The impact of GINA suggested drugs for the treatment of asthma on Health-Related Quality of Life: a GA2LEN review

Authors


G. W. Canonica
Department of Internal Medicine
Genoa University
Pad Maragliano Largo R. Benzi
10 Genoa 16132
Italy

Abstract

Asthma represents a serious global health problem. People of all ages in countries throughout the world are affected by this chronic airway disorder that, when uncontrolled, can place severe limits on daily life and can even be fatal. Asthma cannot be removed, but asthmatic symptoms can be cured; as for many other chronic diseases, pharmacotherapy is important to reduce the risk of asthma-related mortality, decrease disability and improve symptoms and quality of life. The action of antiasthmatic drugs directly contributes to decrease symptoms severity, improve spirometric results, reduce airway hyperresponsiveness and prevent irreversible airway remodelling. Antiasthmatic therapy is necessary for long-term control of asthma symptoms. Asthma and antiasthmatic drugs can influence patient’s quality of life: this is why healthcare systems have recently focused on research studies about Health-Related Quality of Life (HRQL) in asthmatic patients. Numerous validated questionnaires are available and many studies have been performed evaluating HRQL in people affected by asthma, thus testifying a great interest in this topic. The aims of the present review are to examine the scientific literature of the last 4 years (January 2004–December 2007) dealing with the impact of asthma treatments suggested by Global Initiative for Asthma guidelines on patients’ quality of life, and to identify the unexplored or not fully investigated areas concerning this issue.

Health-Related Quality of Life (HRQL) has become a fundamental parameter for achieving a complete description of asthma, focused not only on clinical data but also on the impact of the disease and its therapy as perceived by patients (1–3).

Actually, the presence of asthma deeply influences patients’ lifestyle and can impair quality of life, especially when the disease is not effectively controlled. This is one of the reasons why the aim of asthma therapy indicated by the international guidelines [Global Initiative for Asthma (GINA)] is to achieve and maintain long-term control of the disease, reaching in this way a high level of well-being for patients by minimizing the symptoms and improving physical, psychological and social functioning. Indeed, asthma control implies experiencing no daytime symptoms, no activities limitations, no nocturnal symptoms/awakenings, no need for rescue medications, no exacerbations and no lung function impairment (2).

Patients’ HRQL has to be assessed by means of validated questionnaires, which can be generic or specific: generic tools can be used in all health conditions and allow the comparison of HRQL of patients affected by different diseases with healthy subjects and patients suffering from different diseases. Specific questionnaires focus on the aspects of health status which are relevant for patients with a specific disease or clinical condition. Many questionnaires have been created to evaluate the impact of asthma from patients’ point of view (4).

During the last years many studies have investigated the influence of asthma treatments on HRQL, emphasizing the importance of this parameter in evaluating the effects of any intervention aimed at achieving the disease control. The objective of the present review was to examine the scientific literature of the last 3 years dealing with the impact of asthma treatments suggested by GINA guidelines on patients’ HRQL, in order to draw some considerations, and possibly suggest potential areas for further future research.

Methods

Search strategy

  • • Studies were sought from PubMed archives
  • • The following key words were used:
  • oasthma [AND] quality of life
  • oInhaled glucocorticosteroids, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone, mometasone furoate, triamcinolone acetonide, long-acting inhaled beta2-agonists, formoterol, salmeterol, leukotriene modifiers, cysteinyl-leukotriene 1 receptor antagonists, montelukast, pranlukast, zafirlukast, 5-lipoxygenase inhibitor, zileuton, theophylline, cromones, sodium cromoglycate, nedocromil sodium, Anti-IgE, omalizumab, systemic glucocorticosteroids, oral anti-allergic compounds, tranilast, repirinast, tazanolast, pemirolast, ozagrel, celatrodast, amlexanox, ibudilast, other controller therapies, methotrexate, cyclosporin, macrolide, troleandromycin, rapid-acting inhaled 2-agonists, salbutamol, terbutaline, fenoterol, reproterol, pirbuterol, anticholinergics, ipratropium bromide, oxitropium bromide, short-acting oral _2-agonists, metered-dose inhalers (MDIs), dry powder inhalers (DPIs), soft mist inhalers, nebulized or ‘wet’ aerosols, suspension in chlorofluorocarbons (CFCs), solution in hydrofluoroalkanes (HFAs), oral anti-allergic compounds, allergen-specific immunotherapy (SIT)
  • • The following PubMed limits were used:
  • oPapers published in the last 4 years (January 2004–December 2007)
  • oRandomized controlled trials

Selection criteria

  • • Only randomized controlled clinical studies published as full papers were considered
  • • Full manuscripts published in peer-reviewed journals
  • • Only studies evaluating HRQL by means of validated questionnaires

Results

Our research has brought to a selection of 41 trials, 6 of which involved a paediatric population, 24 involved only adults and 11 a population of adolescents and adults (Table 1).

