Review For reprint orders, please contact [email protected]
Dry-powder inhalers in acute asthma An updated literature search was performed to evaluate the efficacy of rapid-acting b2-agonists delivered via dry powder inhalers in the treatment of moderate-to-severe acute asthma. Databases were searched from 1985 up to December 2012. A total of 23 randomized, double-blind or open clinical studies in acute asthma comparing the efficacy of a dry powder inhaler with a pressurized metered-dose inhaler or a nebulizer, and performed under controlled hospital conditions, were identified. This review found that administration of b2-agonist bronchodilators via dry powder inhalers (formoterol, salbutamol, terbutaline and budesonide/formoterol) was effective during severe asthma worsening and acute asthma attacks, and was as effective as established therapies with a pressurized metered-dose inhaler with or without a spacer, or nebulization. These results ensure that patients can rely upon dry powder inhalers equally well as other inhaler devices during episodes of asthma worsening. Acute severe asthma is the clinical condition where rapidly worsening symptoms (progressive increases in breathlessness, coughs, wheezes, chest tightness) are accompanied by a significant drop in expiratory airway flows (measured as a decrease in forced expiratory volume in one second [FEV1], or in peak expiratory flow, [PEF]) [101]. Mostly the actual decrease in airway function remains unknown but the actual FEV1 or PEF can be compared with the personal best values [101]. In general patients with acute severe asthma are hospitalized and often treated in the emergency department. For maintenance treatment of asthma patients are usually prescribed drugs to be delivered via pressurized metered dose inhalers (pMDIs) with or without a spacer, or dry-powder inhalers (DPIs). Patients experiencing more severe, but temporary asthma symptoms or a mild-to-moderate acute attack of asthma should know that they can rely upon the inhaler they have been prescribed in a more acute situation. A review including information up to 2008 on the use of DPIs in acute exacerbations of asthma and chronic obstructive pulmonary disease was previously published [1]. There are obvious differences between the three most commonly used administration systems for inhaled asthma drugs. The advantages and disadvantages of the devices have been thoroughly reviewed [2–6,101]. The most commonly used device is still the pMDI despite the fact that it is difficult to use correctly and its low lung deposition characteristics. Several handling mistakes can be made when using a pMDI but the most serious one is to achieve a good coordination between inhaler actuation
and inhalation [7]. This dys-coordination problem can be partly overcome by the use of a large volume spacer attached to the pMDI or by using a breath-actuated pMDI [2]. The DPIs are all inspiratory flow driven and easier to use than a pMDI. Capsule-based DPIs must be loaded before use. The multidose reservoirtype DPIs use different mechanisms to dissolve the powder to small respirable particles. Due to differences in internal inhaler resistance an inhaler-specific lowest inspiratory effort (and inspiratory flow) is required for effective degradation of the powder. Some DPIs are moisture sensitive, others not [8]. Jet nebulizers use oxygen or compressed air to make solutions into small respirable droplets. Ultrasound nebulizers can also be used for solutions but not for suspensions. The patient-inhaler interfaces – mouth pieces or facemasks – can add challenges that diminish the efficacy of nebulizer treatment. Acute asthma is characterized by severe expiratory airway obstruction. Inspiration, however, is not affected to the same degree [9]. The aim of acute treatment is to relieve the symptoms and respiratory distress as quickly as possible, and to reverse the airway obstruction. Administration of rapid-acting inhaled b2-agonists is the method of choice for reversal of airway obstruction and the doses should be titrated according to the response [101]. In patients with acute asthma the titration is done by the treating physician. A modest asthma worsening can be the first step into a real exacerbation. Treatment guidelines advocate the use of a rapid-acting inhaled b2-agonist administered via a pMDI or
10.4155/TDE.13.132 © 2014 Future Science Ltd
Ther. Deliv. (2014) 5(1), 69–81
Olof Selroos Skogsvägen 5, SE-26654 Vejbystrand, Sweden Tel.: +46 702 256757 E-mail: [email protected]
ISSN 2041-5990
69
Review | Selroos a DPI [101]. Also, the combination of a rapidacting b2-agonist with an inhaled corticosteroid has been documented for as-needed use [101], and thereby ensuring the important increase in anti-inflammatory therapy for preventing the development of a full exacerbation [10]. When hospitalized, patients with acute asthma are usually treated with nebulizers for administration of rapid-acting b2-agonist. Sometimes in the hospitals, but more often outside hospitals, patients are treated with pMDIs with or without a spacer. Based on in vitro inhalation profiles of DPIs, investigators have expressed concern that patients with more severe airway obstruction may not have the inspiratory effort to achieve the inhalation flow needed to create an efficient drug aerosol from the DPI and thereby the expected clinical effect [11]. This opinion is often expressed despite evidence to the contrary [1,4,12,13]. It is therefore important to carefully analyze whether patients with asthma worsening benefit from the inhaler device they carry with them, be it a pMDI or a DPI, as that device will be what they can use in the first place of asthma worsening and/or exacerbations. Different types of DPIs have been introduced to the market and their characteristics, pros and cons have been reviewed [14]. Aim of the review The aim of this review was to evaluate and report randomized, controlled studies performed with DPIs in patients with acute severe asthma, treated in hospitals or emergency departments, and to compare the results with established therapies (pMDI with or without a spacer or a nebulizer) in the treatment of acute asthma, irrespective of the b2-agonist used. Methods The databases Medline, Embase, Biosis, PubMed and Current Contents were searched from 1985 up to December 2012. Lists of references in accepted publications were searched to secure completeness and duplicate studies were left out. The search was limited to clinical studies in patients with acute asthma. The articles were retrieved using the following search strings, for example, the term ‘acute’ adjacent to the term ‘asthma’ within a specific number of words (two in the case of ‘acute asthma’): (acute adj5 airway$) OR (acute adj5 exacerbation$) OR (acute dyspnea$) OR dyspnoea$ OR (acute adj2 asthma$). 70
Ther. Deliv. (2014) 5(1)
A combination with the terms for acute asthma: [(acute adj5 airway$) OR (acute adj5 exacerbation$) OR (acute dyspnea$) OR (acute adj2 asthma$) AND (Turbuhaler$ OR Turbohaler$, Diskus$, Diskhaler$, Easyhaler$, Aerolizer$, Novolizer$, Spiromax$, Airmax$, Twisthaler$, Pulvinal$ or dry powder inhaler$ or dpi$)] was used. Studies with b2-agonists that have a rapid onset of bronchodilator activity (such as salbutamol, terbutaline, formoterol) were selected [15–17]. Typically these b2-agonists have similar dose– response curves and bronchodilating capacity in patients with stable asthma [16–19]. In addition to being rapid-acting, inhaled formoterol is also classified as a long-acting b2-agonist. However, it should be noted that not all presentations of formoterol DPIs are approved for treatment of acute asthma and as-needed use. The package inserts vary from one country to another. Studies with salmeterol were excluded as this drug does not have a rapid onset of bronchodilation. Studies evaluating the effect of b2-agonists in allergen-, histamine-, methacholine-, adenosine- or exercise-induced bronchoconstriction were not considered as the induced bronchoconstriction for safety reasons remains less severe compared with acute asthma and the typical spontaneous recovery will make interpretations difficult. Due to a wide heterogeneity between study protocols and endpoints neither comparisons between studies nor meta-analyses were performed. Results & discussion A total of 163 publications were found in the preparation of this review on the use of DPIs in patients with acute asthma. The majority of these studies (n = 119) had been performed with Turbuhaler, 34 involved Diskus/Diskhaler and ten involved other DPIs. Studies in which patients were treated under controlled conditions in an emergency department or at least hospitalized, were selected. The majority of the nonselected studies were uncontrolled and had been performed in out-patients with stable asthma. The selected series resulted in 30 publications involving Turbuhaler, three involving Diskus/ Diskhaler, three Rotahaler, three Aerolizer, one Pulvinal and one Easyhaler. In the first case, studies where the same rapid-acting b2-agonist had been administered both via a DPI and another device (pMDI or nebulizer, or both) were included in this review. In other studies doses of two b2-agonists believed to be ‘equi-effective’ future science group
Dry-powder inhalers in acute asthma had been given via the same DPI. The rest were open studies without comparator treatment. In the end, 23 clinical studies in acute asthma met the inclusion criteria. In the acute asthma setting, 14 studies were double-blind, randomized studies (nine in adults [19–28] and five in children [29–33]), nine were open-label studies (five in adults [34–38] and four in children [39–42]). Seven studies were performed with a terbutaline DPI [21,22,29,30,34,39,40], five with a salbutamol DPI [20,32,35,41,42], five with a formoterol DPI [24,26,28,36,37] and two with a budesonide/formoterol DPI [25,38]. Three studies compared two rapid-acting bronchodilators delivered via the same DPI, that is, via Turbuhaler®: formoterol with salbutamol [31], formoterol with terbutaline [23], or budesonide/formoterol with formoterol [27], and one study compared formoterol Aerolizer® with terbutaline Turbuhaler [33]. The Turbuhaler device had been used in 16 out of the 23 studies, Aerolizer in three, Rotahaler in two and Pulvinal inhaler and Easyhaler® in one study each. All these DPIs are driven by the patient’s inspiratory effort. No studies were identified with device driven DPIs. There were neither inclusion criteria fulfilling studies in acute asthma with the following DPIs: Clickhaler, Diskhaler (Accuhaler ®), Diskus®, Flexhaler ®, Genuair ®, HandiHaler®, Neohaler™, Novolizer®, Pressair™, Spinhaler, Twisthaler™. The exact severity of acute asthma of the patients included in the studies is difficult to know based on published data. The change in airway function from a stable state to the attack state has never been reported and is generally unknown. However, all patients made unscheduled visits to hospitals because of worsening symptoms, poor airway function and were hospitalized. The mean FEV1 values of the included adult patients varied from 33 to 44% of predicted normal [24,25]. The exception is an Australian study, where patients were included based on symptoms alone but should have a FEV1 >30% of the predicted normal [27]. The mean FEV1 in this study was 59% of the predicted normal with a range from 30 to 107%. All in all, it appears that the included patients can be classified having a moderate-to-severe attack of acute asthma. In children the FEV1 values at inclusion were generally somewhat higher. A summary of the studies is presented in Tables 1 & 2 . The results of the cited studies indicate that DPIs are as effective as other delivery devices for the treatment of acute asthma. The results also suggest that administration of a rapid-acting future science group
