Respiratory Medicine 126 (2017) 52e58
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Home-made spacer as an auxiliary device in administration of beclomethasone via pressurized metered dose inhaler for asthma control. A randomized controlled pragmatic trial ^ Angelo Deborah Schor a, Jose Rizzo a, b, *, Decio Medeiros a, Ana Carolina Dela Bianca a, a rio Morais-Almeida d, Emanuel Sarinho a Almerinda Rego Silva , Carlos Nunes c, Ma a
Center for Research in Allergy and Clinical Immunology, Health Sciences Post-Graduation Program, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil Pneumology Department, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil c ~o, Portugal Algarve Immuno-Allergology Center, Portima d CUF Descobertas Hospital, Immuno-Allergy Department, Lisbon and CINTESIS (Center for Research in Health Technologies and Information Systems), Faculdade de Medicina Do Porto, Portugal b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 December 2016 Received in revised form 16 February 2017 Accepted 21 March 2017 Available online 22 March 2017
Background: Holding chambers or spacers can enhance the efficacy of pressurized metered dose inhalers (pMDI) in delivering inhaled medications, as they reduce the need for hand-breath coordination and improve lower airways deposition. Nevertheless, their cost can be high for patients in low-income countries. Objective: To compare asthma control achieved with beclomethasone-dipropionate administered through a hydrofluoroalkane-driven pMDI (BDp-pMDI) coupled to a home-made spacer (HmS) or to a valved commercial spacer (VCS) as auxiliary devices. Methods: Sixty-three patients with poorly controlled asthma that had a BDp-pMDI prescription were randomized to use the inhaler coupled to a HmS made of 500 ml plastic bottles (Group HmS, n ¼ 32) or to a VCS (Group VCS, n ¼ 31) for 60 days. All were given training sessions. Asthma control was assessed through the Asthma Control Test (ACT) and forced expiratory volume in the first second (FEV1), both measured before, and 30 and 60 days after treatment began. Results: Both groups showed significant improvement in ACT scores after 30 and 60 days compared to baseline values (an increase of 7 and 7.8 points for the HmS group and 5.9 and 7.0 points for the VCS group, respectively, p < 0.001). There was no statistically significant difference in ACT scores between groups at any observation time (P ¼ 0.261). FEV1 showed the same behavior. Conclusions: A similar level of asthma control was achieved with beclomethasone-dipropionate administered through a pMDI whether the inhaler was coupled to the HmS or VCS. These results are significant for asthma control planning strategies in low-income communities. (Trial Register Number: RBR-5x4dc9). © 2017 Published by Elsevier Ltd.
Keywords: Asthma Inhalers Spacers Beclomethasone-dipropionate Asthma control
1. Introduction
* Corresponding author. Rua de Apipucos, 235/1901, CEP 52071-000 Recife, PE, Brazil. E-mail addresses: [email protected] (D. Schor), [email protected] ^ Rizzo), [email protected] (D. Medeiros), [email protected] (J.A. (A.C. Dela Bianca), [email protected] (A.R. Silva), [email protected] (C. Nunes), [email protected] (M. Morais-Almeida), emanuel.sarinho@ gmail.com (E. Sarinho). http://dx.doi.org/10.1016/j.rmed.2017.03.017 0954-6111/© 2017 Published by Elsevier Ltd.
