Effect of a pharmacist intervention on asthma control. A cluster randomised trial

Open ArchivePublished:July 01, 2013DOI:https://doi.org/10.1016/j.rmed.2013.05.014

      Summary

      Introduction

      Achievement and maintenance of good asthma control is a major objective in asthma management. However, asthma control in many patients is suboptimal, due to improper use of asthma medications and non-adherence. The aim of this study was to evaluate the effect of a pharmacist intervention on asthma control in adult patients.

      Methods

      A 6-month cluster randomized controlled trial was undertaken with allocation of community pharmacies to intervention or control group. Adult asthma patients in the intervention group received a protocol-based intervention addressing individual needs related to asthma control, inhaler technique and medication adherence. Patients in the control group received usual care. Main variables were measured at baseline, 3 and 6 months.

      Results

      336 patients completed the study, 150 in the control group and 186 in the intervention group. The intervention resulted in enhanced asthma control: Patients receiving the intervention had an Odds ratio of 3.06 (95% CI:1.63–5.73; p < 0.001) of having controlled asthma six months later. In the intervention group mean ACQ scores significantly improved [0.66 points (SD: 0.78); p < 0.001] and the number of controlled asthma patients increased by 30.1% (p < 0.001) after 6 months. The intervention also resulted in improved medication adherence (by 40.3%, p < 0.001) and inhaler technique (by 56.2%, p < 0.001). No significant changes for any of these variables were observed in the control group.

      Conclusion

      The AFasma study focused on the important outcomes of asthma management, and showed that through the designed intervention, community pharmacists can increase controlled asthma patients compared to usual care. Trial registration NCT01085474.

      Keywords

      Introduction

      In 2006 a new asthma management approach was adopted by the Global Initiative for Asthma (GINA) signalling an important change of philosophy based on asthma control rather than asthma severity or symptoms [
      • From the Global Strategy for Asthma Management and Prevention
      Global initiative for asthma (GINA).
      ]. Since then, good asthma control has become a primary objective in the management of asthma patients [
      • From the Global Strategy for Asthma Management and Prevention
      Global initiative for asthma (GINA).
      ], that is an absence of daily symptoms and exacerbations, minimisation of lung function variability or no impairment of quality of life. However, asthma control in many patients is sub-optimal [
      • Gonzalez Barcala F.J.
      • de la Fuente-Cid R.
      • Alvarez-Gil R.
      • Tafalla M.
      • Nuevo J.
      • Caamano-Isorna F.
      Factors associated with asthma control in primary care patients: the CHAS study.
      ,
      • Partridge M.R.
      • van der Molen T.
      • Myrseth S.E.
      • Busse W.W.
      Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study.
      ], with negative implications for the patient's health, quality of life and/or health care costs. Reasons for this poor asthma control are complex including clinical and behavioral issues, such as co-morbidity, ineffective delivery of treatment, low adherence and/or ongoing exposure to triggers [
      • Horne R.
      • Price D.
      • Cleland J.
      • Costa R.
      • Covey D.
      • Gruffydd-Jones K.
      • et al.
      Can asthma control be improved by understanding the patient's perspective?.
      ] among others.
      Adherence to preventer medications represents a major challenge [
      • Cochrane M.G.
      • Bala M.V.
      • Downs K.E.
      • Mauskopf J.
      • Ben-Joseph R.H.
      Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique.
      ] since non-adherence to inhaled therapy is common among asthma patients due to intentional or unintentional causes [
      • Horne R.
      Compliance, adherence, and concordance: implications for asthma treatment.
      ]. Despite correct inhaler technique being essential for effective drug delivery, a literature review found that misuse of inhaler devices is frequent in practice [
      • Lavorini F.
      • Magnan A.
      • Dubus J.C.
      • Voshaar T.
      • Corbetta L.
      • Broeders M.
      • et al.
      Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD.
      ] contributing to poor asthma control [
      • Armour C.L.
      • Lemay K.
      • Saini B.
      • Reddel H.K.
      • Bosnic-Anticevich S.Z.
      • Smith L.D.
      • et al.
      Using the community pharmacy to identify patients at risk of poor asthma control and factors which contribute to this poor control.
      ,
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • Cinti C.
      • Lodi M.
      • Martucci P.
      • et al.
      Inhaler mishandling remains common in real life and is associated with reduced disease control.
      ,
      • Garcia-Cardenas V.
      • Sabater-Hernandez D.
      • Faus M.J.
      • Martinez-Martinez F.
      • Benrimoj S.I.
      Is the inhaler technique associated with asthma control?.
      ,
      • Giraud V.
      • Allaert F.A.
      • Roche N.
      Inhaler technique and asthma: feasability and acceptability of training by pharmacists.
      ]. Hence updated asthma guidelines [
      • From the Global Strategy for Asthma Management and Prevention
      Global initiative for asthma (GINA).
      ,

      Spanish guide for asthma management – educators 2010. Asthma educator's guide [internet]. Available from: http://www.gemasma.com/images/stories/GEMASMA/Documentos/GEMA%20Educadores/index.html. [accessed 05.03.12].