| Review
bronchodilator via a DPI is effective irrespective of the severity of the asthma exacerbation. However, the results need to be interpreted with caution as patients entering a hospital with very severe airway obstruction and a FEV1 30% of the predicted normal a rapid-acting bronchodilator is likely to be effective irrespective of whether it is administered via a nebulizer, pMDI or DPI. This means that during worsening of asthma the delivery of a rapid-acting bronchodilator via the delivery device the patient is carrying, be it a pMDI or DPI, is most likely to be effective. However, loading of a DPI is different depending on its construction [14]. Therefore, in an acute situation capsulebased DPIs may be more difficult to handle than preloaded reservoir-based inhalers. Conclusions are not possible to draw across studies as they involve different patient groups, the doses used have not always been equal, and inhalation patterns may have been used that are not optimal for a specific device. In many reports data is also limited. Therefore, a real meta-analysis could not be performed. There was no difference in onset of action of the rapid-acting b2 -agonists, salbutamol, terbutaline or formoterol, used in the studies. This is an expected finding as the overall aim in the acute situation is to administer a dose of the b2-agonist high enough to reverse the airflow obstruction as quickly as possible. One important difference has been documented. Formoterol used as-needed for the treatment of acute asthma significantly prolongs the time to the next severe exacerbation compared with a short-acting b2-agonist, terbutaline, used asneeded [19,43]. It is also noticed that in some studies very high doses of b2-agonists have been given initially (as should be done in clinical practice), and therefore real differences in potency, if they exist, may have been missed. Such a study is, for example, the study by Nana et al. where 2000 µg salbutamol via Turbuhaler was compared with 4000 µg salbutamol pMDI plus spacer during 135 min [21]. In most studies the initial doses have been within the approved dose range for www.future-science.com
71
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15
Phanareth and Laursen (1999) Malolepszy et al. (2001)
Mean age, age range
Patients at an ED with acute severe airway obstruction Adults with acute airway obstruction (high-dose safety study)
Adults with acute asthma
45 years (range 20–64)
Not specified
38 years (range 16–49)
Adults with non-life 31 years threatening acute (range asthma 18–93)
Population
Every 15 min for 90 min
Evaluation point(s) after dosing
Terb TBH 1 mg versus Terb pMDI + Aerochamber 1 mg (Mean PIF through DPI: 48.4 ± 20.3 l/min; minimum: 17 l/min)
Drugs, doses and devices
Main findings
Statistically significant difference between devices in terms of change in FEV1 and PEF (p 18 years asthma (mean 56 and 53 years)
115 Adolescents and adults with acute asthma (FEV1 ≥30 and ≤55% (PN)
Bateman et al. (2006)
Adults with acute 18–69 years Mean 59% of asthma PN (range (FEV1 >30% of 30–107%) PN)
Mean 43% of PN (28–60%)
Mean 44% of PN (17–60%)
Mean age, Baseline FEV1 Evaluation point(s) age range (range) after dosing
Adults with acute 44 years asthma (range 18–67)
Population
103 Adults with acute 45 years asthma (FEV1 (range 30–60% of PN) 13–80)
88
N
Rubinfeld et al. 78 (2006 )
Balanag et al. (2006)
Boonsawat et al. (2003)
Adults
Citation (year)
Table 1. Summary of double-blind, randomized clinical studies with rapid-acting b2-agonists delivered via dry powder inhalers in acute exacerbations of asthma (cont.).
[28]
[27]
[26]
[25]
[24]
Ref.
Dry-powder inhalers in acute asthma
| Review
73
74
Ther. Deliv. (2014) 5(1)
Mean FEV1 (SD) 63 (14)% PN in Form group; 61 (16)% in Terb group. Children requiring only 1 dose 75% and patients requiring more doses 52% PN
FEV1 Mean PN (SD) from 50.7 (10.4) to 56.2 (9.7) in the 4 groups
Drugs, doses and devices
Single doses of Form TBH 12 µg or Salb TBH 200 µg
Terb TBH versus Terb pMDI and spacer 0.5 mg/10 kg bodyweight (max 2 mg) at time 0 and 30 min
Salb 400 µg x 3 via Pulvinal DPI or 0.15 mg/kg x 3 (maximum 5 mg) via nebulizer or 400 µg x 3 pMDI and/or Aerochamber or 400 µg x 3 pMDI and/or homemade spacer 15 min after Form Aerolizer (Fluir, administration Schering-Plough) up to of each 12 µg x 3 or Terb TBH up to bronchodilator 0.5 mg x 3 dose.
0, 20, 40 and 60 min
3, 30 and 60 min
15, 30, 45, 60 min
15, 30, 55 min Terb TBH 1 + 1 + 0.5 mg versus Terb nebulizer 2 + 2 + 1 mg at times 0, 20 and 40 min
Evaluation point(s) after dosing
FEV1 increased by 19.5% to 80 (14)% PN (Form) and 15.3% to 76 (14)% PN (Terb) 37 patients (47%) required only one bronchodilator dose
‘Remarkable’ improvements in clinical asthma score and in FEV1 PN without statistically significant differences between the four treatments
FEV1 3,30,60 min: Form: 78.8, 83.1, 82.0% PN Salb: 79.5, 83.4, 82.0% PN No difference between treatments (p = 0.65)
Comparable improvement in lung function as measured via PEF at all time points Mean increase in PEF at 55 min: Turbuhaler: 57 l/min Nebulizer: 29 l/min Comparable improvement in all lung function measures to 60 min Mean FEV1 change from baseline: Turbuhaler: 49% pMDI + Nebuhaler: 50% No correlation between PIF through Turbuhaler and final FEV1
Main findings
DPI: Dry-powder inhaler; ED: Emergency department; FEV1: Forced expiratory volume in one second; Form: Formoterol; N: Number of participants; PEF: Peak expiratory flow; PIF: Peak inspiratory flow; pMDI: Pressurized metered-dose inhaler; PN: Predicted normal; Salb: Salbutamol; SD: Standard deviation; Terb: Terbutaline.