Asthma is a global problem that affects more than 300 million people worldwide, many of them in low-income countries [1]. The treatment goal is to achieve the best disease control and the main drug administration route is inhalation [2,3]. Pressurized metereddose inhalers (pMDIs) are widely used to deliver inhaled betaagonist bronchodilators or steroids directly to the lower airways, owing to their effectiveness, safety, portability and low cost [4,5]. Many patients make incorrect use of these devices and this is one of
D. Schor et al. / Respiratory Medicine 126 (2017) 52e58
the main causes of failure to achieve asthma control. Lack of coordination between aerosol discharge from pMDIs and patient inhalation (hand-breath coordination) is one of the most common errors committed by the patients [6e8]. Valved spacers (VCS) are pMDI accessory devices designed to improve aerosolized medication penetration into the airway. They are manufactured in different volumes and shapes and have a oneway valve, usually near the mouth opening, which allows some delay between pMDI actuation and aerosol inhalation, minimizing patient's need for hand-breath co-ordination. This delay also facilitates particle evaporation and size reduction, minimizing oropharyngeal drug deposition and local side effects, and improving medication penetration into peripheral airways [9e11]. Nevertheless, the cost of the VCS, although not high, can be prohibitive for low-income populations. Some studies have evaluated the efficacy of treatment of acute asthma using bronchodilator drugs delivered through a pMDI coupled to non-valved home-made spacers manufactured from various recycled materials, such as 500 ml plastic soft drinks bottles, cardboard tubes, plastic cups or empty plastic saline solution bottles [12e15]. However, only the first showed results comparable to those obtained with the same drugs administered by nebulizers or pMDIs coupled to valved commercial spacers [13,15]. The objective of this study was to compare asthma control achieved by the inhaled steroid beclomethasone-dipropionate administered through an HFA-driven pMDI coupled either to a 500 ml non-valved home-made spacer or to an industrially produced valved one in cases of poorly controlled asthma. 2. Material and methods This was an open parallel controlled pragmatic randomized clinical trial [16] conducted in the city of Recife, in the Brazilian State of Pernambuco. Patient inclusion and follow-up occurred between July 2010 and May 2012 and recruitment was carried out during the patient's first visit to the outpatient clinics from the Allergy and the Pulmonology Departments of the Hospital das Clinicas at the Federal University of Pernambuco - Brazil. ES, DM, ACDB and ARS, who were also the attending physicians, recruited the patients. The Institutional Ethics Committee approved the study under the number 0297.0.172.000e1 and all parents/guardians and/or patients signed an informed consent or assent form. The patient shown in Fig. 2 gave her consent for publication. Trial Register Number: RBR-5x4dc9. Patients were invited to participate if they lived within the metropolitan area of the city, were aged between 14 and 65 years, and their asthma was considered non-controlled as defined by the Global Initiative for Asthma [3]. After the initial evaluation, all participants had been prescribed inhaled Beclomethasone for daily use as maintenance treatment by the attending specialist. Hydrofluoroalkane-driven Beclomethasone is the inhaled steroid distributed free-of-charge by the Brazilian health system. Participants were reimbursed only for transport expenses and were offered a lunch. At beginning of the trial (Visit 1) all patients underwent forced expiratory volume in the first second (FEV1) measurements before and after administration of an inhaled bronchodilator using a calibrated spirometer (MicroQuark, Cosmed, Rome-Italy) in accordance with ATS/ERS guidelines [17]. The patients also completed the Asthma Control Test (ACT) questionnaire [18,19] translated into Portuguese (Brazil) and validated [20]. Only those patients who showed a 10% increase in FEV1 after bronchodilator administration and had a score 18 points on the ACT were included in the trial. Patients were excluded if they had smoked in the past decade, had other lung diseases or failed to
53