      ] highlight the importance of implementing strategies aimed at improving patients' knowledge, skills and aptitudes to self-manage their asthma.
      A literature review [
      • Benavides S.
      • Rodriguez J.C.
      • Maniscalco-Feichtl M.
      Pharmacist involvement in improving asthma outcomes in various healthcare settings: 1997 to present.
      ] revealed an increase of pharmacists' participation in outcome-based asthma management programs, with positive impact in symptoms [
      • Barbanel D.
      • Eldridge S.
      • Griffiths C.
      Can a self-management programme delivered by a community pharmacist improve asthma control? A randomised trial.
      ,
      • Bunting B.A.
      • Cranor C.W.
      The Asheville Project: long-term clinical, humanistic, and economic outcomes of a community-based medication therapy management program for asthma.
      ,
      • Cordina M.
      • McElnay J.C.
      • Hughes C.M.
      Assessment of a community pharmacy-based program for patients with asthma.
      ,
      • Emmerton L.
      • Shaw J.
      • Kheir N.
      Asthma management by New Zealand pharmacists: a pharmaceutical care demonstration project.
      ,
      • Mangiapane S.
      • Schulz M.
      • Muhlig S.
      • Ihle P.
      • Schubert I.
      • Waldmann H.C.
      Community pharmacy-based pharmaceutical care for asthma patients.
      ,
      • McLean W.
      • Gillis J.
      • Waller R.
      The BC community pharmacy asthma study: a study of clinical, economic and holistic outcomes influenced by an asthma care protocol provided by specially trained community pharmacists in British Columbia.
      ,
      • Narhi U.
      • Airaksinen M.
      • Tanskanen P.
      • Erlund H.
      Therapeutic outcomes monitoring by community pharmacists for improving clinical outcomes in asthma.
      ], pulmonary function [
      • Bunting B.A.
      • Cranor C.W.
      The Asheville Project: long-term clinical, humanistic, and economic outcomes of a community-based medication therapy management program for asthma.
      ,
      • Cordina M.
      • McElnay J.C.
      • Hughes C.M.
      Assessment of a community pharmacy-based program for patients with asthma.
      ,
      • Emmerton L.
      • Shaw J.
      • Kheir N.
      Asthma management by New Zealand pharmacists: a pharmaceutical care demonstration project.
      ,
      • Mangiapane S.
      • Schulz M.
      • Muhlig S.
      • Ihle P.
      • Schubert I.
      • Waldmann H.C.
      Community pharmacy-based pharmaceutical care for asthma patients.
      ,
      • McLean W.
      • Gillis J.
      • Waller R.
      The BC community pharmacy asthma study: a study of clinical, economic and holistic outcomes influenced by an asthma care protocol provided by specially trained community pharmacists in British Columbia.
      ,
      • Narhi U.
      • Airaksinen M.
      • Tanskanen P.
      • Erlund H.
      Therapeutic outcomes monitoring by community pharmacists for improving clinical outcomes in asthma.
      ,
      • Saini B.
      • Krass I.
      • Armour C.
      Development, implementation, and evaluation of a community pharmacy-based asthma care model.
      ,
      • Schulz M.
      • Verheyen F.
      • Muhlig S.
      • Muller J.M.
      • Muhlbauer K.
      • Knop-Schneickert E.
      • et al.
      Pharmaceutical care services for asthma patients: a controlled intervention study.
      ] or severity [
      • Bunting B.A.
      • Cranor C.W.
      The Asheville Project: long-term clinical, humanistic, and economic outcomes of a community-based medication therapy management program for asthma.
      ,
      • Saini B.
      • Krass I.
      • Armour C.
      Development, implementation, and evaluation of a community pharmacy-based asthma care model.
      ,
      • Schulz M.
      • Verheyen F.
      • Muhlig S.
      • Muller J.M.
      • Muhlbauer K.
      • Knop-Schneickert E.
      • et al.
      Pharmaceutical care services for asthma patients: a controlled intervention study.
      ,
      • Armour C.
      • Bosnic-Anticevich S.
      • Brillant M.
      • Burton D.
      • Emmerton L.
      • Krass I.
      • et al.
      Pharmacy Asthma Care Program (PACP) improves outcomes for patients in the community.
      ]. At the time this study was undertaken only one other intervention study [
      • Mehuys E.
      • Van Bortel L.
      • De Bolle L.
      • Van Tongelen I.
      • Annemans L.
      • Remon J.P.
      • et al.
      Effectiveness of pharmacist intervention for asthma control improvement.
      ] in a community pharmacy setting had applied the new asthma management “control” approach. Results showed a positive impact on asthma control only in a subgroup of uncontrolled patients at baseline, suggesting that the impact of a community pharmacist's intervention on asthma control had yet to be established. An additional recently published study in 2012 has found significant improvements in asthma control for patients receiving a pharmacy asthma service during 6 months of follow-up [
      • Armour C.L.
      • Reddel H.K.
      • Lemay K.S.
      • Saini B.
      • Smith L.D.
      • Bosnic-Anticevich S.Z.
      • et al.
      Feasibility and effectiveness of an evidence-based asthma service in Australian community pharmacies: a pragmatic cluster randomized trial.
      ].
      The objective of the present trial (AFasma study) was to evaluate whether a pharmacist intervention focused on asthma control, medication adherence and inhaler technique would result in an improved asthma control in adult asthma patients.

      Methods

       Study design

      This study was a 6-month cluster randomized controlled trial undertaken between November 2010 and June 2011 in Spain.