Table 1.   List of trials analysed in the review, showing comparison groups for treatments, author, year and journal of publication with relative impact factor (IF), number of patients (included/completed), disease by which they were affected (severity indicated if specified, comorbidities indicated if specified), duration of treatment, type of questionnaire used for measuring quality of life, quality of life as primary outcome (PO)
Comparison groupsAuthorYearJournalIFDisease and comorbiditiesTarget populationPatientsDurationHRQL questionnairesPO
HFA-BDP, HFA-BDP + inhalation deviceThoda Y2006Journal of Asthma1.476Asthma (step 2 to 3)Adults (18–85)61/4424 weeksSF-36 and LWAQNo
Beclomethasone, montelukastLazarus SC2007American Journal of Respiratory and Critical Care Medicine9.091Asthma (FEV1 70–90%) in smokers and nonsmokersAdults83/748 weeksAQLQNo
Beclometasone dipropionate extrafine aerosol, fluticasone propionate formulated with chlorofluorocarbon propellentvan Aalderen WMC2007Respiratory Medicine2.086Asthma (PEF ≥ 60%)Chidren (5–12)280/11118 weeksPAQLQ, PACQLQNo
Budesonide, triamcinolone acetonideWeiss KB2005Journal of Asthma1.476Asthma (40% < FEV1 < 90%)Adults945/86812 monthsSF-36, AQLQNo
Mometasone fuorate 100 mcg, mometasone fuorate 100 + 100 mcg, placeboBerger WE2006Annals of Allergy, Asthma and Immunology2.254Asthma (60% < FEV1 < 85%)Children (4–11)296/not reported12 weeksCHQ; Usherwood asthma-specific moduleNo
Mometasone, placeboKarpel JP2007Respiratory Medicine2.086Severe persistent asthmaAdolescents and adults (13–83)123/1023 months (DBPC phase), 9 months (open-label phase)SF-36, AQLQNo
Ciclesonide, fluticasone propionateLee D2004British Journal of Clinical Pharmacology2.718Moderate persistent asthmaAdults28/194 weeksMini-AQLQNo
Ciclesonide, fluticasone propionate Lee D2005Chest3.924Moderate persistent asthmaAdults20/144 weeksMini-AQLQNo
Ciclesonide, fluticasone propionateBoulet LP2007Respiratory Medicine2.086Moderate asthmaAdolescents and adults (12–75)474/42012 weeksAQLQNo
Ciclesonide, budesonidevon Berg A2007Paediatric Allergy and Immunology2.849Persistent asthmaChildren (6–11)621/51312 weeksPAQLQ, PACQLQNo
ICS + tulobuterol patch, ICS + salmeterol, ICS double doseFujimoto K2006Journal of Asthma1.476Asthma (step 3 or more severe)Adults54/498 weeksAQLQYes
Formoterol, albuterol, placeboBusse W2004Clinical Therapeutics2.893Persistent asthmaAdolescents and adults (13–85)239/20912 weeksMini-AQLQNo
Tulobuterol patch, salmeterolNishiyama O2006Clinical and Experimental Pharmacology and Physiology1.780Moderate-to-severe asthmaAdults54/444 weeksSGRQYes
Levalbuterol, racemic albuterol, placeboSkoner DP2005Paediatric Pulmonology1.965AsthmaChildren (2–5)211/1763 weeksCHQ, PACQLQNo
Formoterol, albuterolLa Force C2005Journal of Asthma1.476Persistent asthma (FEV1 > 40%)Adolescents and adults (13–85)265/23512 weeksMini-AQLQNo
Salmeterol/fluticasone vs fluticasoneBateman E2004American Journal of Respiratory and Critical Care Medicine9.091Uncontrolled asthmaAdults3421/289012 monthsAQLQNo
Salmeterol/fluticasone, fluticasoneSchermer TR2007Family Practice1.558AsthmaAdults137/13012 weeksAQLQ, SGRQNo
Salmeterol/fluticasone, fluticasoneRowe BH2007Academic Emergency Medicine1.741Acute asthmaAdults (18–55)137/13721 daysAQLQNo
Budesonide/formoterol, fluticasone/salmeterolKuna P2007International Journal of Clinical Practice1.188Asthma (FEV1 ≥ 50%)Adults3335/31726 monthsAQLQNo
Salmeterol/fluticasone, formoterol/budesonidePrice D2007Respiratory Research2.335Asthma (FEV1 60–90%)Adults (18–70)688/56852 weeksAQLQNo
Budesonide/formoterol vs budesonidePohl WP2006Respiratory Medicine2.086Asthma (FEV1 40–85%)Adults (>19)133/10220 weeksSF-36No
Salmeterol/fluticasone vs placebovan den Toorn L2005Respiratory Medicine2.086Allergic asthma (according to ATS criteria)Young adults (18–30)28/283 monthsSF-36No
Budesonide/formoterol (fixed vs adjustable dose)Bruggenjurgen B2005Pharmacoeconomics2.242Mild-to-moderate perennial asthmaAdults3297/303712 weeksAQLQYes
Adjustable dosing of budesonide/formoterol vs fixed dosing of budesonide/formoterolBuhl R2004Current Medical Research and opinion3.062Mild-to-moderate perennial asthmaAdults3297/303712 weeksAQLQYes
Budesonide/formoterol, salmeterolo/fluticasone, salbutamolVogelmeier C2005European Respiratory Journal5.076Asthma (FEV1 40–90%)Adolescents and adults (12–84)2509/187412 monthsAQLQNo
Adjustable dosing of budesonide/formoterol vs fixed dosing of budesonide/formoterolPrice D2004Current Medical Research and Opinion3.062AsthmaAdults1553/128916 weeksMini-AQLQYes
Salmeterol/fluticasone + tiotropium, salmereol/ fluticasone + placeboFardon T2007Respiratory Medicine2.086Asthma (FEV1 ≤ 65%)Adults (35/68)26/258 weeksMini-AQLQNo
Montelukast, fluticasoneZeiger RS2005The American Journal of Medicine4.518Mild persistent asthmaAdults400/28948 weeksAQLQNo
Budesonide 1600 μg, budesonide 800 μg + montelukastBarnes N2007Respiratory Medicine2.086AsthmaAdolescents and adults (15–70)75/6512 weeksNot indicatedNo
Montelukast + fluticasone, salmeterol + fluticasoneIlowite J2004Annals of Allergy, Asthma & Immunology2.254Moderate-to-severe persistent asthmaAdolescents and adults (14–73)1473/105948 weeksAQLQNo
Montelukast, zafirlukastRiccioni G2004Allergy and Asthma Proceedings0.750Mild asthmaAdults40/4012 weeksAQLQYes
Theophyllne 300 mg, montelukast 10 mg, placebo Irvin G2007American Journal of Respiratory and Critical Care Medicine9.091Asthma (FEV1 > 50%)Adults489/46524 weeksAQLQNo
Omalizumab, placeboVignola AM2004Allergy5.334Moderate-to-severe allergic asthma, persistent allergic rhinitisAdolescents and adults (12–74)405/38528 weeksAQLQ and RQLQYes
Omalizumab placebo controlledOba Y2004Journal of Allergy and Clinical mmunology8.829Moderate-to-severe allergic asthmaAdolescents and adults (12–76)107152 weeksAQLQYes
Omalizumab placebo controlledHumbert M2005Allergy5.334Asthma (step 4)Adolescents and adults (12–75)482/41928 weeksAQLQNo
Sublingual carbamylated allergoid immunotherapy, placeboPassalacqua G2006Allergy5.334Mild intermittent asthma, rhinitisAdults (18–49)68/562 yearsSF-36, SAT-PYes
Modified allergen extract of Dermatophagoides pteronyssinus, placeboAmeal A2005Allergy5.334Mild-to-moderate asthma, rhinoconjuntivitisAdolescents and adults (14–48)63/5512 monthsAQLQNo
Fel d 1-derived T-cell peptides, placeboAlexander C2005Allergy5.334Asthma, rhinitisAdults (23–52)30/2812 monthsAQLQ,RQLQYes
Sublingual immunotherapy, placeboPham-Thi N2007Pediatric Allergy Immunology2.849House dust mite-induced allergic asthma optimally controlled by pharmacologic treatment ± perennial rhinitisChildren and adolescents (5–16)111/9218 monthsChildhood asthma questionnaireNo
Influenza vaccination, placeboBueving HJ2004European Respiratory Journal5.076AsthmaChildren and adolescents (6–18)696/68812 monthsPAQLQYes
Encasement of bedding: impermeable covers, cotton coversDharmage S2005International Archives of Allergy and Immunology2.524Asthma (house dust mites sensitization)Adults32/306 monthsMarks asthma quality of life questionnaireNo

All the selected papers were published in peer-reviewed journals, with an impact factor ranging from 0.750 to 9.091. The trials’ duration ranged from 21 days to 2 years.

The trials included a number of randomized patients ranging from 26 to 3421, for a total of 27 750. The patients who completed the trials were 23 909. Only in one study the authors did not provide any information about this parameter.

HRQL was evaluated by different validated tools (Fig. 1). The Asthma Quality of Life Questionnaire (AQLQ) questionnaire was used in 22 studies, and its reduced form (mini-AQLQ) was adopted in six trials. The Marks AQLQ was used in one trial. The St George’s Respiratory Questionnaire (SGRQ) was applied in two studies. The Living with Asthma Questionnaire (LWAQ) was adopted in one study. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used along with the AQLQ in two trials in which patients were affected by asthma and rhinitis. Generic SF-36 was used together with the specific questionnaire in three trials, and in two studies it was used alone. In one trial, SF-36 was used along with another generic questionnaire aimed at assessing subjective satisfaction [Satisfaction Profile (SAT-P)]. In one study, the authors did not indicate the specific questionnaire that was adopted. For children and adolescents two specific questionnaires were used: Paediatric AQLQ (PAQLQ) in three trials, and Childhood Asthma Questionnaire (CAQ) in one study. The generic Child Health Questionnaire (CHQ) was adopted in two studies. The parent’s viewpoint was assessed by Paediatric Asthma Caregiver’s Quality of Life Questionnaire (PACQLQ) in three trials.