perform the maneuvers for FEV1 measurements properly. Patients were allocated in equal proportion to use the beclomethasone-HFA pMDI coupled to home-made spacer or to valved commercial spacer following a simple block randomization (blocks of four) carried out by a person not involved in the research. The same person generated the randomization sequence on the Excel 2010 program (Microsoft Corp.) and kept it in a sealed envelope. The study was not blinded as it was not possible to mask the spacers. A person not involved in the inclusion process notified field researchers of the allocations. The beclomethasone (Clenil HFA - Chiesi e Brazil) dose was chosen according to patient's asthma severity classification: 250 mcg/day for those with mild persistent asthma, 500 mcg/day for those with moderate persistent and 1000 mcg/day for patients with severe persistent asthma in accordance with Brazilian asthma guidelines recommendations for treatment at the time of the research project elaboration [21]. Fifty and 250 mg/puff canisters were dispensed according to dosage allocations. Patients on 250 mcg/day were instructed to use two puffs in the morning and three at night from the 50 mcg/puff canister; those on 500 mcg/day or 1000 mcg/day were instructed to take one or two puffs in the morning and at night, respectively, from the 250 mcg/puff canister. All patients were also provided with an Albuterol pMDI 100mcg/puff (Aerolin, GSK e Brazil) for recovery as needed (2 puffs each time, maximum six times a day). Patients were told to return to the clinic in case of exacerbations that did not respond to the recovery medication. After allocation, patients were instructed to use the pMDI coupled to the home-made spacer (HmS group) or valved spacer (VCS group) using a movie specifically produced for this purpose following steps adapted from GINA [3] and Melani et al. [22] in order to minimize bias. At the end of the session, patients were asked to repeat the learned technique. If errors were made the patient could watch the movie up to two more times. Patients only remained in the study if they did not commit critical errors in the use of pMDI coupled to the spacer. Critical errors were those that prevented medication inhalation. As the HmS has no valve, an inhalation delay of more than 3 s after pMDI actuation was considered a critical error. Other critical errors were more than one pMDI actuation in the same inhalation, inhalation through the nose, stopping inhalation immediately after pMDI actuation and not positioning the inhaler upright before actuation [22]. Thirty days after treatment began (Visit 2 - V2), patients underwent a second evaluation with FEV1 measurements and completed the ACT questionnaire. Those who made mistakes in the use of pMDI/spacer underwent further training as described above. The same procedures were carried out 60 days after the first visit (Visit 3 - V3). (Fig. 1). Patients were given a telephone call (when available) between visits, reminding them of the time of the next appointment. The ACT [18e20] is a 5-item survey for asthma control assessment with questions about asthma disruption of work, home or school activities, shortness of breath, sleep disturbance, use of recovery medication and the patient's own classification of disease control in the last four weeks. The ratings vary on a Likert-like scale ranging from 1(worse) to 5 (best) e maximum 25 points. Patients with a score 18 points are considered to have non-controlled asthma [19]. The ACT was read to all patients by DS on all occasions to circumvent the problem of illiteracy. No clarifications were provided regarding the ACT questions after the enrolment visit. To make the home-made spacers, identical 500 ml mineral water bottles (Indai a, Recife, Brazil) were purchased at a local supermarket. A heated iron cast was used to produce a hole in the bottom of the transparent polyethylene plastic bottles for coupling
54
D. Schor et al. / Respiratory Medicine 126 (2017) 52e58
Fig. 1. Home-made spacer in use.