       Patients

      Patients were recruited consecutively in the participant pharmacies (recruitment period: November–December 2010). To be eligible, patients were required to have been prescribed Symbicort (Budesonide/Formeterol, AstraZeneca) for their own use. Inclusion criteria were: aged 18 years or older and have a physician's diagnosis of asthma. Exclusion criteria included: participation in another asthma education program, pregnancy, presence of communication difficulties, suffering from seasonal asthma (asthma symptoms that only occurred in a seasonal pattern) or other pathologies such as Chronic Obstructive Pulmonary Disease, emphysema, lung cancer, respiratory infection and terminal illness (considered as any disease that was reasonably expected to result in the death of the patient).
      Sample size was calculated to detect a difference in asthma control of greater than or equal to 20% between study groups. We applied a two-tailed test for comparing two binominal proportions, considering a type II error of 20% (β = 0.80) and 95% significance (p = 0.05). Sample size was adjusted according to standard criteria for cluster randomized trials, using a design effect (DE) of 1.45. The DE was calculated as follows: DE = 1 + (nc − 1)*ICC (Where nc is the mean number of individuals in the cluster and ICC the intra-cluster correlation coefficient). The ICC in the present work was considered to be 0.05, and the mean cluster size was assumed to be 10 patients [
      • Simpson S.H.
      • Johnson J.A.
      • Biggs C.
      • et al.
      Practice-based research: lessons from community pharmacist participants.
      ]. A potential loss of 20% was estimated. Therefore, a minimum of 342 patients and 35 pharmacies were required.
      All community pharmacies in the province of Malaga and all members of the Spanish Society of Community Pharmacy in the province of Madrid were invited by letter, with all responders enrolled.
      Pharmacies were the unit of randomization and were assigned by an independent researcher after they agreed to participate in the study to either intervention (IG) or control group (CG) using a computer-generated list of random numbers with ratio 1:1. Cluster-randomization was used to minimize cross-contamination. Given the nature of the intervention pharmacists or patients could not be blinded.

       Outcome measures

      Asthma control was the primary outcome and was assessed using the Asthma Control Questionnaire (ACQ; 5 item version, Spanish) [
      • Juniper E.F.
      • O'Byrne P.M.
      • Guyatt G.H.
      • Ferrie P.J.
      • King D.R.
      Development and validation of a questionnaire to measure asthma control.
      ,
      • Juniper E.F.
      • Svensson K.
      • Mork A.C.
      • Stahl E.
      Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.
      ]. ACQ was self-completed by the patient and the pharmacist calculated the mean of 5 items scored on a 7-point interval scale. For statistical purposes this variable was dichotomized into well-controlled (ACQ score ≤ 0.75) and uncontrolled/partly controlled (ACQ score > 0.75) [
      • Juniper E.F.
      • Bousquet J.
      • Abetz L.
      • Bateman E.D.
      Identifying 'well-controlled' and 'not well-controlled' asthma using the asthma control questionnaire.
      ]. A decrease of 0.5 points on the patient's ACQ punctuation was considered clinically relevant [
      • Juniper E.F.
      • Svensson K.
      • Mork A.C.
      • Stahl E.
      Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.
      ].
      Secondary outcomes included inhaler technique and medication adherence. Inhaler technique was assessed by the pharmacist using a 10-step turbuhaler checklist consistent with the Spanish Guide for Asthma Management-Guide for Asthma Educators (GEMA-Educators) [

      Spanish guide for asthma management – educators 2010. Asthma educator's guide [internet]. Available from: http://www.gemasma.com/images/stories/GEMASMA/Documentos/GEMA%20Educadores/index.html. [accessed 05.03.12].

      ]. The patient was asked to perform the inhaler technique with a placebo device in front of the pharmacist. Patients who performed all the checklist steps correctly were classified as having correct inhaler technique. Asthma medication adherence was assessed using the 4-item Morisky–Green–Levine scale [
      • Morisky D.E.
      • Green L.W.
      • Levine D.M.
      Concurrent and predictive validity of a self-reported measure of medication adherence.
      ], which allows the patient to be classified as adherent or non-adherent.
      Primary and secondary outcomes were measured at baseline (initial visit), 3 months (intermediate visit) and 6 months (final visit). Demographic variables and other variables related to asthma control were recorded and used for adjustment in the statistical analysis.

       Pharmacist training

      33 pharmacists allocated to the IG attended a one-day workshop. They were trained to provide education on asthma control, medication adherence and inhaler technique by a respiratory physician and a pharmacist educator/researcher. Training on the study protocol and documentation forms was also delivered. All pharmacists received the Spanish Guide for Asthma Management (GEMA 2009) [

      GEMA 2009. Spanish guide for asthma management. Available from: http://www.gemasma.com/images/stories/GEMASMA/Documentos/GEMA%202009/index.html. [accessed 05.03.12].

      ] and the GEMA-Educators [

      Spanish guide for asthma management – educators 2010. Asthma educator's guide [internet]. Available from: http://www.gemasma.com/images/stories/GEMASMA/Documentos/GEMA%20Educadores/index.html. [accessed 05.03.12].

      ].
      In addition to the training, pharmacists were assisted by a facilitator through regular visits to the pharmacies, to check for compliance with the protocol and solve any problem or query during the study [
      • Garcia-Cardenas V.
      • Gastelurrutia M.A.
      • Benrimoj S.I.
      • Martinez-Martinez F.
      • Faus M.J.
      Factors affecting community pharmacists' participation in a pharmaceutical care service for asthmatic patients.
      ]. Counseling via email and phone was also offered.
      32 Pharmacists allocated in the CG received instructions by phone about the study protocol before the beginning of the study and were monitored through 2 visits to the pharmacy.