Bussamra et al. 79 (2009) 9.9 ± 2.5 years
Children aged ≥6 and 11.0 ± 30% over basal value. FEV1>70% predicted
40
Mean 45% of PN (range 25–60%)
Mean PEF 66% of PN
Baseline FEV1 (range)
8.9 ± FEV1 % PN 3.4 years 75.2 ± 17.1 (Form) Range 5–15 78.5 ± 17.4 (Salb)
6–16 years
7–12 years
Mean age, age range
Avila-Castañón 36 et al. (2004)
112 Children with acute asthma (FEV1 25–60% of PN)
Drblik et al. (2003)
Children with acute asthma in need of treatment at the emergency room
Population
12
N
Springer et al. (1996)
Children
Citation (year)
Table 1. Summary of double-blind, randomized clinical studies with rapid-acting b2-agonists delivered via dry powder inhalers in acute exacerbations of asthma (cont.).
[33]
[32]
[31]
[30]
[29]
Ref.
Review | Selroos
future science group
future science group
www.future-science.com
Adolescents and adults with acute asthma (FEV1>30% of PN)
54
34
32
Cordova and Accinelli (2004)
Lee-Wong et al. (2008)
Chew et al. (2012)
(SD) Turbuhaler: 50 (20) years pMDI + spacer 51 (19) years 18–65 years Mean ages (SD) 33.7 (5.6) –42.8 (16) >14 years
18 years and older
Salb 3600 µg via Rotahaler, or 45 mg via nebulizer, or 3600 µg pMDI and Aerochamber
Mean PEF (SD) 196 (88.9) l/min (bud/form) and 238 (100.6) l/min (salb)
15 min
Bud/form Turbuhaler 320/9 µg versus nebulized salbutamol (dose not mentioned)
Increase in PEF to 51.9 and 54.5% predicted at 30 and 60 min (salbutamol) and to 49.3 and 55.5% predicted respectively (formoterol). No statistically sign difference between treatments (p = 0.64 and p = 0.57 at 30 and 60 min) Improvements in PEF 78.7 (44.9) l/min (bud/form); 89.4 (45.5) l/min (salb) Difference p = 0.507
Comparable improvement in all lung function measures up to 60 min Comparable (p = 0.323) response (FEV1>70% predicted) after 60 min: Form TBH: 66.7% of patients Salb pMDI: 77.8% of patients
At 360 min FEV1 1.6 ± 0.5 l in all three groups without significant differences between the groups
Increases in FEV1 Turbuhaler: + 0.40 l (SD 0.40) pMDI + spacer: + 0.21 (0.25) The difference in increase was statistically significant (p = 0.0004, ANOVA)
Main findings
ANOVA: Analysis of variance; Bud: Budesonide; DPI: Dry powder inhaler; ED: Emergency department; FEV1: Forced expiratory volume in one second; Form: Formoterol; GINA: Global Initiative for Asthma; N: Number of participants; PEF: Peak expiratory flow, pMDI: Pressurized metered-dose inhaler; PN: Predicted normal; Salb: Salbutamol; SD: Standard deviation; Terb: Terbutaline.
Adults with mild to moderate asthma attacks as defined by GINA
30, 60, 90, 120, 180, 240, 300, 360 (primary) min
10 and 25 min Terb 2.5 mg at times 0 and 15 min via TBH or pMDI with spacer
Evaluation Drugs, doses and point(s) devices after dosing
10, 20, 30, 40, Form TBH 4.5 µg x 2 in mild 50, 60 cases, up to ten times in (primary) min severe cases, then 9 µg at times 30 and 60 min versus salbutamol pMDI 100 µg x 2 in mild cases, up to ten times in severe cases, then 200 µg/10 min up to 60 min Mean PEF 43.7% (salb) 30, 60, 90, Formoterol Aerolizer up to and 49.3% PN (form) 120 min two doses of 12 µg, salbutamol up to two nebulisations of 2.5 mg at times 0 and 30 min
FEV1 >30% of PN
FEV1 0.71 (0.23), 0.64 (0.14),0.58 (0.17)
FEV1 Turbuhaler 0.81 (SD 0.64) L pMDI + spacer 0.90 (0.90) L
Mean Baseline FEV1 age, age range
Adults with acute 18–65 asthma; PEF 40–60% years of PN, pulse rate >80 beats/min
Adults with acute asthma (FEV150% of PN)
5, 15, 25, 30 min
0, 15, 30 min
Mean PEF 30 min 74.3% (Rotahaler) and 77.5% (pMDI) ≤7 on a 20, 40, 60 min modified Wood’s asthma score
>50% of PN
Mean FEV1 1.20 l (pMDI) and 1.61 l (TBH)
Salb Easyhaler 600 µg, salb pMDI + spacer 600 µg or salb 0.15 mg/kg via nebulizer
Salb single doses of 400 µg via Rotacaps or pMDI + spacer
Terb TBH 0.5 mg versus terb nebulized solution 1%
Terb 0.5 mg delivered via TBH or pMDI and spacer
Mean Baseline FEV1 Evaluation Drugs, doses and age, point(s) after devices age range dosing
Children with asthma and 4–14 years acute wheeze
Population
No differences in % successfully treated patients (clinical score reduction ≥50% from baseline or clinical score ≤3) between the three treatments. Successfully treated patients 71.8, 72.1, and 79.2% with Easyhaler, pMDI and spacer and nebulizer respectively
Increase in FEV1 at 15 and 30 min with TBH to 1.82 and 1.83 l and with pMDI and spacer to 1.53 and 1.56 l The difference in improvements was not statistically significant Comparable improvement in all lung function measures up to 30 min Patients with FEV1
Dry-powder inhalers in acute asthma An updated literature search was performed to evaluate the efficacy of rapid-acting b2-agonists delivered via dry powder inhalers in the treatment of moderate-to-severe acute asthma. Databases were searched from 1985 up to December 2012. A total of 23 randomized, double-blind or open clinical studies in acute asthma comparing the efficacy of a dry powder inhaler with a pressurized metered-dose inhaler or a nebulizer, and performed under controlled hospital conditions, were identified. This review found that administration of b2-agonist bronchodilators via dry powder inhalers (formoterol, salbutamol, terbutaline and budesonide/formoterol) was effective during severe asthma worsening and acute asthma attacks, and was as effective as established therapies with a pressurized metered-dose inhaler with or without a spacer, or nebulization. These results ensure that patients can rely upon dry powder inhalers equally well as other inhaler devices during