the pMDI as tightly as possible. The patient positioned the open bottle mouth between the lips and pressed the pMDI to inhale the medication after a full exhalation (Fig. 1). The commercial valved holding chamber used was a spindle shaped, one valve, 700 ml ~o Paulo, Brazil), made of semi-transparent polyFlumax® (Sa carbonate plastic with no audible feedback mechanism and no antistatic properties [23]. The inhalation technique instructions were identical to those for the home-made spacers. All HmS and VCS were previously dipped into detergent diluted in water and allowed to dry in ambient air in order to reduce electrostatic charge [11,24]. This procedure was not repeated. Patients were instructed not to wash the devices and to keep them in a dry place inside a transparent plastic bag. 2.1. Statistical analysis The study was designed considering a bilateral hypothesis for the comparison of groups regarding ACT score. The sample size calculation assumed a standard deviation of 4.4 points on the ACT in poorly controlled patients [19] and a minimum clinically important difference for patients with persistent asthma of 3 points in this test [25]. The number of subjects required to detect this difference between groups in the final score was 32 patients per group, considering a probability of a and b errors of 0.05 and 0.80 respectively. For comparison of data between baseline and at the two subsequent visits in both groups the general linear model for longitudinal repeated measurements was adopted considering two factors: group and time. The Sidak test was performed to correct the significant differences among multiple comparisons between the 3 visits. All analyses were conducted by a professional statistician using SPSS for Windows version 18.0 and a P-value of
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Home-made spacer as an auxiliary device in administration of beclomethasone via pressurized metered dose inhaler for asthma control. A randomized controlled pragmatic trial ^ Angelo Deborah Schor a, Jose Rizzo a, b, *, Decio Medeiros a, Ana Carolina Dela Bianca a, a rio Morais-Almeida d, Emanuel Sarinho a Almerinda Rego Silva , Carlos Nunes c, Ma a
Center for Research in Allergy and Clinical Immunology, Health Sciences Post-Graduation Program, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil Pneumology Department, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil c ~o, Portugal Algarve Immuno-Allergology Center, Portima d CUF Descobertas Hospital, Immuno-Allergy Department, Lisbon and CINTESIS (Center for Research in Health Technologies and Information Systems), Faculdade de Medicina Do Porto, Portugal b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 December 2016 Received in revised form 16 February 2017 Accepted 21 March 2017 Available online 22 March 2017
Background: Holding chambers or spacers can enhance the efficacy of pressurized metered dose inhalers (pMDI) in delivering inhaled medications, as they reduce the need for hand-breath coordination and improve lower airways deposition. Nevertheless, their cost can be high for patients in low-income countries. Objective: To compare asthma control achieved with beclomethasone-dipropionate administered through a hydrofluoroalkane-driven pMDI (BDp-pMDI) coupled to a home-made spacer (HmS) or to a valved commercial spacer (VCS) as auxiliary devices. Methods: Sixty-three patients with poorly controlled asthma that had a BDp-pMDI prescription were randomized to use the inhaler coupled to a HmS made of 500 ml plastic bottles (Group HmS, n ¼ 32) or to a VCS (Group VCS, n ¼ 31) for 60 days. All were given training sessions. Asthma control was assessed through the Asthma Control Test (ACT) and forced expiratory volume in the first second (FEV1), both measured before, and 30 and 60 days after treatment began. Results: Both groups showed significant improvement in ACT scores after 30 and 60 days compared to baseline values (an increase of 7 and 7.8 points for the HmS group and 5.9 and 7.0 points for the VCS group, respectively, p < 0.001). There was no statistically significant difference in ACT scores between groups at any observation time (P ¼ 0.261). FEV1 showed the same behavior. Conclusions: A similar level of asthma control was achieved with beclomethasone-dipropionate administered through a pMDI whether the inhaler was coupled to the HmS or VCS. These results are significant for asthma control planning strategies in low-income communities. (Trial Register Number: RBR-5x4dc9). © 2017 Published by Elsevier Ltd.
Keywords: Asthma Inhalers Spacers Beclomethasone-dipropionate Asthma control
1. Introduction
* Corresponding author. Rua de Apipucos, 235/1901, CEP 52071-000 Recife, PE, Brazil. E-mail addresses: [email protected] (D. Schor), [email protected] ^ Rizzo), [email protected] (D. Medeiros), [email protected] (J.A. (A.C. Dela Bianca), [email protected] (A.R. Silva), [email protected] (C. Nunes), [email protected] (M. Morais-Almeida), emanuel.sarinho@ gmail.com (E. Sarinho). http://dx.doi.org/10.1016/j.rmed.2017.03.017 0954-6111/© 2017 Published by Elsevier Ltd.
