longer during inspiration and thus are more likely to reach the lungs, even with poorly coordinated inhaler technique, as long as the breath is held after inhalation.
It is likely that this reasoning can be applied when comparing HFA-driven extrafine versus larger-particle beclometasone formulations, although to our knowledge there is no published comparison of their deposition characteristics.
In this study, patients receiving extrafine beclometasone also appeared to show significantly better adherence to therapy compared with those receiving larger-particle beclometasone. Again the present data provide no information as to the reasons for this better adherence, but one might speculate that it reflects better inhaler technique tolerance (a softer, warmer and longer duration spray) or the possibility that patients prescribed the extrafine preparation were more likely to be instructed to take it regularly and/or monitored more closely while doing so. We cannot rule out the possibility that prescribers of extrafine-particle beclometasone formulations are more knowledgeable and interested in asthma care than their counterparts. However, we identified no other indicators of practice or physician differences; indeed, the fact that similar proportions of patients in each cohort (e.g., 65% and 70% in switch population extrafine- and large-particle beclometasone cohorts, respectively) had recorded PEF values suggests no differences.
In addition to increased adherence, patients in the extrafine beclometasone cohorts received significantly higher median daily doses of beclometasone over the outcome year than those in the larger-particle beclometasone cohorts (compared using larger-particle equivalent doses).
This might reflect the observed improved adherence (patients taking doses as instructed whether or not they were necessary for disease control), or the fact that patients needed a higher dose of the extrafine preparation for disease control because it is not actually twice as effective as larger-particle beclometasone, at least in some patients, or a mixture of both. Further information gained on examining the dose–response relationships indicates that patients who were prescribed extrafine beclometasone experienced similar or better control than those prescribed larger-particle beclometasone at similar levels of adherence or ICS dose consumed, with increasing benefits of the extrafine particle being evident at the higher doses required by less-controlled patients (please see Figs. 3 and 4). We note that patients appeared to self-titrate, showing more adherence to therapy with worse levels of control, an observation also reported by others.
We feel that the significantly higher mean index date doses for the extrafine beclometasone cohort of the initiation population most likely reflect the earlier index dates for extrafine beclometasone, at a time when asthma guidelines recommended starting ICS at a high dose and then stepping down.
Asthma in adults and schoolchildren. The General Practioner in Asthma Group, the British Association of Accident and Emergency Medicine, the British Paediatric Respiratory Society and the Royal College of Paediatrics and Child Health.
Rawlins MD. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. In: Harveian Oration. Oct-2008 ed. London: Royal College of Physicians. Available from: http://bookshop.rcplondon.ac.uk/details.aspx?e=262.
The strengths of this study include its large size and its use of representative data from general practice, where over 90% of patients with asthma are managed in the UK.
We studied patients prescribed their first ICS, a relatively uniform population with regard to degree of experience using inhaler devices, as well as those newly switched to inhaled beclometasone, all of whom had prior experience using ICS. Outcome assessment over a full year helped to limit the influence of seasonal effects and to capture less frequent events such as hospitalisations. While we cannot rule out the possibility that smokers or ex-smokers with concomitant COPD were included in the study, the percentages of smokers and ex-smokers over 40 years of age were similar in the treatment cohorts of each study population; thus, the likelihood of including patients with COPD would be roughly the same in each cohort.
The limitations of our study findings are those common to all observational studies, in particular the lack of a placebo group and the absence of randomised assignment to treatment cohorts, allowing the possibility of treatment selection bias and other potential confounding effects. Using a matched cohort design helped us to minimise these effects; and we made statistical adjustments to address minor residual confounding that existed after matching. Nonetheless, the index prescription dates were significantly different between the two cohorts because of the earlier availability of extrafine beclometasone (1998 versus 2006 for larger-particle HFA-delivered beclometasone). While this may have influenced the typical, initial prescribed dose of ICS, the only other major change in asthma therapy over this time period was the increasingly earlier use of add-on therapy, not a factor in this study.
In conclusion, our findings in this matched cohort study of patients receiving the same ICS molecule delivered using the same device and propellant allow the empirical observation that the use of extrafine beclometasone contributes to improved real-life outcome measures when managing asthma in primary care. What this study does not tell us is precisely why, although one might speculate that better and deeper airways penetration, better tolerance of sub-optimal inhaler technique, better adherence with prescribing instructions, and a better informed patient clientele may be contributory factors.