       Pharmacist-patient intervention

      During the 6 months of follow-up, patients attended 3 scheduled visits to the pharmacy. However, additional visits (up to 6) to intervention patients could be provided if needed. Patient's demographic details were collected in the initial visit and an individualized patient needs analysis on asthma control, medication adherence and inhaler technique was conducted at every visit by the pharmacist in a private counseling area. Control patients received no intervention other than the pharmacist's usual care (normally the safe supply of medicines and medication-taking advice to the patient), whereas patients enrolled in the IG received a protocol based intervention based on GEMA recommendations. Patients were educated using verbal instructions, physical demonstration and written information about turbuhaler use. When appropriate the type of non-adherence (intentional or unintentional) and causes of intentional non-adherence were explored with the Beliefs about Medicines Questionnaire and Health Beliefs Model [
      • Perpina Tordera M.
      • Martinez Moragon E.
      • Belloch Fuster A.
      • Lloris Bayo A.
      • Pellicer Ciscar C.
      Spanish asthma patients' beliefs about health and medicines: validation of 2 questionnaires.
      ]. Several aspects of asthma control were also covered in each visit. Finally pharmacist and patient jointly agreed goals for the next visit.
      Approval for the study was given by the Ethics and Research Committee of the Virgen de las Nieves University Hospital. A written information sheet was provided and informed consent was obtained.

       Statistical analysis

      Statistical analyses were performed using SPSS for Windows 15.0 (SPSS Inc, Chicago, Illinois, USA) and SAS 9.3 (SAS Institute, 2011). A p-value < 0.05 was considered to indicate statistical significance.
      Quantitative variables were expressed as the mean SD and categorical variables were expressed as frequency and percentages. To compare quantitative variables, Student's t-test for independent samples and Student's t-test for paired samples were used. Chi-square analysis was performed for comparisons between groups at baseline and study completion. McNemar test was performed before and after intragroup comparisons to further measure categorical variables.
      ACQ scores through the study visits were analysed using a repeated measures multivariate ANOVA. To compare changes on ACQ means through the visits between the study groups, covariance analysis (ANCOVA) was performed, using the study group as the principal effect and baseline ACQ scores as co-variable. A sub-analysis of the effect of the intervention based on asthma control at baseline was also performed.
      It is recommended that the analysis of cluster randomised trials takes account of clustering, even where the ICC is small [
      • Murray D.
      The design and analysis of group-randomized trials.
      ]. The regression analysis of the primary outcome used the mixed model approach recommended by Murray [
      • Murray D.
      The design and analysis of group-randomized trials.
      ]. However, accounting for clustering had little impact on estimates or precision, possibly because of the extremely small ICC and small number of patients per pharmacy. Consequently, analysis of the secondary outcomes (deemed to be part of the causal pathway to the primary endpoint) used simpler methods which assumed no clustering by pharmacy.
      A multivariate logistic regression analysis was performed to explore the association between asthma control and study group; estimation was by maximum likelihood using the SAS GLIMMIX procedure. This analysis included a random intercept for pharmacy nested within group to account for clustering of patients within pharmacies and was adjusted by covariates that could affect asthma control (Asthma control at baseline, gender, age, Body Mass Index, smoking status, number of asthma drugs and living area). This analysis was repeated using an intention to treat approach (ITT) assuming a worst-case scenario (patients in the CG ended with controlled asthma and patient in the IG ended with uncontrolled asthma) for patients with missing outcomes data.