Asthma is a global problem that affects more than 300 million people worldwide, many of them in low-income countries [1]. The treatment goal is to achieve the best disease control and the main drug administration route is inhalation [2,3]. Pressurized metereddose inhalers (pMDIs) are widely used to deliver inhaled betaagonist bronchodilators or steroids directly to the lower airways, owing to their effectiveness, safety, portability and low cost [4,5]. Many patients make incorrect use of these devices and this is one of
D. Schor et al. / Respiratory Medicine 126 (2017) 52e58
the main causes of failure to achieve asthma control. Lack of coordination between aerosol discharge from pMDIs and patient inhalation (hand-breath coordination) is one of the most common errors committed by the patients [6e8]. Valved spacers (VCS) are pMDI accessory devices designed to improve aerosolized medication penetration into the airway. They are manufactured in different volumes and shapes and have a oneway valve, usually near the mouth opening, which allows some delay between pMDI actuation and aerosol inhalation, minimizing patient's need for hand-breath co-ordination. This delay also facilitates particle evaporation and size reduction, minimizing oropharyngeal drug deposition and local side effects, and improving medication penetration into peripheral airways [9e11]. Nevertheless, the cost of the VCS, although not high, can be prohibitive for low-income populations. Some studies have evaluated the efficacy of treatment of acute asthma using bronchodilator drugs delivered through a pMDI coupled to non-valved home-made spacers manufactured from various recycled materials, such as 500 ml plastic soft drinks bottles, cardboard tubes, plastic cups or empty plastic saline solution bottles [12e15]. However, only the first showed results comparable to those obtained with the same drugs administered by nebulizers or pMDIs coupled to valved commercial spacers [13,15]. The objective of this study was to compare asthma control achieved by the inhaled steroid beclomethasone-dipropionate administered through an HFA-driven pMDI coupled either to a 500 ml non-valved home-made spacer or to an industrially produced valved one in cases of poorly controlled asthma. 2. Material and methods This was an open parallel controlled pragmatic randomized clinical trial [16] conducted in the city of Recife, in the Brazilian State of Pernambuco. Patient inclusion and follow-up occurred between July 2010 and May 2012 and recruitment was carried out during the patient's first visit to the outpatient clinics from the Allergy and the Pulmonology Departments of the Hospital das Clinicas at the Federal University of Pernambuco - Brazil. ES, DM, ACDB and ARS, who were also the attending physicians, recruited the patients. The Institutional Ethics Committee approved the study under the number 0297.0.172.000e1 and all parents/guardians and/or patients signed an informed consent or assent form. The patient shown in Fig. 2 gave her consent for publication. Trial Register Number: RBR-5x4dc9. Patients were invited to participate if they lived within the metropolitan area of the city, were aged between 14 and 65 years, and their asthma was considered non-controlled as defined by the Global Initiative for Asthma [3]. After the initial evaluation, all participants had been prescribed inhaled Beclomethasone for daily use as maintenance treatment by the attending specialist. Hydrofluoroalkane-driven Beclomethasone is the inhaled steroid distributed free-of-charge by the Brazilian health system. Participants were reimbursed only for transport expenses and were offered a lunch. At beginning of the trial (Visit 1) all patients underwent forced expiratory volume in the first second (FEV1) measurements before and after administration of an inhaled bronchodilator using a calibrated spirometer (MicroQuark, Cosmed, Rome-Italy) in accordance with ATS/ERS guidelines [17]. The patients also completed the Asthma Control Test (ACT) questionnaire [18,19] translated into Portuguese (Brazil) and validated [20]. Only those patients who showed a 10% increase in FEV1 after bronchodilator administration and had a score 18 points on the ACT were included in the trial. Patients were excluded if they had smoked in the past decade, had other lung diseases or failed to
53