Figure 1.

 Frequency of use for each adopted tool.

Out of 41 trials, only two evaluated the possible presence of concomitant rhinitis.

Concerning the distribution of the studies on HRQL according to treatment options for asthma, we have to consider that among the 41 studies analysed in this review: the combination therapy with inhaled corticosteroids and beta2-agonists was evaluated in 7 trials, the beta2-agonists in 11, inhaled corticosteroids in 14 trials, antileukotrienes in 6, anti-IgE therapy in 3, immunotherapy in 4 and of prevention strategies in 2. Figure 2 shows the number of studies comparing each treatment option to placebo. Figure 3 shows the number of studies comparing different treatment options.

Figure 2.

 Number of studies comparing each treatment option to placebo.

Figure 3.

 Number of studies comparing different treatment options.

HRQL was a primary outcome in 11 trials.

During the analysed period no randomized controlled trials were published on flunisolide, pranlukast, 5-lipoxygenase inhibitor, zileuton, cromones, sodium cromoglycate, nedocromil sodium, systemic glucocorticosteroids, oral anti-allergic compounds, tranilast, repirinast, tazanolast, pemirolast, ozagrel, celatrodast, amlexanox, ibudilast, other controller therapies, methotrexate, cyclosporin, macrolide, troleandromycin, terbutaline, fenoterol, reproterol, pirbuterol, anticholinergics, ipratropium bromide, oxitropium bromide, short-acting oral β2-agonists, MDIs, DPIs, soft mist inhalers, nebulized or ‘wet’ aerosols, and oral anti-allergic compounds.

An overview of the results of each study subdivided into pharmacological categories is presented below.

Inhaled corticosteroids

The role of corticosteroids is essential in persistent asthma therapy. It has been demonstrated that these medications are effective in reducing asthma symptoms, improving lung function, reducing hyperresponsiveness, decreasing the number and the severity of exacerbations, and, as some studies have shown, improving quality of life (2).

In a Japanese randomized controlled trial (RCT) study with an open crossover design, HRQL in asthmatic patients treated with HFA-beclomethasone dipropionate (QVAR) with or without the use of an inhalation device [INSPIR-EASE (IE)] was evaluated with both a generic and a disease-specific questionnaire (SF-36 and LWAQ). The results showed that the use of inhalation device leads to an improvement (P < 0.05) in one out of eight SF-36 domains (physical functioning). By stratifying the survey results according to patients’ age (<70 and ≥70), no significant difference was found between treatments in either age category in SF-36 domains. As regards LWAQ, QVAR + IE was reported to be significantly superior to QVAR alone in improving physical mobility (P < 0.01); on the contrary, QVAR alone was found to be significantly superior to QVAR alone in improving medication usage (P < 0.05): in patients over 70 years of age, QVAR alone significantly improved dysphoric states and attitudes (< 0.05) compared with QVAR + IE. In patients less than 70 years age, QVAR + IE was significantly superior to QVAR alone in improving physical mobility (P < 0.05), but significantly inferior in medication usage (P < 0.01). In conclusion, the impact of inhalation device, from patients’ viewpoint, seems to have an effect only on some specific domains, variable according to patients’ age (5).

The Smoking Modulates Outcomes of Glucocorticoid therapy study was aimed at determining if the response to inhaled corticosteroid or leukotriene antagonist might be attenuated in subjects with asthma who smoke. A total of 44 nonsmokers and 39 light smokers were randomized to receive inhaled beclomethasone twice daily and oral montelukast once daily. The primary outcome was change in FEV1; secondary outcomes included HRQL, assessed through AQLQ. At baseline, smokers and nonsmokers did not differ significantly in any major demographic and physiologic characteristics, whereas AQLQ overall score were significantly lower in nonsmokers, indicating a worse HRQL, but after 8 weeks smokers differed from nonsmokers in their response to both treatments: changes in physiologic outcomes and in smokers were in the same direction as in nonsmokers, but significantly lower. Moreover, treatment with montelukast was associated to a significant improvement in HRQL in nonsmokers compared with smokers; no difference was detected in AQLQ score between the two groups if treated with beclomethasone (6).

The therapeutic effect of beclomethasone dipropionate extrafine aerosol and CFC–fluticasone propionate (CFC–FP) in children (5–12 years) with symptomatic mild-to-moderate asthma, was evaluated in a 18-week multinational study. HRQL in children (PAQLQ) and in their caregivers (PACQLQ) was included as outcome measure along with pulmonary function and asthma control. The therapeutic equivalence of the two treatments was demonstrated: the reformulation of beclomethasone dipropionate (BDP) as a CFC-free extrafine aerosol provided comparable symptom control to CFC–FP at the same daily dose. Reported data concerning pulmonary function and symptoms were confirmed by the subjective prospective of children and caregivers. Indeed, as regards HRQL, the proportion of patients and caregivers with a clinically significant improvement during the initial 6-week treatment period was comparable in both treatment groups (PAQLQ, BDP extrafine aerosol 68%vs CFC–FP, = 1.99; PACQLQ, BDP extrafine aerosol 44%vs CFC–FP 42%, P = 0.369). No statistically significant differences were detected between the two treatment groups with respect to the improvement in overall HRQL scores or the individual domains (7).

A prospective, multicentre, randomized, open-label, parallel group, 1-year study was performed to evaluate patient satisfaction with budesonide delivered by a DPI vs triamcinolone acetonide delivered by a pressurized MDI. A total of 945 participants were randomized and allocated to receive the two different treatments. Patients satisfaction was assessed by using a 17-item self-administered questionnaire that addressed four domains: side-effects, knowledge/ease of use, convenience and overall satisfaction. Along with satisfaction, HRQL was evaluated by a generic questionnaire (SF-36) and a specific questionnaire (AQLQ). Patients treated with budesonide reported significantly higher satisfaction scores in all the four satisfaction domains and better quality of life than patients treated with triamcinolone acetonide. All satisfaction subscales were significantly correlated with AQLQ and SF-36 scores, indicating that in patient’s real life, budesonide has the potential to improve quality of care in asthmatic patients (8).

The efficacy of mometasone furoate, used with the DPI device, was assessed in 12 weeks, multicentre, randomized, double-blind, parallel group, placebo-controlled study. A total of 296 paediatric patients (4 to 11 years old) with mild-to-moderate persistent asthma, who required daily treatment with inhaled corticosteroids (ICS), were randomized in three groups: the first one treated with mometasone furoate DPI 100 mcg once daily, the second one with 100 mcg twice daily and the third one with placebo. HRQL was evaluated by means of the generic questionnaire CHQ; moreover, the Usherwood asthma-specific module was used to assess daytime and nocturnal symptoms, disability, chest pain and how much asthma interrupts a child’s life. Mean baseline scores for all the CHQ-PF28 domains, except self-esteem, showed poorer HRQL in study participants compared with the general US population, 5 to 18 years of age. Statistically significant changes from baseline to endpoint were observed with both mometasone furoate DPI treatments compared with placebo for the physical summary score of the CHQ-PF28 and for disability, daytime symptoms, and nocturnal symptoms domains of the asthma-specific questionnaire, showing that both mometasone furoate doses improved participants quality of life compared with placebo, with statistically significant changes from baseline to endpoint. No differences were observed between the mometasone furoate DPI treatment groups (9).