      Results

       Study sample

      Initially 65 pharmacies were enrolled, and after withdrawals, 51 pharmacies (22 in the CG and 29 in the IG) completed the study. 384 patients were offered to enter the study and 373 patients accepted, of which 346 finished the study (160 in the CG and 186 in the IG). However one pharmacy and its 10 patients were excluded from the analysis due to lack of reliable data, leaving 50 pharmacies (21 in the CG and 29 in the CG) and 336 patients analysed (150 in the CG and 186 in the IG). There were 7 patients per pharmacy on average ranging from 2 to 10. 107 out of 186 patients in the IG attended more than three times to the pharmacy, and 51 (27.4%) completed 6 visits (Fig. 1).
      Figure thumbnail gr1
      Figure 1Flowchart of patients and pharmacies during the AFasma study.
      Patients in both IG and CG had similar demographic and clinical characteristics (Table 1). However percentage of uncontrolled patients, mean number of anti-asthmatic drugs and percentage of patients living in an urban area were significantly higher in the IG (p = 0.005, p = 0.038 and p < 0.001 respectively).
      Table 1Baseline characteristics of study patients.
      Total (n = 336)IG (n = 186)CG (n = 150)p Value
      Primary variables
       ACQ punctuation; mean (SD)1.4 (1.1)1.4 (1.1)1.3 (1.2)0.444
       Controlled asthma; n (%)116 (34.5)52 (28.0)64 (42.7)0.005
       Correct inhaler technique; n (%)
      Correct performance of all steps for Turbuhaler inhaler technique. 10-step Turbuhaler checklist.
      72 (21.4)36 (19.5)36 (24.0)0.302
       Adherence to asthma treatment; n (%)
      Morisky-Green-Levine test.
      130 (38.7)71 (38.2)59 (39.3)0.828
      Other variables
       Male; n (%)155 (46.1)82 (44.1)73 (48.7)0.402
       Age (years); mean (SD)55.8 (19.1)54.3 (19.1)57.8 (19.0)0.097
       BMI (kg/m2); mean (SD)27.1 (5.3)27.0 (5.5)27.2 (5.1)0.676
       Current smoker; n (%)70 (20.8)40 (21.5)30 (20.0)0.736
       Urban living area; n (%)242 (72.0)112 (66.2)130 (86.7)<0.001
       Marital status (with partner); n (%)185 (55.1)98 (52.7)87 (58.0)0.331
      Level of education
       No education; n (%)50 (14.9)23 (12.4)27 (18.1)0.351
       Primary; n (%)123 (36.7)66 (35.5)57 (38.3)
       Secondary/Vocational education; n (%)86 (25.7)52 (28.0)34 (22.8)
       University; n (%)76 (22.7)45 (24.2)31 (20.8)
      Employment status
       Unpaid worker; n (%)103 (30.7)54 (29.0)49 (32.7)0.711
       Paid worker; n (%)112 (33.3)65 (34.9)47 (31.3)
       Unemployed or retired person; n (%)121 (36.0)67 (36.0)54 (36.0)
       Anti-asthmatic drugs; mean (SD)1.5 (0.7)1.6 (0.7)1.4 (0.7)0.038
      Type of controller treatment
       Low-dose ICS plus long-acting β2 agonists13 (3.9)7 (3.8)6 (4.0)0.275
       Medium-dose ICS plus long-acting β2 agonists276 (82.1)158 (84.9)118 (78.7)
       High-dose ICS plus long-acting β2 agonists47 (14.0)21 (11.3)26 (17.3)
       Use of other ICS; n (%)8 (2.4)5 (2.7)3 (2.0)0.681
       Use of oral corticosteroids; n (%)2 (0.6)1 (0.5)1 (0.7)0.879
       Use of anticholinergic drugs; n (%)36 (10.7)24 (12.9)12 (8.0)0.149
       Use of antileukotriene drugs; n (%)34 (10.1)24 (12.9)10 (6.7)0.060
       Use of short-acting β2 agonists; n (%)99 (29.5)59 (31.7)40 (26.7)0.312
      CG: control group; IG: intervention group; SD: standard deviation; Kg: kilograms; m: meters; BMI: body mass index; ICS: inhaled corticosteroids.
      a Correct performance of all steps for Turbuhaler inhaler technique. 10-step Turbuhaler checklist.
      b Morisky-Green-Levine test.

       Primary outcome: asthma control

      Mean ACQ scores significantly decreased from the initial to the intermediate visit in both IG (0.32 points, SD: 0.91, p < 0.001) and CG (0.16 points, SD: 0.73, p = 0.017), while between the intermediate visit and the final visit the decrease was only observed in the IG (0.34 points, SD: 0.65, p < 0.001). In the IG a final clinically relevant reduction of 0.66 (SD: 0.78, p < 0.001) in mean ACQ scores was observed (Fig. 2).
      Figure thumbnail gr2
      Figure 2Mean ACQ scores across the study visits.