episodes of asthma worsening. Acute severe asthma is the clinical condition where rapidly worsening symptoms (progressive increases in breathlessness, coughs, wheezes, chest tightness) are accompanied by a significant drop in expiratory airway flows (measured as a decrease in forced expiratory volume in one second [FEV1], or in peak expiratory flow, [PEF]) [101]. Mostly the actual decrease in airway function remains unknown but the actual FEV1 or PEF can be compared with the personal best values [101]. In general patients with acute severe asthma are hospitalized and often treated in the emergency department. For maintenance treatment of asthma patients are usually prescribed drugs to be delivered via pressurized metered dose inhalers (pMDIs) with or without a spacer, or dry-powder inhalers (DPIs). Patients experiencing more severe, but temporary asthma symptoms or a mild-to-moderate acute attack of asthma should know that they can rely upon the inhaler they have been prescribed in a more acute situation. A review including information up to 2008 on the use of DPIs in acute exacerbations of asthma and chronic obstructive pulmonary disease was previously published [1]. There are obvious differences between the three most commonly used administration systems for inhaled asthma drugs. The advantages and disadvantages of the devices have been thoroughly reviewed [2–6,101]. The most commonly used device is still the pMDI despite the fact that it is difficult to use correctly and its low lung deposition characteristics. Several handling mistakes can be made when using a pMDI but the most serious one is to achieve a good coordination between inhaler actuation
and inhalation [7]. This dys-coordination problem can be partly overcome by the use of a large volume spacer attached to the pMDI or by using a breath-actuated pMDI [2]. The DPIs are all inspiratory flow driven and easier to use than a pMDI. Capsule-based DPIs must be loaded before use. The multidose reservoirtype DPIs use different mechanisms to dissolve the powder to small respirable particles. Due to differences in internal inhaler resistance an inhaler-specific lowest inspiratory effort (and inspiratory flow) is required for effective degradation of the powder. Some DPIs are moisture sensitive, others not [8]. Jet nebulizers use oxygen or compressed air to make solutions into small respirable droplets. Ultrasound nebulizers can also be used for solutions but not for suspensions. The patient-inhaler interfaces – mouth pieces or facemasks – can add challenges that diminish the efficacy of nebulizer treatment. Acute asthma is characterized by severe expiratory airway obstruction. Inspiration, however, is not affected to the same degree [9]. The aim of acute treatment is to relieve the symptoms and respiratory distress as quickly as possible, and to reverse the airway obstruction. Administration of rapid-acting inhaled b2-agonists is the method of choice for reversal of airway obstruction and the doses should be titrated according to the response [101]. In patients with acute asthma the titration is done by the treating physician. A modest asthma worsening can be the first step into a real exacerbation. Treatment guidelines advocate the use of a rapid-acting inhaled b2-agonist administered via a pMDI or
10.4155/TDE.13.132 © 2014 Future Science Ltd
Ther. Deliv. (2014) 5(1), 69–81
Olof Selroos Skogsvägen 5, SE-26654 Vejbystrand, Sweden Tel.: +46 702 256757 E-mail: [email protected]
ISSN 2041-5990
69
Review | Selroos a DPI [101]. Also, the combination of a rapidacting b2-agonist with an inhaled corticosteroid has been documented for as-needed use [101], and thereby ensuring the important increase in anti-inflammatory therapy for preventing the development of a full exacerbation [10]. When hospitalized, patients with acute asthma are usually treated with nebulizers for administration of rapid-acting b2-agonist. Sometimes in the hospitals, but more often outside hospitals, patients are treated with pMDIs with or without a spacer. Based on in vitro inhalation profiles of DPIs, investigators have expressed concern that patients with more severe airway obstruction may not have the inspiratory effort to achieve the inhalation flow needed to create an efficient drug aerosol from the DPI and thereby the expected clinical effect [11]. This opinion is often expressed despite evidence to the contrary [1,4,12,13]. It is therefore important to carefully analyze whether patients with asthma worsening benefit from the inhaler device they carry with them, be it a pMDI or a DPI, as that device will be what they can use in the first place of asthma worsening and/or exacerbations. Different types of DPIs have been introduced to the market and their characteristics, pros and cons have been reviewed [14]. Aim of the review The aim of this review was to evaluate and report randomized, controlled studies performed with DPIs in patients with acute severe asthma, treated in hospitals or emergency departments, and to compare the results with established therapies (pMDI with or without a spacer or a nebulizer) in the treatment of acute asthma, irrespective of the b2-agonist used. Methods The databases Medline, Embase, Biosis, PubMed and Current Contents were searched from 1985 up to December 2012. Lists of references in accepted publications were searched to secure completeness and duplicate studies were left out. The search was limited to clinical studies in patients with acute asthma. The articles were retrieved using the following search strings, for example, the term ‘acute’ adjacent to the term ‘asthma’ within a specific number of words (two in the case of ‘acute asthma’): (acute adj5 airway$) OR (acute adj5 exacerbation$) OR (acute dyspnea$) OR dyspnoea$ OR (acute adj2 asthma$). 70