Another recent trial evaluated the effect of mometasone furoate on the reduction of oral prednisone in oral corticosteroid-dependent patients with severe persistent asthma. A total of 123 patients were randomized to receive mometasone furoate 400 or 800 μg or placebo; HRQL was assessed as secondary outcome by means of SF-36 and AQLQ. At the endpoint of the double-blind, placebo-controlled phase, no differences were detected among the three arms in SF-36 scores, although the patients in the active groups tended to improvement. As regards AQLQ, only the mometasone furoate 800 μg group showed significantly greater improvement (P < 0.05) in total score and in psychosocial impact domain than the placebo group (10).

In two different studies with almost identical structures (randomized, double dummy, double-blind, crossover trial), Lee and co-workers evaluated the effects of HFA formulations of ciclesonide and FP, including HRQL as secondary outcome, by means of mini-AQLQ. The first one involved 28 patients with mild-to-moderate asthma, treated for 4 weeks. As well as for the other outcomes (methacholine challenge, exhaled nitric oxide, lung function, diary cards), no significant differences were found between the randomized treatments in the change from baseline both in mini-AQLQ overall score and for each factor (11). Similarly, the results of the second study, which involved 20 patients with moderate asthma for a 4-week treatment, did not report any difference between the two treatments, both in relation to clinical and functional outcomes (plasma cortisol response to stimulation with human corticotropin-releasing factor, bronchial hyperresponsiveness) and to mini-AQLQ scores (overall score and domain scores). Both drugs significantly improved efficacy outcomes, with a superimposable effect on patients’ HRQL scores (12).

On the contrary, Boulet and co-workers found that ciclesonide is able to guarantee significantly greater improvement in HRQL (measured through AQLQ). In fact the ‘net benefit’ (calculated as the proportion of patients with an increase of at least 0.5 in the overall AQLQ score, minus the proportion of patients with a decrease of at least 0.5 in the overall AQLQ score) was higher with ciclesonide than with fluticasone (21.2%vs 6.5%). Moreover, noninferiority of ciclesonide to FP was found in all AQLQ domain scores (all P < 0.0001) (13).

The effect of ciclesonide was evaluated also in paediatric patients. A multicentric study assessed the efficacy, safety and effect on QoL of ciclesonide 160 μg vs budesonide 400 μg administered once daily in the evening, for 12 weeks, to children with moderate-to-severe asthma. Along with pulmonary function, asthma symptoms and use of rescue medication, HRQL was assessed in children and parents by means of PAQLQ and PACQLQ. From patients’ and caregivers’ points of view, both treatments achieved statically significant improvements in overall HRQL scores vs baseline. The comparison of the two treatments did not show any significant difference in term of HRQL: both ciclesonide and budesonide caused clinically relevant improvements of PAQLQ and PACQLQ scores in more than 50% of cases (14).

Inhaled bronchodilators

Generally long-acting inhaled beta2-agonists are used in combination with inhaled corticosteroids as a daily treatment to allow clinical control of moderate-to-severe asthma; whereas they should not be used as monotherapy because they have not any influence on airways inflammation (but it has been proven that, when in association with ICS, they can increase their anti-inflammatory effect) (15). Short-acting beta2-agonist are instead used as rescue medication to relieve bronchospasm. Both short- and long-acting beta2-agonist can be used to prevent exercise-induced bronchoconstriction.

Some studies assessed the efficacy and the role of these inhaled bronchodilators in HRQL.

Fujimoto and colleagues conducted a study to compare the efficacy of salmeterol and tulobuterol patch on patients with difficult asthma. Patients involved in the study were randomly assigned to receive salmeterol, tulobuterol patch or a double dose of ICS for a period of 8 weeks. HRQL was evaluated by means of AQLQ. The results showed that only the salmeterol group had a significant (P < 0.05) improvement superior to 0.5, which indicates a clinically relevant change, in the AQLQ total score and in two domains: symptoms (P < 0.01) and emotional function (P < 0.01). This higher effect on QoL could be due to the fact that salmeterol directly reaches the respiratory tract (16).

Different results were found by a Japanese group of authors who investigated the effects of a 4-week treatment with tulobuterol patch vs salmeterol in an open-labelled, crossover RCT. The outcomes considered in the study were morning pick expiratory flow (PEF) and HRQL, assessed using the SGRQ. The morning PEF and HRQL score were significantly improved in both treatment groups (salmeterol and tulobuterol) compared with the run-in period. The effect of salmeterol in increasing morning PEF was significantly higher compared with tulobuterol. However, in terms of HRQL, SGRQ total score was significantly improved in both the salmeterol and the tulobuterol (P < 0.05) treatment periods compared with the run-in period and the effect of both treatments on HRQL were comparable. The reason for this similar effectiveness of the two drugs in improving HRQL remains unclear, and the authors suppose that this could be due to the effect of tulobuterol on the small airways in the distal lung (17).

Asthma-related quality of life was evaluated also by Busse and co-workers, by means of a RCT, in a double-blind and double-dummy study. A total of 239 patients were enrolled, and 209 completed the study; they were randomized to receive formoterol bid, albuterol qid and placebo for 12 weeks. The primary efficacy variable was the 12 h area under curve (AUC) of FEV1 at the end of the treatment; among the secondary efficacy variables, asthma-related QoL was evaluated, by using the mini-AQLQ. The results showed a consistent increase in mini-AQLQ scores from baseline in formoterol recipients both in total instrument score, and in each domains (symptoms, activity limitation, emotional function, environmental stimuli) after 4 and 12 weeks of treatment. In contrast, patients treated with albuterol did not report any improvements in mini-AQLQ scores compared with placebo group (18).

A comparison of the efficacy formoterol vs albuterol was performed also by La Force and colleagues in a study involving 265 patients with persistent asthma: 86 patients received formoterol, 88 placebo and 91 albuterol. In this RCT, the mini-AQLQ was used to assess quality of life. Compared with placebo, the formoterol group showed higher mini-AQLQ scores after 4 and 12 weeks of treatment, indicating improved HRQL. Although in general such differences were not statistically significant, increases of at least 0.2 points relative to placebo are clinically relevant. Similar findings were observed for albuterol; no significant differences were observed between the two active treatment groups, indicating that from a patient’s perspective, albuterol and formoterol have similar effects on well-being (19).

A paediatric study evaluated the safety and the efficacy of levalbuterol in children aged 2 to 5. HRQL was among the outcomes considered in this RCT. It was assessed by using two specific questionnaires, the specific PACQLQ that permits to take into account the impact of paediatric asthma on parents, and the generic CHQ, which provides data about children health status. All treatment groups had an improvement in CHQ scores at the end of the 3-week treatment period, although the results are not statistically significant. Caregivers of children treated with levalbuterol had a greater improvement in PACQLQ scores than those of patients treated with the racemic albuterol and placebo. The improvement in overall score and in both domain scores (activity limitation and emotional function) exceeded the minimal important difference (MID) fixed at the value of 0.5, thus indicating the clinical relevance of these results. Moreover, all HRQL scores showed an improvement trend over time in patients treated with levalbuterol (20).