      In the IG, the proportion of patients with controlled asthma significantly increased from baseline (28.0%, n = 52) to the intermediate visit (43.0%, n = 80) and from the intermediate visit to the final visit (58.1%, n = 108), while this proportion in the CG remained similar (Fig. 3). At the end of the study, asthma was controlled in significantly more patients in the IG than in the CG (58.1% versus 46.0%, p = 0.028), with an Odds Ratio of 3.06 (95% CI:1.63–5.73; p < 0.001) (Table 2). The Intrapharmacy correlation coefficient was found to be very small (<0.001), signaling there was no cluster effect. The results for the ITT approach, where patients with missing outcomes were included (20 IG and 5 CG) showed an adjusted odds ratio of 1.94 (95% CI:1.06–3.55; p = 0.032).
      Figure thumbnail gr3
      Figure 3Proportion of patients with controlled asthma across the study visits.
      Table 2Multivariate logistic regression analysis to assess the effect of pharmacist intervention on asthma control at the endpoint (n = 327, missing data on age and BMI of 9 patients).
      VariableAdjusted OR95%CIp Value
      Group assignment
       ControlReference
       Intervention3.0591.632–5.733<0.001
      Sex
       FemaleReference
       Male1.2540.724–2.1730.418
      Age
       Older than 78Reference
       From 18 to 300.9580.293–3.1300.943
       From 30 to 420.8310.243–2.8370.766
       From 42 to 540.4680.140–1.5620.216
       From 54 to 660.7120.240–2.1080.538
       From 66 to 780.3980.137–1.1590.091
      Smoking status
       Non-smokerReference
       Smoker0.8590.429–1.7190.0667
      Living area
       UrbanReference
       Rural1.3860.746–2.5740.301
      BMI
       Obese (BMI ≥30 kg/m2)Reference
       Normal weight (18.5 ≤ BMI ≤24.99 kg/m2)1.5450.733–3.2570.252
       Overweight (25 ≤ BMI ≤ 29.99 kg/m2)1.2910.628–2.6540.487
      Number of anti-asthmatic drugs
       Three or moreReference
       One0.9020.378–2.1470.814
       Two0.6870.275–1.7150.420
      Asthma control at baseline
       ControlledReference
       Uncontrolled0.0570.028–0.114<0.001
      OR: Odds Ratio; 95%CI: 95% confidence interval; BMI: body mass index.
      Raw data OR (simple logistic regression analysis): 1.625 (95%CI: 1.054–2.507; p = 0.028).
      Assuming mean values for age and BMI (n = 336); OR: 3.117; IC: 1.669–5.823; p < 0.001.
      Intention to treat (n = 352); OR: 1.942; IC: 1.061–3.553; p = 0.032.
      Intention to treat assuming mean values for age and BMI (n = 361); OR: 1.997; IC: 1.089–3.662; p = 0.026.
      Hosmer–Lemeshow test (Chi-squared = 6.038; p = 0.643); Nagelkerke R-squared: 0.407.
      A subgroup analysis of uncontrolled asthma patients at baseline showed a greater effect of the intervention on both proportion of controlled patients and mean ACQ scores after 6 months of follow up compared to those patients that were well-controlled at baseline (Table 3).
      Table 3Sub-analysis of the effect of the intervention based on asthma control at baseline.
      Patients with controlled asthma at baseline (n = 116)
      Intervention group (n = 52), Control group (n = 64).
      Patients with uncontrolled asthma at baseline (n = 220)
      Intervention group (n = 134), Control group (n = 86).
      IGCGp-ValueIGCGp-Value
      Controlled asthma (final visit); n (%)47 (90.4)54 (84.4)0.33761 (45.5)15 (17.4)<0.001
      Correct Turbuhaler inhaler technique (final visit); n (%)
      Analysis of covariance (ANCOVA), using the patient's group assignment as the primary effect and baseline ACQ punctuation as the co-variable (differences are expressed compared to the CG).
      38 (73.1)36 (56.3)0.061103 (76.9)39 (45.3)<0.001
      Difference between groups in adjusted mean changes for ACQ from baseline to intermediate visit; points (IC95%)
      Analysis of covariance (ANCOVA), using the patient's group assignment as the primary effect and baseline ACQ punctuation as the co-variable (differences are expressed compared to the CG).
      0.05 (−0.15–0.25)0.634−0.21 (−0.01–0.44)0.065
      Difference between groups in adjusted mean changes for ACQ from baseline to final visit; points (IC95%)
      Analysis of covariance (ANCOVA), using the patient's group assignment as the primary effect and baseline ACQ punctuation as the co-variable (differences are expressed compared to the CG).
      −0.18 (−0.37–0.02)0.079−0.62 [−0.80 −(−0.43)]<0.001
      CG: control group; IG: intervention group; 95%CI: 95% confidence interval.
      a Intervention group (n = 52), Control group (n = 64).
      b Intervention group (n = 134), Control group (n = 86).
      c Analysis of covariance (ANCOVA), using the patient's group assignment as the primary effect and baseline ACQ punctuation as the co-variable (differences are expressed compared to the CG).