Ther. Deliv. (2014) 5(1)
A combination with the terms for acute asthma: [(acute adj5 airway$) OR (acute adj5 exacerbation$) OR (acute dyspnea$) OR (acute adj2 asthma$) AND (Turbuhaler$ OR Turbohaler$, Diskus$, Diskhaler$, Easyhaler$, Aerolizer$, Novolizer$, Spiromax$, Airmax$, Twisthaler$, Pulvinal$ or dry powder inhaler$ or dpi$)] was used. Studies with b2-agonists that have a rapid onset of bronchodilator activity (such as salbutamol, terbutaline, formoterol) were selected [15–17]. Typically these b2-agonists have similar dose– response curves and bronchodilating capacity in patients with stable asthma [16–19]. In addition to being rapid-acting, inhaled formoterol is also classified as a long-acting b2-agonist. However, it should be noted that not all presentations of formoterol DPIs are approved for treatment of acute asthma and as-needed use. The package inserts vary from one country to another. Studies with salmeterol were excluded as this drug does not have a rapid onset of bronchodilation. Studies evaluating the effect of b2-agonists in allergen-, histamine-, methacholine-, adenosine- or exercise-induced bronchoconstriction were not considered as the induced bronchoconstriction for safety reasons remains less severe compared with acute asthma and the typical spontaneous recovery will make interpretations difficult. Due to a wide heterogeneity between study protocols and endpoints neither comparisons between studies nor meta-analyses were performed. Results & discussion A total of 163 publications were found in the preparation of this review on the use of DPIs in patients with acute asthma. The majority of these studies (n = 119) had been performed with Turbuhaler, 34 involved Diskus/Diskhaler and ten involved other DPIs. Studies in which patients were treated under controlled conditions in an emergency department or at least hospitalized, were selected. The majority of the nonselected studies were uncontrolled and had been performed in out-patients with stable asthma. The selected series resulted in 30 publications involving Turbuhaler, three involving Diskus/ Diskhaler, three Rotahaler, three Aerolizer, one Pulvinal and one Easyhaler. In the first case, studies where the same rapid-acting b2-agonist had been administered both via a DPI and another device (pMDI or nebulizer, or both) were included in this review. In other studies doses of two b2-agonists believed to be ‘equi-effective’ future science group
Dry-powder inhalers in acute asthma had been given via the same DPI. The rest were open studies without comparator treatment. In the end, 23 clinical studies in acute asthma met the inclusion criteria. In the acute asthma setting, 14 studies were double-blind, randomized studies (nine in adults [19–28] and five in children [29–33]), nine were open-label studies (five in adults [34–38] and four in children [39–42]). Seven studies were performed with a terbutaline DPI [21,22,29,30,34,39,40], five with a salbutamol DPI [20,32,35,41,42], five with a formoterol DPI [24,26,28,36,37] and two with a budesonide/formoterol DPI [25,38]. Three studies compared two rapid-acting bronchodilators delivered via the same DPI, that is, via Turbuhaler®: formoterol with salbutamol [31], formoterol with terbutaline [23], or budesonide/formoterol with formoterol [27], and one study compared formoterol Aerolizer® with terbutaline Turbuhaler [33]. The Turbuhaler device had been used in 16 out of the 23 studies, Aerolizer in three, Rotahaler in two and Pulvinal inhaler and Easyhaler® in one study each. All these DPIs are driven by the patient’s inspiratory effort. No studies were identified with device driven DPIs. There were neither inclusion criteria fulfilling studies in acute asthma with the following DPIs: Clickhaler, Diskhaler (Accuhaler ®), Diskus®, Flexhaler ®, Genuair ®, HandiHaler®, Neohaler™, Novolizer®, Pressair™, Spinhaler, Twisthaler™. The exact severity of acute asthma of the patients included in the studies is difficult to know based on published data. The change in airway function from a stable state to the attack state has never been reported and is generally unknown. However, all patients made unscheduled visits to hospitals because of worsening symptoms, poor airway function and were hospitalized. The mean FEV1 values of the included adult patients varied from 33 to 44% of predicted normal [24,25]. The exception is an Australian study, where patients were included based on symptoms alone but should have a FEV1 >30% of the predicted normal [27]. The mean FEV1 in this study was 59% of the predicted normal with a range from 30 to 107%. All in all, it appears that the included patients can be classified having a moderate-to-severe attack of acute asthma. In children the FEV1 values at inclusion were generally somewhat higher. A summary of the studies is presented in Tables 1 & 2 . The results of the cited studies indicate that DPIs are as effective as other delivery devices for the treatment of acute asthma. The results also suggest that administration of a rapid-acting future science group
| Review