Combination between bronchodilators and inhaled corticosteroids

As we previously said, the combination of inhaled long-acting beta2-agonist and corticosteroids is very effective to achieve an optimal clinical control of asthma.

Their effects on HRQL were evaluated in some studies in the last 4 years.

A randomized, stratified, double-blind, parallel-group study evaluated during 1 year the efficacy of FP compared with salmeterol/fluticasone in 3421 patients with uncontrolled asthma, in achieving two well-defined measures of control: totally and well-controlled asthma. Patients were divided into different strata according to the dose of treatment. More patients in each stratum achieved control with the combination of salmeterol/fluticasone than with fluticasone alone, even more rapidly and at a lower corticosteroid dose. Exacerbation rates and improvement in health status were also significantly better with the association of salmeterol and fluticasone. AQLQ was used to evaluate HRQL: overall AQLQ scores improved in both groups throughout the study, with a statistically significant difference in favour of salmeterol/fluticasone in strata 2 and 3. There was a trend for higher quality of life scores in patients who gained control. Achieving totally controlled and well-controlled asthma in phase I was associated with mean overall AQLQ scores of 6.4 and 6.1, respectively, in phase II; in contrast, the mean overall AQLQ score for those not achieving at least well-controlled asthma was 5.3 (all strata, both treatments combined) (21).

A study performed in family practice showed that the salmeterol/fluticasone combination, compared with conventional fluticasone treatment, permits to better achieve several treatment goals: FEV1 (P = 0.025), PEF (P = 0.016) and symptoms-free days for week (P = 0.044). These benefits were not perceived by patients, since, in AQLQ overall score and SGRQ scores, no differences were detected between the two treatments (22).

A recent study was aimed at determining if the addition of long-acting beta-agonists can reduce the relapses of asthma following emergency department. A total of 137 patients were randomized to receive either salmeterol/fluticasone or fluticasone alone. After 21 days, 7 out of 69 patients treated with salmeterol/fluticasone and 10 out of 68 patients treated with fluticasone experienced a relapse. No statistically or clinically significant differences were found regarding AQLQ overall score and domains. In patients without relapse, better HRQL was detected in the group treated with salmeterol/fluticasone (23).

A 6-month, randomized, double-blind, double-dummy, parallel-group study compared the SMART approach (budesonide/formoterol maintenance and reliever) with a fixed dose of salmeterol/fluticasone plus terbutaline, or a comparable fixed maintenance dose of budesonide/formoterol plus terbutaline as needed. The primary outcome was the time to the first severe exacerbations. HRQL was assessed as secondary outcome, by means of AQLQ. By reducing the maintenance dose of budesonide/formoterol by 50% and by using budesonide/formoterol as reliever medication it is possible to reduce the risk and rate of severe exacerbations compared with a higher fixed dose salmeterol/fluticasone and budesonide/formoterol. Moreover, a similar marked and clinically significant improvement (0.76–0.78) in AQLQ overall score was detected in all the three treatment groups, showing that, also from patients’ perspective, the SMART strategy has a positive impact on HRQL (24).

A 52 weeks multicentric study evaluated the long-term efficacy and impact on HRQL of a stable-dose regimen of salmeterol/FP and an adjustable maintenance dosing regimen of salmeterol (SAL)/budesonide (BUD). Stable dose of SAL/FP resulted in significantly greater increase not only in symptom-free days and exacerbation rates, but also in patients’ well-being. In fact, despite in both group the improvement of AQLQ scores was clinically relevant, it did not reach a statistical significance; a greater number of patients in the SAL/FP group reached a >0.5 point improvement in AQLQ overall score at week 28 and this trend was confirmed at week 52. These results suggest that treatment success is achieved in a higher percentage in patients receiving SAL/FP than in those receiving formoterol (FOR)/BUD (25).

A study conducted by an Austrian group investigated the effects of a 20-week treatment with budesonide/formoterol vs budesonide alone. Quality of life was evaluated by means of the generic SF-36. Treatment with budesonide/formoterol compared with treatment with budesonide alone, showed greater HRQL improvements in SF-36 questionnaire domain scores between weeks 0 and 20. Significant and clinically relevant differences between the two treatment groups were found in physical functioning (6.0 units; P = 0.025) and emotional role functioning (12.1 units; P = 0.035). Patients treated with budesonide/formoterol showed a trend towards greater improvements also for the following domains: physical role functioning, bodily pain, general health, vitality and social functioning. Although patients in the budesonide group showed a greater improvement in mental health domain, than those receiving budesonide/formoterol, this difference was not statistically significant (26).

A 3 months, double-blind, randomized placebo-controlled trial was conducted by van den Toorn and colleagues in 28 asymptomatic subjects with a history of atopic asthma. Intervention consisted of the salmeterol/FP combination product (50/250 μg via the Diskus) or placebo. The aim of this study was to investigate the effect of a short course of combination treatment with salmeterol and FP on indices of airway inflammation and remodelling in young adults. HRQL was evaluated as secondary outcome by mean of SF-36. The results demonstrated that the improvement in bronchial hyperresponsiveness, fractional expired nitric oxide (FENO) values and mast cell activation is not accompanied by improved SF-36 scores. In fact no evidence of subjective improvement or better QoL was found in this study: the added value of the long-acting β-2 agonist (LABA) in patients with subclinical asthma remains conceptual. Authors suggested that slow changes in the degree of airway inflammation and remodelling are not easily perceived by asthmatics, especially in patients with asthma in clinical remission or with mild asthma. The results of this study provide important implications for the management of asthma, as the presence of symptoms is not obviously a sensitive indicator of ongoing disease (27).

Furthermore in patients using combination therapy with budesonide/formoterol as maintenance, it can be used also as rescue medication achieving a better protection against severe exacerbation and improving asthma control with a low dose of drug.

In a randomized, open-labelled trial conducted in asthmatic patients by Bruggenjurgen and co-workers, the effect of a fixed dose of budesonide/formoterol was compared with an adjustable dose. The primary outcome was the change in HRQL, measured by AQLQ. The results showed that both treatments were equally effective on HRQL and asthma control, even though patients on an adjustable dose took fewer inhalations of drug (28).

Similar results were found in the AstThmA Control plan (ATACO), a 16-week, randomized, open-label, multicentre parallel-group study, conducted in 4025 patients with mild-to-moderate perennial asthma. Patients were enrolled to receive two inhalation bid of budesonide/formoterol in a single inhaler for 4 weeks, in order to gain control of their symptoms. After the run-in period, patients were randomized to either fixed dosing or adjustable dosing for 12 weeks. The primary outcome was the effect on AQLQ overall score from randomization to the end of the study. Secondary outcomes were AQLQ domain scores and SF-36 scores [physical component summary (PCS) and mental component summary (MCS)], along with asthma control. At the end of the run-in period, clinically significant improvements were observed in AQLQ (overall score and single domains) and in PCS and MCS scores. Despite adjustable-dosing patients took fewer daily inhalation than fixed-dosing patients during randomized treatment period, improvements were maintained in both groups. In fact further small improvements in AQLQ overall and domain scores were detected irrespective of dosing regimen. Similarly, run-in improvements in SF-36 scores were maintained with both treatment arms. In addition, the good level of asthma control obtained in the run-in period was maintained in both groups at the end of the study. On the basis of these results, authors suggest that adjustable maintenance dosing with budesonide/formoterol in a single inhaler may represent an effective treatment strategy to achieve the goal of reaching effective asthma control by using the lowest adequate dose of medication (29).