perform the maneuvers for FEV1 measurements properly. Patients were allocated in equal proportion to use the beclomethasone-HFA pMDI coupled to home-made spacer or to valved commercial spacer following a simple block randomization (blocks of four) carried out by a person not involved in the research. The same person generated the randomization sequence on the Excel 2010 program (Microsoft Corp.) and kept it in a sealed envelope. The study was not blinded as it was not possible to mask the spacers. A person not involved in the inclusion process notified field researchers of the allocations. The beclomethasone (Clenil HFA - Chiesi e Brazil) dose was chosen according to patient's asthma severity classification: 250 mcg/day for those with mild persistent asthma, 500 mcg/day for those with moderate persistent and 1000 mcg/day for patients with severe persistent asthma in accordance with Brazilian asthma guidelines recommendations for treatment at the time of the research project elaboration [21]. Fifty and 250 mg/puff canisters were dispensed according to dosage allocations. Patients on 250 mcg/day were instructed to use two puffs in the morning and three at night from the 50 mcg/puff canister; those on 500 mcg/day or 1000 mcg/day were instructed to take one or two puffs in the morning and at night, respectively, from the 250 mcg/puff canister. All patients were also provided with an Albuterol pMDI 100mcg/puff (Aerolin, GSK e Brazil) for recovery as needed (2 puffs each time, maximum six times a day). Patients were told to return to the clinic in case of exacerbations that did not respond to the recovery medication. After allocation, patients were instructed to use the pMDI coupled to the home-made spacer (HmS group) or valved spacer (VCS group) using a movie specifically produced for this purpose following steps adapted from GINA [3] and Melani et al. [22] in order to minimize bias. At the end of the session, patients were asked to repeat the learned technique. If errors were made the patient could watch the movie up to two more times. Patients only remained in the study if they did not commit critical errors in the use of pMDI coupled to the spacer. Critical errors were those that prevented medication inhalation. As the HmS has no valve, an inhalation delay of more than 3 s after pMDI actuation was considered a critical error. Other critical errors were more than one pMDI actuation in the same inhalation, inhalation through the nose, stopping inhalation immediately after pMDI actuation and not positioning the inhaler upright before actuation [22]. Thirty days after treatment began (Visit 2 - V2), patients underwent a second evaluation with FEV1 measurements and completed the ACT questionnaire. Those who made mistakes in the use of pMDI/spacer underwent further training as described above. The same procedures were carried out 60 days after the first visit (Visit 3 - V3). (Fig. 1). Patients were given a telephone call (when available) between visits, reminding them of the time of the next appointment. The ACT [18e20] is a 5-item survey for asthma control assessment with questions about asthma disruption of work, home or school activities, shortness of breath, sleep disturbance, use of recovery medication and the patient's own classification of disease control in the last four weeks. The ratings vary on a Likert-like scale ranging from 1(worse) to 5 (best) e maximum 25 points. Patients with a score 18 points are considered to have non-controlled asthma [19]. The ACT was read to all patients by DS on all occasions to circumvent the problem of illiteracy. No clarifications were provided regarding the ACT questions after the enrolment visit. To make the home-made spacers, identical 500 ml mineral water bottles (Indai a, Recife, Brazil) were purchased at a local supermarket. A heated iron cast was used to produce a hole in the bottom of the transparent polyethylene plastic bottles for coupling
54
D. Schor et al. / Respiratory Medicine 126 (2017) 52e58
Fig. 1. Home-made spacer in use.
the pMDI as tightly as possible. The patient positioned the open bottle mouth between the lips and pressed the pMDI to inhale the medication after a full exhalation (Fig. 1). The commercial valved holding chamber used was a spindle shaped, one valve, 700 ml ~o Paulo, Brazil), made of semi-transparent polyFlumax® (Sa carbonate plastic with no audible feedback mechanism and no antistatic properties [23]. The inhalation technique instructions were identical to those for the home-made spacers. All HmS and VCS were previously dipped into detergent diluted in water and allowed to dry in ambient air in order to reduce electrostatic charge [11,24]. This procedure was not repeated. Patients were instructed not to wash the devices and to keep them in a dry place inside a transparent plastic bag. 2.1. Statistical analysis The study was designed considering a bilateral hypothesis for the comparison of groups regarding ACT score. The sample size calculation assumed a standard deviation of 4.4 points on the ACT in poorly controlled patients [19] and a minimum clinically important difference for patients with persistent asthma of 3 points in this test [25]. The number of subjects required to detect this difference between groups in the final score was 32 patients per group, considering a probability of a and b errors of 0.05 and 0.80 respectively. For comparison of data between baseline and at the two subsequent visits in both groups the general linear model for longitudinal repeated measurements was adopted considering two factors: group and time. The Sidak test was performed to correct the significant differences among multiple comparisons between the 3 visits. All analyses were conducted by a professional statistician using SPSS for Windows version 18.0 and a P-value of