       Secondary outcomes: inhaler technique and medication adherence

      Proportion of patients with incorrect performance of steps for Turbuhaler inhaler technique at baseline is summarised in Table 4.
      Table 4Proportion of patients with incorrect performance of steps for Turbuhaler inhaler technique at baseline.
      Turbuhaler inhaler technique stepTotal (n = 336)IG (n = 186)CG (n = 150)p Value
      1Unscrew and lift off the cover9 (2.7)2 (1.1)7 (4.7)0.043
      2Hold the inhaler upright81 (24.1)37 (19.9)44 (29.3)0.044
      3Twist the red grip fully to the right as far as it will go and twist it back again to the left. A “click” will be heard41 (12.2)26 (14.0)15 (10.0)0.268
      4Breathe out gently taking care not to breathe into the Turbuhaler157 (46.7)90 (48.4)67 (44.7)0.497
      5Place mouthpiece between teeth and lips52 (15.5)27 (14.5)25 (16.7)0.588
      6Inhale forcefully and deeply75 (22.3)51 (27.4)24 (16.0)0.012
      7Remove the inhaler from the mouth, hold breath for 8 s and exhale away from the mouthpiece140 (41.7)86 (46.2)54 (36.0)0.058
      8If further doses are needed wait 30 s and repeat steps from 2 to 7
      This step was assessed in those patients prescribed with two consecutive inhalations (118 patients: CG = 52; IG = 66).
      59 (50.0)35 (53.0)24 (46.2)0.458
      9Replace white cap22 (6.5)15 (8.1)7 (4.7)0.211
      10Rinse mouth with water. Do not swallow142 (42.3)77 (41.4)65 (43.3)0.721
      a This step was assessed in those patients prescribed with two consecutive inhalations (118 patients: CG = 52; IG = 66).
      The percentage of intervention patients with correct inhaler technique significantly increased between baseline (19.5%) and intermediate visit (57.0%, p < 0.001), and between intermediate visit and final visit (75.7%, p < 0.001). Significant increase was also observed in patients included in the CG between baseline (24.0%) and intermediate visit (46.0%, p < 0.001), but not between intermediate visit and final visit (50.0%, p = 0.286). Proportion of patients with correct inhaler technique at the end of the study was significantly higher in the IG (75.8% versus 50.0%, p < 0.001) (Fig. 4).
      Figure thumbnail gr4
      Figure 4Proportion of patients with correct inhaler technique across the study visits.
      When compared with the CG, proportion of patients in the IG who performed steps 2, 4, 6, 7, 8, and 10 of the inhaler technique correctly was significantly higher at the final visit (Table 5).
      Table 5Proportion of patients with incorrect performance of steps for Turbuhaler inhaler technique at final visit.
      Turbuhaler inhaler technique stepIG (n = 186)p Value
      For intra-group comparisons between baseline and end point (McNemar test).
      CG (n = 150)p Value
      For intra-group comparisons between baseline and end point (McNemar test).
      p Value
      For comparisons between groups (Chi–Square test).
      1Unscrew and lift off the cover1 (0.5)1.0000 (0.0)
      McNemar test was not calculated since at least one of the variables used for the calculation of measures of association was a constant.
      0.368
      2Hold the inhaler upright6 (3.2)<0.00134 (22.7)0.076<0.001
      3Twist the red grip fully to the right as far as it will go and twist it back again to the left. A “click” will be heard2 (1.1)<0.0016 (4.0)0.0350.080
      4Breathe out gently taking care not to breathe into the Turbuhaler20 (10.8)<0.00137 (24.7)<0.0010.001
      5Place mouthpiece between teeth and lips9 (4.8)0.00110 (6.7)<0.0010.471
      6Inhale forcefully and deeply12 (6.5)<0.00120 (13.3)0.4810.033
      7Remove the inhaler from the mouth, hold breath for 8 s and exhale away from the mouthpiece14 (7.5)<0.00131 (20.7)<0.001<0.001
      8If further doses are needed wait 30 s and repeat steps from 2 to 7
      This step was assessed in those patients prescribed with two consecutive inhalations (120 patients: CG = 53; IG = 67).
      4 (6.0)<0.00114 (26.4)0.0120.002
      9Replace white cap3 (1.6)0.0048 (5.3)1.0000.057
      10Rinse mouth with water. Do not swallow9 (4.8)<0.00136 (24.0)<0.001<0.001
      a For intra-group comparisons between baseline and end point (McNemar test).
      b For comparisons between groups (Chi–Square test).
      c This step was assessed in those patients prescribed with two consecutive inhalations (120 patients: CG = 53; IG = 67).
      d McNemar test was not calculated since at least one of the variables used for the calculation of measures of association was a constant.
      In the IG, proportion of patients adherent to asthma treatment significantly increased from baseline (38.2%) to intermediate visit (60.8%; p < 0.001), as well as between intermediate visit and final visit (78.5%; p < 0.001). In the CG this increase was observed between baseline (39.3%) and intermediate visit (53.3%; p < 0.001), but not between intermediate visit and final visit (52.0%; p = 0.839). Proportion of adherent patients at the end of the study was significantly higher in the IG (78.5% versus 52.0%, p < 0.001) (Fig. 5).
      Figure thumbnail gr5
      Figure 5Proportion of adherent patients to asthma treatment.