The results of ATACO study were reported in a paper that focused on AQLQ change during the randomization period. After a clinically significant improvement of 0.73 units in overall scores at the end of the run-in period, further small improvements were found in both treatment groups during the randomized phase. From the patient’s perspective, no statically or clinically relevant differences were found between the treatment strategies. This result suggests that both adjustable maintenance dosing and fixed dosing were equally effective in maintaining the improvement in AQLQ scores. The simplified strategy using budesonide/formoterol for maintenance and reliever therapy improved all efficacy variables with a significant effect also on patient’s HRQL (30).

The ASSURE study was a pragmatic, open-label, parallel-group multicentre, 16 weeks trial aimed at assessing the costs and effectiveness of fixed dosing of budesonide/formoterol compared with adjustable maintenance dosing in a primary care setting. The primary outcome for the economic evaluation was the net percentage of patients experiencing clinically significant improvement in HRQL (‘net benefit’), assessed by the mini-AQLQ. About 54% of patients enrolled reported a clinically significant improvement between baseline and randomization. This benefit was maintained over the 12 week randomized period. In addition, during the period from randomization to the end of the study, additional net benefit in HRQL scores, was found in 1% of patients in the adjustable dosing group, and 6% of patients in the fixed dosing group, without any significant difference between the two arms. The results of this study suggest that self-management with budesonide/formoterol guarantees HRQL improvement similar to that obtained with the fixed dose, but requesting lower costs. This study found that compared with fixed dosing, adjustable dosing with budesonide/formoterol was associated with equivalent HRQL (31).

Recently, the potential benefit of the addition of a long-acting bronchodilator for a step down of ICS treatment in severe asthma was evaluated and the result showed that the addition of salmeterol and triotropium to half dose of fluticasone is able to guarantee small but significant improvements in pulmonary function. These benefits have no consequence on patients’ well-being, since no significant difference was found in mini-AQLQ domains and overall score comparing the three treatment options (32).

Leukotriene antagonists

Leukotriene modifiers (montelukast, zafirlukast and zileuton) are a new class of antiasthmatic drugs, used in many countries since the last decade. These drugs used as add-on therapy may reduce the dose of inhaled glucocorticosteroids required by patients with moderate-to-severe asthma, and may improve asthma-related symptoms when asthma is not controlled with low or high doses of inhaled glucocorticosteroids (2).

The aim of a randomized, multicentre, parallel group, double-blind study was to evaluate whether montelukast is as effective as fluticasone in controlling mild persistent asthma. In this study 400 asthmatic patients were randomly assigned to receive oral montelukast or inhaled fluticasone during a 12 weeks double-blind period, followed by a 36 weeks open-label period. By means of an AQLQ, HRQL was assessed at the initial, 12- and 48-week visits, thus during the double-blind and during the open-label period. It was reported that both in the first part and in the second part of the study, patient-reported asthma outcome measures significantly improved for both montelukast and fluticasone groups, compared with baseline. In detail, patients treated with montelukast reported an AQLQ overall score improvement of 0.7, and patients treated with fluticasone reported an improvement of 0.8. Both results point out that the improvement is significant from a clinical point of view. No significant difference exists between the two treatments (33).

In another study, the clinical effect of the addition of a 12-week treatment of montelukast vs double dose of budesonide was evaluated in asthmatic patients. HRQL was included as secondary outcome. No differences in terms of HRQL were found between the two treatments, despite patients treated with montelukast reached a clinically significant improvement (0.73), unlike patients treated with double dose of budesonide (0.48). From patients’ point of view, treatment with budesonide seems to guarantee a subjectively perceivable improvement (34).

The effect of add-on therapy with montelukast was compared with that of salmeterol in a large 48 weeks study involving patients with asthma whose symptoms were not optimally controlled using ICSs alone. A total of 1473 patients were randomized to receive montelukast or salmeterol concomitantly administered with inhaled fluticasone. HRQL was included as secondary endpoint, and was evaluated by means of the AQLQ. The results of this study showed that differences between treatments were small both in term of clinical efficacy and HRQL. Concerning this issue, both montelukast and salmeterol improved AQLQ score more than 0.5, but the difference between the two treatment was not of clinical significance (35).

The aim of a study by Riccioni et al. was to compare the efficacy of different leukotriene antagonists on QoL. Forty patients with asthma were randomized to receive montelukast or zafirlukast once a day for 12 treatment weeks. All the patients underwent clinical examination, spirometry and HRQL was assessment by using AQLQ. Compared with baseline, in both treatment groups a significant improvement in AQLQ overall score and domains (P < 0.05) was detected. No difference was found between the two groups of treatment, showing that montelukast and zafirlukast have similar effect in improving HRQL (36).

The effects of low-dose theophylline or montelukast, added to the treatment of patients with poorly controlled asthma, was assessed in a randomized, double-masked, placebo-controlled trial with 489 participants. Patients were assigned to theophylline 300 mg/day, montelukast 10 mg/day or placebo group and monitored for 24 weeks to measure the rate of episodes of poor asthma control. Secondary outcome was the assessment of HRQL. The AQLQ was used, and the results showed that neither theophylline nor montelukast have additional benefit in improving HRQL scores compared with placebo (37).

Anti-IGE

Anti-IgE treatment is an innovative therapy reserved to the treatment of patients with severe uncontrolled allergic asthma. Four trials assessed HRQL in patients treated with omalizumab in the last 4 years.

A multicentre, randomized, double-blind, parallel group, placebo-controlled trial was performed to evaluate the efficacy and the safety of omalizumab. The assessment of HRQL through the AQLQ and RQLQ was a co-primary outcome in this study. A total of 405 patients with concomitant moderate-to-severe allergic asthma and persistent allergic rhinitis were randomized. Omalizumab treatment resulted in more responders (a responder was a patient with a ≥1 point improvement from baseline in AQLQ and RQLQ) than placebo; indeed, a clinically significant improvement was reported in 57.7% of omalizumab patients vs 40.6% of placebo group in all RQLQ domains and in the symptoms and environmental AQLQ domains .In patients with concomitant asthma and persistent allergic rhinitis (PAR), omalizumab is significantly more efficacious in improving HRQL when added to standard therapy for asthma and rhinitis, providing an additional, clinically relevant, benefit (38).

Effectiveness of omalizumab in improving HRQL was confirmed in a 28 weeks, randomized, placebo-controlled, double-blind study involving 419 patients with inadequately controlled by inhaled corticosteroids and long-acting beta2-agonists: benefits were reported in patients with concomitant asthma and perennial rhinitis. Quality of life was assessed at weeks 0, 12 and 28 of the treatment phase by AQLQ and RQLQ, with the aim of globally assessing patient’s subjectivity. Omalizumab provided significantly greater improvements compared with placebo in AQLQ symptoms and environmental domains and in all RQLQ domains, and in each domain, with a significantly greater percentage of patients receiving omalizumab who achieved a clinically meaningful ≥ 0.5 point improvement from baseline compared with those treated with placebo (60.8%vs 47.8%, P = 0.008) (39).