bronchodilator via a DPI is effective irrespective of the severity of the asthma exacerbation. However, the results need to be interpreted with caution as patients entering a hospital with very severe airway obstruction and a FEV1 30% of the predicted normal a rapid-acting bronchodilator is likely to be effective irrespective of whether it is administered via a nebulizer, pMDI or DPI. This means that during worsening of asthma the delivery of a rapid-acting bronchodilator via the delivery device the patient is carrying, be it a pMDI or DPI, is most likely to be effective. However, loading of a DPI is different depending on its construction [14]. Therefore, in an acute situation capsulebased DPIs may be more difficult to handle than preloaded reservoir-based inhalers. Conclusions are not possible to draw across studies as they involve different patient groups, the doses used have not always been equal, and inhalation patterns may have been used that are not optimal for a specific device. In many reports data is also limited. Therefore, a real meta-analysis could not be performed. There was no difference in onset of action of the rapid-acting b2 -agonists, salbutamol, terbutaline or formoterol, used in the studies. This is an expected finding as the overall aim in the acute situation is to administer a dose of the b2-agonist high enough to reverse the airflow obstruction as quickly as possible. One important difference has been documented. Formoterol used as-needed for the treatment of acute asthma significantly prolongs the time to the next severe exacerbation compared with a short-acting b2-agonist, terbutaline, used asneeded [19,43]. It is also noticed that in some studies very high doses of b2-agonists have been given initially (as should be done in clinical practice), and therefore real differences in potency, if they exist, may have been missed. Such a study is, for example, the study by Nana et al. where 2000 µg salbutamol via Turbuhaler was compared with 4000 µg salbutamol pMDI plus spacer during 135 min [21]. In most studies the initial doses have been within the approved dose range for www.future-science.com
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15
Phanareth and Laursen (1999) Malolepszy et al. (2001)
Mean age, age range
Patients at an ED with acute severe airway obstruction Adults with acute airway obstruction (high-dose safety study)
Adults with acute asthma
45 years (range 20–64)
Not specified
38 years (range 16–49)
Adults with non-life 31 years threatening acute (range asthma 18–93)
Population
Every 15 min for 90 min
Evaluation point(s) after dosing
Terb TBH 1 mg versus Terb pMDI + Aerochamber 1 mg (Mean PIF through DPI: 48.4 ± 20.3 l/min; minimum: 17 l/min)
Drugs, doses and devices
Main findings
Statistically significant difference between devices in terms of change in FEV1 and PEF (p 18 years asthma (mean 56 and 53 years)
115 Adolescents and adults with acute asthma (FEV1 ≥30 and ≤55% (PN)
Bateman et al. (2006)
Adults with acute 18–69 years Mean 59% of asthma PN (range (FEV1 >30% of 30–107%) PN)
Mean 43% of PN (28–60%)
Mean 44% of PN (17–60%)
Mean age, Baseline FEV1 Evaluation point(s) age range (range) after dosing
Adults with acute 44 years asthma (range 18–67)
Population
103 Adults with acute 45 years asthma (FEV1 (range 30–60% of PN) 13–80)
88
N
Rubinfeld et al. 78 (2006 )
Balanag et al. (2006)
Boonsawat et al. (2003)
Adults
Citation (year)
Table 1. Summary of double-blind, randomized clinical studies with rapid-acting b2-agonists delivered via dry powder inhalers in acute exacerbations of asthma (cont.).
[28]
[27]
[26]
[25]
[24]
Ref.
Dry-powder inhalers in acute asthma
| Review
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Mean FEV1 (SD) 63 (14)% PN in Form group; 61 (16)% in Terb group. Children requiring only 1 dose 75% and patients requiring more doses 52% PN
FEV1 Mean PN (SD) from 50.7 (10.4) to 56.2 (9.7) in the 4 groups
Drugs, doses and devices
Single doses of Form TBH 12 µg or Salb TBH 200 µg
Terb TBH versus Terb pMDI and spacer 0.5 mg/10 kg bodyweight (max 2 mg) at time 0 and 30 min
Salb 400 µg x 3 via Pulvinal DPI or 0.15 mg/kg x 3 (maximum 5 mg) via nebulizer or 400 µg x 3 pMDI and/or Aerochamber or 400 µg x 3 pMDI and/or homemade spacer 15 min after Form Aerolizer (Fluir, administration Schering-Plough) up to of each 12 µg x 3 or Terb TBH up to bronchodilator 0.5 mg x 3 dose.
0, 20, 40 and 60 min
3, 30 and 60 min
15, 30, 45, 60 min
15, 30, 55 min Terb TBH 1 + 1 + 0.5 mg versus Terb nebulizer 2 + 2 + 1 mg at times 0, 20 and 40 min
Evaluation point(s) after dosing
FEV1 increased by 19.5% to 80 (14)% PN (Form) and 15.3% to 76 (14)% PN (Terb) 37 patients (47%) required only one bronchodilator dose
‘Remarkable’ improvements in clinical asthma score and in FEV1 PN without statistically significant differences between the four treatments
FEV1 3,30,60 min: Form: 78.8, 83.1, 82.0% PN Salb: 79.5, 83.4, 82.0% PN No difference between treatments (p = 0.65)
Comparable improvement in lung function as measured via PEF at all time points Mean increase in PEF at 55 min: Turbuhaler: 57 l/min Nebulizer: 29 l/min Comparable improvement in all lung function measures to 60 min Mean FEV1 change from baseline: Turbuhaler: 49% pMDI + Nebuhaler: 50% No correlation between PIF through Turbuhaler and final FEV1
Main findings
DPI: Dry-powder inhaler; ED: Emergency department; FEV1: Forced expiratory volume in one second; Form: Formoterol; N: Number of participants; PEF: Peak expiratory flow; PIF: Peak inspiratory flow; pMDI: Pressurized metered-dose inhaler; PN: Predicted normal; Salb: Salbutamol; SD: Standard deviation; Terb: Terbutaline.