Funding
Data acquisition and analysis were funded by Teva Pharmaceuticals Ltd of Petach Tikva, Israel. Access to data from the General Practice Research Database was co-funded by Merck & Co., Inc. (Whitehouse Station, NJ, USA), and access to data from the Optimum Patient Care Research Database was co-funded by Research in Real Life Ltd. Merck played no role in the study. Teva played no role in the conduct of the study, final interpretation of the results, or decision to submit the manuscript for publication. RiRL designed the study, conducted the analyses, and coordinated the writing and revision of the manuscript.
Conflict of interest statement
David Price has consultant arrangements with Almirral, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Medapharma, Novartis, Napp, Nycomed, Pfizer, Sandoz, and Teva. He or his research team have received grants and support for research in respiratory disease from the following organisations in the last 5 years: UK National Health Service, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Novartis, Nycomed, Orion, Pfizer, Takeda, and Teva. He has spoken for Almirral, AstraZeneca, Activaero, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Merck, Mundipharma, Novartis, Pfizer, Takeda, and Teva. He has shares in AKL Ltd which produces phytopharmaceuticals. He is the sole owner of Research in Real Life Ltd (RiRL) and its subsidiary social enterprise Optimum Patient Care. Neither Mike Thomas nor any member of his close family has any shares in pharmaceutical companies. In the last 3 years he has received speaker's honoraria for speaking at sponsored meetings from the following companies marketing respiratory and allergy products: Astra Zeneca, Boehringer Inglehiem, GSK, MSD, Napp, Schering-Plough, Teva. He has received honoraria for attending advisory panels with Almirall, Astra Zeneca, BI, Chiesi, GSK, MSD, Merck Respiratory, Schering-Plough, Teva, Novartis. He has received sponsorship to attend international scientific meetings from GSK, MSD, Astra Zeneca, Mundipharma. He has received funding for research projects from GSK, Almirall. He is chief medical adviser to the charity Asthma UK, a member of the BTS SIGN Asthma guideline group. He is a member of the EPOS Rhinosinusitis guideline group. John Haughney has received reimbursements for attending symposia, fees for speaking, organising educational events, funds for research, or fees for consulting from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, Novartis, Nycomed, and Teva. Richard A Lewis has received an honorarium for consultancy from the Clenil Steering Committee and sponsorship for international respiratory meetings from GlaxoSmithKline, Teva, and 3M Pharmaceuticals. Elizabeth V Hillyer has done freelance writing work for Merck and Aerocrine. Christopher J Corrigan has received an honorarium for consultancy from the Clenil Steering Committee, has received one off fees for consultancy and lecturing at conferences from Meda Pharma, Teva Pharmaceuticals, Allergy Therapeutics, GlaxoSmithKline, Trinity Chiesi, Novartis, Allergopharma Joachim Ganzer, and has research contracts held with King's College London from Novartis, GlaxoSmithKline, AstraZeneca. Anne Burden, Julie von Ziegenweidt, and Alison Chisholm are employees of RiRL.
Acknowledgements
We thank Muzammil Ali and Francesca Barion for their contributions to the statistical analyses and Ben Rooke, patient representative on the Norfolk and Suffolk Comprehensive Local Research Network (CLRN) Board, for his input and advice on the study protocol.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers.
Hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose.
Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma.
Clinically important improvements in asthma-specific quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropionate.
The cost effectiveness of chlorofluorocarbon-free beclomethasone dipropionate in the treatment of chronic asthma: a cost model based on a 1-year pragmatic, randomised clinical study.
Rawlins MD. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. In: Harveian Oration. Oct-2008 ed. London: Royal College of Physicians. Available from: http://bookshop.rcplondon.ac.uk/details.aspx?e=262.
Use of the General Practice Research Database (GPRD) for respiratory epidemiology: a comparison with the 4th Morbidity Survey in General Practice (MSGP4).
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study.
Asthma in adults and schoolchildren. The General Practioner in Asthma Group, the British Association of Accident and Emergency Medicine, the British Paediatric Respiratory Society and the Royal College of Paediatrics and Child Health.
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