A retrospective economic analysis was performed to assess the cost-effectiveness of omalizumab in adolescents and adults with moderate-to-severe allergic asthma. Data from two randomized controlled trials with an identical study design were analysed; outcome measures included only direct expenditures and the cost to reach an improvement in HRQL scores. In this analysis, the daily cost to achieve an improvement of 0.5 points or more in AQLQ was evaluated. The cut-off value of 0.5 points was taken because this represents the difference perceived as clinically relevant by patients and maybe considered an indicator of treatment success. In 2003, the cost to achieve a successfully controlled day associated with the use of omalizumab was estimated to be $523; an adjunctive daily cost of treatment to achieve at least a 0.5-point improvement in AQLQ score has been calculated to be $378. The results of this study clearly indicate that omalizumab is more expensive than other controller drugs in patients with moderate asthma, by evaluating not only direct expenditures, but also the cost associated with an improvement perceived as significant by patient (40).

Immunotherapy

Allergen SIT is the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to improve the symptoms associated with the subsequent exposure to the causative allergen. The major objectives of SIT in asthma are to reduce the allergic triggers precipitating symptoms and to decrease bronchial inflammation bronchial hyperreactivity (41). We found four studies that evaluated the role of specific allergen immunotherapy in the last 4 years.

A multicentre, randomized, double-blind, placebo-controlled study was performed to assess the efficacy of sublingual carbamylated allergoid immunotherapy in patients with rhinitis, with or without asthma, due to mites. Sixty-eight patients were enrolled and, after a run-in period, they were randomized in two groups to receive sublingual immunotherapy or placebo. The percentage of asthmatic patients in the two groups was of 17.9% in sublingual immunotherapy (SLIT) group and 28.6% in placebo group. Before and after the observation period patients had to complete the SF-36 and SAT-P. SF-36 showed a statistically significant change in the SLIT group for the item ‘change in health status’ in the second year of treatment. SAT-P did not show any change after treatment. In providing an interpretation of data, authors underline that patients’ HRQL profiles were not different from the healthy reference group. The generic questionnaires used in this study, due to their characteristics, could be unable to detect the impact of moderate pathology and the improvements caused by therapy (42).

No significant effects of SLIT on HRQL were found also in a 18-month, double-blind, placebo-controlled trial involving 111 children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment. After a run-in period, the children were randomized 1 : 1 to receive SLIT (mixture of D.p. and D.f. [Stallergenes]) or placebo with a stratification based on inhaled corticosteroid daily intake. Forty-four patients with SLIT and 48 patients with placebo completed the study. HRQL was assessed by using two forms of the CAQ: CAC-B was used for 6 to 11 years children and CAC-C for 12–16 years adolescents. In the CAC-B population (age 6–11 years, n = 82), 20% of the children had the maximum HRQL score at inclusion for passive activities dimension, indicating a great impact of asthma on this aspect of daily life. During the trial only the severity dimension showed a significant improvement in the SLIT group compared with the placebo group (P = 0.04) in children younger than 12 years. In the CAC-C population (age 12–16 years, n = 29), 14% of patients had a maximum HRQL score for the reactivity dimension. In both SLIT and placebo groups, the average changes in all dimensions were comparable and no statistically significant between group differences were observed. In conclusion, from a patient’s perspective, SLIT had no relevant effect on HRQL, excepted for the severity dimension, in youngest children (43).

HRQL was included as secondary endpoint in a randomized, double-blind, placebo-controlled study that evaluate the efficacy of a 1-year immunotherapy with a modified Dermatophagoides pteronyssinus extract in mild-to-moderate asthma. Fifty-five patients were randomized to receive active treatment (n = 29) or placebo (n = 26). The AQLQ of Marks was administered four times during the trial. After the inclusion in the trial, both groups showed a highly significant improvement (P < 0.0001) that could not be explained as a consequence of the therapy. Authors justified these results as an example of Hawtorn effect: it states that by merely participating in a test, trial or study the participants (or patients) have better experience because of the focusing of interest toward them which is gratifying and thus rewarding in its own sake. Moreover, the differences between the two groups at the end of the study were significant (P = 0.0025), the improvement being only in the active group (44).

The effect of the Fel d 1-derived T-cell peptides on clinically relevant outcome measurements (allergen-induced nasal and bronchial reaction and asthma/rhinitis HRQL) in cat-allergic patients was evaluated in a randomized, double-blind, placebo-controlled study. Sixteen patients were randomized to receive active treatment or placebo; HRQL was assessed with the standardized versions of RQLQ and AQLQ. While active treatment significantly improved three RQLQ domains (nonnose/noneyes symptoms, practical problems, nasal problems), the effect on AQLQ was shown only in activity limitation (P = 0.014), thus testifying that patients perceive a more incisive effect on problems related to rhinitis than those depending on asthma (45).

Prevention strategies

Many studies confirm that influenza vaccine reduces the risks for asthma exacerbations, hospitalizations and death in patients during an influenza epidemic if the vaccine strain is identical or similar to the epidemic strain. This is the reason why vaccination programmes should involve also asthmatic patients.

The purpose of a randomized, double-blind, placebo-controlled, parallel trial was to assess the effect of influenza vaccination on symptoms and HRQL in asthmatic children. A total of 200 general practitioners selected 696 asthmatic children aged 6–18 years. Of these, 347 were vaccinated with influenza vaccine and 349 with placebo. A baseline PAQLQ was obtained from 662 children, 331 in the placebo group and 331 in the vaccine group. Compared with placebo, influenza vaccination was found to have a moderately beneficial effect on quality of life in influenza-positive weeks of illness related to influenza-positive swabs, despite no effect for respiratory symptoms. More in detail, the improvement was found in total score (P = 0.02) and in activities (P = 0.02) and symptoms (P = 0.04) domains, and it was clinically relevant (46).

Bedding is the preferred habitat of house dust mites: mattresses, pillows and duvets provide all the most propitious conditions to the growth of house dust mites, namely warmth, humidity and food (in the form of debris derived from human bodies). It has been scientifically demonstrated that the consistent use of Anti-Mite Covers results in the mitigation of the nocturnal symptoms of allergy to house dust mites.

A RCT double-blind was conducted by a group of Australians researchers, comparing the effects of the use of encasement of bedding with impermeable covers vs identical-appearing nonimpermeable cotton covers, in a group of 32 asthmatic patients sensitized to house dust mites. The results showed a significant reduction in the level of der p 1 in the active group after 6 months, but no significant difference in lung function change, symptoms and use of rescue medications. As regards AQLQ scores, there was a significant improvement in total score, breathlessness and physical restrictions and mood disturbance in both groups, without any difference between groups. A significant increase in the ‘social disruption’ and ‘concern of health’ domains was observed in the active group (P < 0.05) but not in the placebo group. However, the differences in change of scores between the two groups did not reach the level of significance. The reduction of der p 1 levels due to encasement of bedding, do not seem to be able to have any significant influence on patients’ HRQL (47).