      Discussion

      The results show that the educational intervention in this 6-month study significantly improved asthma control in patients allocated in the IG, compared to usual care. Secondary outcomes important for asthma management were also improved, and the results remained significant when a more restrictive ITT analysis was used.
      Within the first 3 months of follow-up, a significant improvement in ACQ scores, inhaler technique and medication adherence among patients in both study groups was observed. These positive results in the CG could be attributed to several factors; patients may have modified their behavior because they knew they were being studied (Hawthorne effect) or because as part of the measurement of the main variables, they were asked questions about their asthma control, medication adherence and inhaler technique, activities that may not usually have been performed in the pharmacy. Additionally, even though control pharmacists were asked not to change their usual care during the study, they might have provided more information than the one usually provided. Although community pharmacists have specific medication and disease knowledge, they usually demand and are provided additional specific training prior to the delivery of a specific pharmaceutical care service. Intervention pharmacists were provided with training above and beyond the usual training a pharmacist would receive on asthma management and so that they could effectively address patients needs based on asthma control, medication adherence and/or inhaler use. However, it should be noted that these improvements were sustained at 6 months only in intervention patients, suggesting that to detect an impact in patient outcomes, future similar research should be carried out during at least that period of time.
      Our overall findings agree with other published research [
      • Barbanel D.
      • Eldridge S.
      • Griffiths C.
      Can a self-management programme delivered by a community pharmacist improve asthma control? A randomised trial.
      ,
      • Bunting B.A.
      • Cranor C.W.
      The Asheville Project: long-term clinical, humanistic, and economic outcomes of a community-based medication therapy management program for asthma.
      ,
      • Cordina M.
      • McElnay J.C.
      • Hughes C.M.
      Assessment of a community pharmacy-based program for patients with asthma.
      ,
      • Emmerton L.
      • Shaw J.
      • Kheir N.
      Asthma management by New Zealand pharmacists: a pharmaceutical care demonstration project.
      ,
      • Mangiapane S.
      • Schulz M.
      • Muhlig S.
      • Ihle P.
      • Schubert I.
      • Waldmann H.C.
      Community pharmacy-based pharmaceutical care for asthma patients.
      ,
      • McLean W.
      • Gillis J.
      • Waller R.
      The BC community pharmacy asthma study: a study of clinical, economic and holistic outcomes influenced by an asthma care protocol provided by specially trained community pharmacists in British Columbia.
      ,
      • Narhi U.
      • Airaksinen M.
      • Tanskanen P.
      • Erlund H.
      Therapeutic outcomes monitoring by community pharmacists for improving clinical outcomes in asthma.
      ,
      • Saini B.
      • Krass I.
      • Armour C.
      Development, implementation, and evaluation of a community pharmacy-based asthma care model.
      ,
      • Schulz M.
      • Verheyen F.
      • Muhlig S.
      • Muller J.M.
      • Muhlbauer K.
      • Knop-Schneickert E.
      • et al.
      Pharmaceutical care services for asthma patients: a controlled intervention study.
      ,
      • Armour C.
      • Bosnic-Anticevich S.
      • Brillant M.
      • Burton D.
      • Emmerton L.
      • Krass I.
      • et al.
      Pharmacy Asthma Care Program (PACP) improves outcomes for patients in the community.
      ]. Two studies in a community pharmacy setting [
      • Mehuys E.
      • Van Bortel L.
      • De Bolle L.
      • Van Tongelen I.
      • Annemans L.
      • Remon J.P.
      • et al.
      Effectiveness of pharmacist intervention for asthma control improvement.
      ,
      • Armour C.L.
      • Reddel H.K.
      • Lemay K.S.
      • Saini B.
      • Smith L.D.
      • Bosnic-Anticevich S.Z.
      • et al.
      Feasibility and effectiveness of an evidence-based asthma service in Australian community pharmacies: a pragmatic cluster randomized trial.
      ] were found to measure asthma control as the primary outcome, reflecting the GINA 2006 shift of paradigm in asthma management. Armour et al. [
      • Armour C.L.
      • Reddel H.K.
      • Lemay K.S.
      • Saini B.
      • Smith L.D.
      • Bosnic-Anticevich S.Z.
      • et al.
      Feasibility and effectiveness of an evidence-based asthma service in Australian community pharmacies: a pragmatic cluster randomized trial.
      ] assessed asthma control using a symptom/activity tool and the ACQ for patients receiving either a three- or four- visit asthma pharmacy service. They found an increase in patients classified as having good asthma control by 32% (for the three-visit group) and by 38% (for the four-visit group) and a mean decrease in ACQ scores of 0.57 and 0.56 respectively. Similar results in both increase percentage of controlled patients and mean decrease of ACQ scores were also found in our study. Mehuys et al. [
      • Mehuys E.
      • Van Bortel L.
      • De Bolle L.
      • Van Tongelen I.
      • Annemans L.
      • Remon J.P.
      • et al.
      Effectiveness of pharmacist intervention for asthma control improvement.
      ] measured asthma control with a clinically validated tool (Asthma Control Test, ACT) and found that the intervention significantly improved ACT scores only in a subgroup of patients having insufficiently controlled asthma at baseline. However in the present study, positive results were found not only in a subgroup of uncontrolled patients at baseline but also in the aggregated data. As previously suggested [
      • Armour C.L.
      • Lemay K.
      • Saini B.
      • Reddel H.K.
      • Bosnic-Anticevich S.Z.
      • Smith L.D.
      • et al.
      Using the community pharmacy to identify patients at risk of poor asthma control and factors which contribute to this poor control.
      ], this greater improvement in asthma control on uncontrolled patients at baseline can establish a different interventional approach in asthma management. The identification of uncontrolled patients through health initiatives in different settings would allow targeting asthma management strategies and probably reducing asthma-related costs over time.
      The intervention delivered to patients allocated to the IG was effective, individualized and tailored to the patients' current asthma control, following GEMA recommendations. Adherence education was provided using different strategies according to the kind of non-adherence identified in the patient. The intervention was individualised, taking into account specific barriers to medication adherence, using validated tools for patients presenting intentional non-adherence. This allowed the assessment of necessity beliefs and concerns about asthma treatment and effectively addressed them. Inhaler training was delivered using written and verbal counselling plus physical demonstration (proven to be the most effective way of delivering such education [
      • Bosnic-Anticevich S.Z.
      • Sinha H.
      • So S.
      • Reddel H.K.
      Metered-dose inhaler technique: the effect of two educational interventions delivered in community pharmacy over time.
      ]), improving the percentage of patients performing correct inhaler technique. As medication adherence and inhaler technique are both critical issues for successful asthma management, their improvement probably contributed to the enhancement of asthma control in 30.1% of patients allocated in the IG. Unfortunately, neither assessment nor training on inhaler technique is regularly being performed in many clinical settings, increasing the risk of misuse of inhaler devices [
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • Cinti C.
      • Lodi M.
      • Martucci P.
      • et al.
      Inhaler mishandling remains common in real life and is associated with reduced disease control.
      ]. Nevertheless at the end of the study there still were non-adherent patients (21.5%) and patients failing to use the inhaler device correctly (24.2%). Whether these issues in association with other factors, such as smoking status or exposure to triggers, may have contributed to 41.9% of patients failing to achieve good asthma control is unknown.
      Some limitations of this study must be mentioned. Firstly, only patients treated with Symbicort were included in the study; therefore, our sample may not be representative of the whole asthma population. Secondly, significant differences between study groups were found at baseline in mean number of anti-asthmatic drugs and percentage of patients living in an urban area. Although patients had similar ACQ scores at baseline, when categorized according to their level of asthma control, significant differences were also observed. This concern was controlled for by adjusting the statistical analysis to take these baseline differences into account. Finally, since patient's outcomes were achieved after a 6-month intervention, sustainability of these results on a longer term follow-up cannot be assured.
      In conclusion, asthma represents a worldwide problem and public health initiatives are essential to encourage asthma education for patients and healthcare providers. The AFasma study focused on the important outcomes of asthma management, and showed that through the designed intervention, community pharmacists can increase controlled asthma patients compared to usual care. Although the intervention delivered seemed to be compatible with the pharmacists' daily practice, additional research would be needed to define the core issues for a future implementation of the service in a community pharmacy setting.

      Funding

      The study was funded by the AstraZeneca Foundation , who did not interfere with the study design, collection statistical analysis, interpretation of the data and writing of the manuscript, nor in the decision to submit this manuscript for publication.

      Conflict of interest statement

      All the authors have declared that they have no conflict of interest.

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