Bussamra et al. 79 (2009) 9.9 ± 2.5 years
Children aged ≥6 and 11.0 ± 30% over basal value. FEV1>70% predicted
40
Mean 45% of PN (range 25–60%)
Mean PEF 66% of PN
Baseline FEV1 (range)
8.9 ± FEV1 % PN 3.4 years 75.2 ± 17.1 (Form) Range 5–15 78.5 ± 17.4 (Salb)
6–16 years
7–12 years
Mean age, age range
Avila-Castañón 36 et al. (2004)
112 Children with acute asthma (FEV1 25–60% of PN)
Drblik et al. (2003)
Children with acute asthma in need of treatment at the emergency room
Population
12
N
Springer et al. (1996)
Children
Citation (year)
Table 1. Summary of double-blind, randomized clinical studies with rapid-acting b2-agonists delivered via dry powder inhalers in acute exacerbations of asthma (cont.).
[33]
[32]
[31]
[30]
[29]
Ref.
Review | Selroos
future science group
future science group
www.future-science.com
Adolescents and adults with acute asthma (FEV1>30% of PN)
54
34
32
Cordova and Accinelli (2004)
Lee-Wong et al. (2008)
Chew et al. (2012)
(SD) Turbuhaler: 50 (20) years pMDI + spacer 51 (19) years 18–65 years Mean ages (SD) 33.7 (5.6) –42.8 (16) >14 years
18 years and older
Salb 3600 µg via Rotahaler, or 45 mg via nebulizer, or 3600 µg pMDI and Aerochamber
Mean PEF (SD) 196 (88.9) l/min (bud/form) and 238 (100.6) l/min (salb)
15 min
Bud/form Turbuhaler 320/9 µg versus nebulized salbutamol (dose not mentioned)
Increase in PEF to 51.9 and 54.5% predicted at 30 and 60 min (salbutamol) and to 49.3 and 55.5% predicted respectively (formoterol). No statistically sign difference between treatments (p = 0.64 and p = 0.57 at 30 and 60 min) Improvements in PEF 78.7 (44.9) l/min (bud/form); 89.4 (45.5) l/min (salb) Difference p = 0.507
Comparable improvement in all lung function measures up to 60 min Comparable (p = 0.323) response (FEV1>70% predicted) after 60 min: Form TBH: 66.7% of patients Salb pMDI: 77.8% of patients
At 360 min FEV1 1.6 ± 0.5 l in all three groups without significant differences between the groups
Increases in FEV1 Turbuhaler: + 0.40 l (SD 0.40) pMDI + spacer: + 0.21 (0.25) The difference in increase was statistically significant (p = 0.0004, ANOVA)
Main findings
ANOVA: Analysis of variance; Bud: Budesonide; DPI: Dry powder inhaler; ED: Emergency department; FEV1: Forced expiratory volume in one second; Form: Formoterol; GINA: Global Initiative for Asthma; N: Number of participants; PEF: Peak expiratory flow, pMDI: Pressurized metered-dose inhaler; PN: Predicted normal; Salb: Salbutamol; SD: Standard deviation; Terb: Terbutaline.
Adults with mild to moderate asthma attacks as defined by GINA
30, 60, 90, 120, 180, 240, 300, 360 (primary) min
10 and 25 min Terb 2.5 mg at times 0 and 15 min via TBH or pMDI with spacer
Evaluation Drugs, doses and point(s) devices after dosing
10, 20, 30, 40, Form TBH 4.5 µg x 2 in mild 50, 60 cases, up to ten times in (primary) min severe cases, then 9 µg at times 30 and 60 min versus salbutamol pMDI 100 µg x 2 in mild cases, up to ten times in severe cases, then 200 µg/10 min up to 60 min Mean PEF 43.7% (salb) 30, 60, 90, Formoterol Aerolizer up to and 49.3% PN (form) 120 min two doses of 12 µg, salbutamol up to two nebulisations of 2.5 mg at times 0 and 30 min
FEV1 >30% of PN
FEV1 0.71 (0.23), 0.64 (0.14),0.58 (0.17)
FEV1 Turbuhaler 0.81 (SD 0.64) L pMDI + spacer 0.90 (0.90) L
Mean Baseline FEV1 age, age range
Adults with acute 18–65 asthma; PEF 40–60% years of PN, pulse rate >80 beats/min
Adults with acute asthma (FEV150% of PN)
5, 15, 25, 30 min
0, 15, 30 min
Mean PEF 30 min 74.3% (Rotahaler) and 77.5% (pMDI) ≤7 on a 20, 40, 60 min modified Wood’s asthma score
>50% of PN
Mean FEV1 1.20 l (pMDI) and 1.61 l (TBH)
Salb Easyhaler 600 µg, salb pMDI + spacer 600 µg or salb 0.15 mg/kg via nebulizer
Salb single doses of 400 µg via Rotacaps or pMDI + spacer
Terb TBH 0.5 mg versus terb nebulized solution 1%
Terb 0.5 mg delivered via TBH or pMDI and spacer
Mean Baseline FEV1 Evaluation Drugs, doses and age, point(s) after devices age range dosing
Children with asthma and 4–14 years acute wheeze
Population
No differences in % successfully treated patients (clinical score reduction ≥50% from baseline or clinical score ≤3) between the three treatments. Successfully treated patients 71.8, 72.1, and 79.2% with Easyhaler, pMDI and spacer and nebulizer respectively
Increase in FEV1 at 15 and 30 min with TBH to 1.82 and 1.83 l and with pMDI and spacer to 1.53 and 1.56 l The difference in improvements was not statistically significant Comparable improvement in all lung function measures up to 30 min Patients with FEV1