Discussion

During the last years, HRQL has become more and more important, and its use as a tool for the assessment of the impact of diseases on patients has continuously increased. Especially for asthma and allergic diseases HRQL is now considered a fundamental parameter for achieving a more complete assessment of the effects of any therapeutic measure. As a consequence it is very often used as a complementary outcome in clinical research and in clinical trials, since it makes it possible to capture many and different components of patients’ health status. For both regulatory authorities for pharmaceutical marketing, Food and Drug Administration in the USA and European Agency for the Evaluation of Medicinal Products (EMEA) in the European Union, HRQL has become an important parameter to be included in clinical trials (1, 2, 48, 49).

We previously performed a similar review (50), examining the recent trials dealing with the impact of allergic rhinitis treatments suggested by ARIA guidelines on patients’ HRQL, identifying the unexplored or not fully investigated areas concerning this issue. In line with this investigation, we wanted to perform a comparable analysis concerning GINA guidelines for the treatment of asthma to further explore how HRQL is considered and evaluated.

The analysis of the trials selected for this review highlights some considerations, and permits to suggest future possible research areas for improving and clarify the methods to evaluate this parameter.

The reason for introducing HRQL evaluation in clinical trials was to assess the patient’s perspective. The result of this approach is the identification, in some areas related to patient’s life, of a change due to the treatment. HRQL assessment requires the use of tools to evaluate different aspects of the subjective experience.

What emerges from our analysis is that the majority of the studies do not give a clear explanation of the criteria that were used in choosing the questionnaire and do not state clearly the objectives to be achieved. Considering that each questionnaire explores specific HRQL aspects, this approach provides some information about treatment effects on HRQL, but other relevant aspects may be omitted. Hence, the importance of using the most proper tool available in order to capture and detect, in the specific susceptible area investigated by the questionnaire, the changes due to the drug.

For example, although the impact of asthma on sleep has been emphasized by the international guidelines such as the GINA, in the studies examined in this review, sleep was only marginally taken into consideration in HRQL evaluation. This lack appears to be relevant if we consider that the Asthma Insights and Reality in Europe study (51) showed that 28% of children and 30.5% of adults reported asthma-related sleep problems at least once a week. The specific questionnaires used for the assessment of HRQL in the studies selected for this review (except the LWAQ in the study by Thoda) contain only few questions about sleep disturbances and do not include any domain specifically addressed to detect sleep impairment. Therefore, no information is provided about such important area of patient’s well-being.

In the same way the choice of the questionnaire – generic or specific – determines the kind of data we will obtain. Among the studies included in this review, three of them assess HRQL only by means of generic questionnaires, so that only an evaluation of the health status is provided. Despite a generic questionnaire is useful for cross-population comparisons, it provides very little depth and may be unresponsive to small but clinically meaningful changes in HRQL in a given disease state.

The severity of the pathology is not a determinant factor of HRQL in itself, but it represents an important criterion in the choice of the adequate instrument and it is binding when making group comparison. The use of different severity selection criteria adopted in the 41 trials considered, represents a significant limitation to a correct comparison of the treatment effect on patient’s HRQL. Furthermore, it is worth to underline that it would be difficult to develop a stout meta-analysis combining HRQL data deriving from such studies. Another omitted issue is the choice of the tailored questionnaire for specific age groups. Among the selected studies, 11 evaluated a population of adolescents and adults, but only quality of life instruments for adults have been used. Only six trials were conducted enrolling a paediatric population. The small number of paediatric studies is disappointing because asthma, like other allergic diseases, is one of the most common chronic conditions in children and young adults, and its prevalence is increasing especially in this population (52). Therefore, it would be useful to obtain more data on paediatric patients.

HRQL evaluation tools discern the aspects of patients’ life that are linked to the disease but that can be influenced by the concomitance of other pathologies. It is well-known that concomitant rhinitis has an influence on asthmatic patients’ HRQL (53).

It is remarkable that only two studies out of the 41 analysed, considered the comorbidity of asthma and rhinitis. On the contrary, the presence of rhinitis as a comorbidity, should always be taken into account when building up a clinical trial on asthmatic patients. Recently it has been demonstrated that the two diseases are strictly connected, and that the treatment of rhinitis is beneficial in controlling asthma symptoms and improving patients’ HRQL (53, 54). To ignore a comorbidity could interfere in the correct evaluation of patients, and this could eventually lead to a bias in the evaluation of the effects of a therapeutic intervention.

HRQL is a parameter clearly differentiated from the core symptoms of a disease assessed by the patient himself, which are well-accepted primary and secondary efficacy endpoints in registration trials for medicinal products. It is one of the patient-reported outcome assessed in clinical research and it is based on patient’s perception of a disease and its treatment(s). As HRQL is distinguished by its multidimensionality, the analysis of the questionnaires provides the scores related to each domain investigated, plus a total score summarizing the values of each domain. Another important concept is the definition of the entity of the score variation (of each domain, or of the total score) that is perceived as relevant by the patient. This permits to understand the true effect on HRQL, as perceived by the patient. Few data are available about this aspect. Only the AQLQ allows to calculate the MID, namely how much a score must change so that it is perceived as such by the patient, irrespective of its statistical significance. MID has not been calculated for the other instruments, and the studies that use AQLQ not always indicate if the significance has been achieved. Therefore, in the majority of cases it is impossible to know if the changes obtained, irrespective of statistical significance, are perceived as relevant by patients and have a real impact on their life. As suggested by EMEA reflection paper (49) concerning the evaluation of obtained scores, to establish that a drug improves HRQL it is necessary to demonstrate that there has been an improvement of the most important and clinically relevant HRQL domains. Moreover, it is recommended that all the changes in HRQL are specified, by including in the description of the results not only the improved domains, but also the unvaried and worsened ones, if any. In the same way, the change in the total score should be provided.

In conclusion the attention reserved by patients, policy makers and physicians to HRQL parameter requires that its evaluation is carried out with the proper tool, with an evidence-based method, correctly analysed and clearly shared.

In this regard, some suggestions should be drawn by this review concerning HRQL assessment method.

  • • Use a validated questionnaire
  • • Choose a questionnaire suitable for the investigated population
  • • Choose a questionnaire on the basis of expected drug effects (investigating the domains more susceptible to changes due to the drug effects)
  • • Clearly define the objectives of HRQL evaluation
  • • Consider, in planning the study, the presence of HRQL confounding factors (i.e. comorbidities)
  • • Indicate the statistically significant changes, and the domains remained unvaried or worsened
  • • Do not only consider the statistical significance, but also the clinical relevance of changes (MID) where possible
  • • Remember the nontransferability of the result to different populations of patients (i.e. different age group/demographic data, disease severity, duration of treatment, presence or absence of comorbidity)

The use of a correct methodology allows to improve the quality of data regarding patients’ point of view, and to obtain more comprehensive information, with the aim of optimizing asthmatic patients’ management and pharmacologic treatment. The quality of collected data is essential also in the light of the role attributed to patients’ viewpoint by the GRADE approach (55, 56) for the judgement of evidence and recommendations in healthcare.

Acknowledgments

This study was supported by GA2LEN, Associazione Ricerca Malattie Immunologiche e Allergiche (ARMIA), and by the Italian Medicines Agency (AIFA) within the independent drug research programme, contract no. FARM5JYS5A. Authors acknowledge Dr Silvia Raco for the linguistic review.

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