Introduction
According to international guidelines, once treatment has been established, therapeutic management of asthma should be based on asthma control, rather than asthma severity [
1,
2]. Patients with controlled asthma can prevent the majority of attacks, avoid daytime and nighttime symptoms, stay physically active and have reduced risk to exacerbate [
3].
Recognizing the importance of the patient’s perspective and of the poor correlation between lung function and symptoms [
3,
4], clinical trials and clinical practice have increasingly focused on the assessment of asthma control. This is a general term that implies a global assessment of actual status and future risk including symptoms, reliever use, lung function, and the frequency/severity of exacerbations [
5]. The level of asthma control is usually categorized into controlled, partly controlled and uncontrolled [
1]. Moreover, a positive correlation between asthma control and quality of life (QoL) has been demonstrated [
3]. Awareness of patient reported outcomes such as asthma control and QoL is increasing, together with an emphasis in clinical research and by regulatory bodies because of their relevance in the overall treatment efficacy assessment [
5].
The PRISMA (PRospectIve Study on asthMA control) observational study was designed to include a cross-sectional phase and a 12-month prospective phase in order to estimate the level of asthma control in real life and its evolution during a 1-year follow up. The results of the cross-sectional phase of the PRISMA study, investigating the level of asthma control in 2853 patients with asthma recruited in 56 respiratory clinics in Italy have been recently published [
6]. The main findings indicate that despite a high proportion of patients have controlled asthma, one third of patients are still uncontrolled or partly controlled. Previous studies were available evaluating the control of asthma but comprised smaller populations and with a less representative distribution throughout the country [
7‐
11]. In the PRISMA study, patients filled in validated questionnaires for asthma control and QoL measurement and data were collected during visits by respiratory specialists. In contrast, previous studies have collected data by telephone interviews [
7‐
9], web-based questionnaires [
11‐
13], or postal screening questionnaires [
14].
Moreover, all the above studies are cross-sectional but only prospective monitoring of patients’ asthma control using composite measures can describe how this reflect asthma outcomes and/or future risks [
5]. Unfortunately, no information is yet available on the rate of achievement of asthma control among poorly controlled asthma patients. It has been suggested that monitoring outcomes and taking appropriate action through regular visits may improve current levels of asthma control [
15]. Behavioral factors such as smoking and non-adherence may reduce the efficacy of treatment and patients' perceptions influence these behaviors. Under-treatment may also be related to patients' underestimation of the significance of symptoms, and lack of awareness of achievable control. There is a need to raise patient expectations by increasing awareness of the QoL that could be attained.
The aim of the present study was to measure asthma control in a prospective 12 months observation period in patients whose asthma was classified as uncontrolled or partly controlled in a cross-sectional phase visit [
6]. The prospective phase described in this manuscript aimed to evaluate the proportion of patients with uncontrolled or partly controlled asthma who achieve asthma control at 12 months. Secondary objectives were: to evaluate the reasons for lack of asthma control, perceived QoL and association with level of asthma control, the impact of pharmacological treatment, the number of exacerbations and the healthcare resource consumption.
Discussion
PRISMA is the first prospective observational study specifically designed to evaluate the proportion of patients achieving asthma control during a 1-year follow-up in real life conditions.
The main findings from this prospective study demonstrate that 22.2% of patients that previously had partly controlled or uncontrolled asthma (n = 739) achieved full asthma control after 1 year, 58.7% had controlled asthma, 11.8% had partly controlled asthma and 7.3% were still uncontrolled.
Among those patients who, after the 1-year follow-up, did not attain asthma control (n = 141), the reasons were anyway different, according to the physician assessment, from those at study start. Actually, when comparing the last visit of the prospective phase with the cross-sectional visit, reasons for lack of asthma control changed from lack of adequate therapy/follow-up/communication or smoking habits, i.e. all external factors that therefore can be improved by a better asthma care, to the presence of comorbidities. This finding suggests that during 1-year monitoring in real life conditions, an improvement in patient behavioral factors that contribute to the lack of asthma control such as adherence to medication, patient-doctor communication and follow up can be obtained. An additional observation coming from the present study is that the rate of outpatients visits, hospitalizations and emergency room visits was reduced approximately 3-fold by the end of the follow-up period. This is in line with the AIRE study that examined the use of healthcare resources in 7 European countries and showed that worse asthma control was associated with an increased requirement for unscheduled care and higher costs [
8].
Moreover, our findings indicate that asthma control can be achieved in a great proportion of patients treated with the ICS/LABA fixed combinations, which is in agreement with recent observational studies reporting the ICS/LABA combination being the most effective treatment choice [
19‐
21]. In a 12-month office-based observational study, patients recently started on FP/S combination, had significantly greater improvement in both asthma control and QoL, compared with patients newly started on montelukast [
20]. Another study with a 12-month real life observation period showed a greater change in asthma control score in FP/S treated patients compared to other forms of treatment that were in accordance with asthma treatment guidelines (including BUD/F but not including BDP/F extrafine) [
21]. We observed that a greater proportion of patients treated with extrafine BDP/F fixed combination achieved good asthma control and the maximum ACT score (i.e. full control) compared to either BUD/F or FP/S -treated patients, the difference being significant versus BUD/F. Moreover, the proportion of patients achieving a clinically meaningful change in ACT score (3 points) was greater in BDP/F treated patients compared to BUD/F treated patients. We considered only patients who had been on the same therapy in the last 4 weeks for the comparison of asthma control level among treatments to match with ACT that evaluates asthma control in the last 4 weeks.
As regards QoL assessed by EQ-5D, an improvement of approximately 21% was observed after 1 year in the whole population studied. When looking at patients treated with ICS/LABA fixed combinations, extrafine BDP/F-treated patients experienced significantly higher QoL compared to either BUD/F or FP/S-treated patients at the end of the 12-month observation period. These results are consistent with those obtained in the cross-sectional phase of the PRISMA study [
6] and may be attributed to the formulation of this combination, which is characterized by extrafine particles able to reach and treat the whole bronchial tree, including small airways [
22]. Indeed, asthma control and QoL correlate with functional parameters reflecting small airways function and improvements in ventilation heterogeneity are associated with improvements in symptoms [
23,
24].
A better asthma control with extrafine BDP/F combination compared to BUD/F and FP/S combinations was recently shown in two observational cross-sectional studies [
6,
25]. This is also confirmed by results from a recent observational study which showed that initiating or increasing therapy with an extrafine beclomethasone formulation results in similar or better asthma control compared with non-extrafine fluticasone [
26].
The evidence of improvement in asthma control and QoL in patients treated with extrafine formulations compared to large particles formulations is supported by randomized controlled trials (RCTs) [
27,
28]. Moreover, an RCT demonstrated that a greater asthma control was achieved in patients treated with extrafine BDP/F combination compared to the same drugs administered with separate inhalers delivering large particles [
29]. This evidence is particularly interesting when compared with similarly designed studies with the other two available combinations, as shown in a recently published review, thus supporting the concept of greater efficacy of BDP/F due to extrafine particles [
30].
The difference in asthma control was detected despite the lower ICS dose and the higher percentage of smokers in the BDP/F patient cohort. This is of particular interest since smoking is associated with an increased risk of poor control [
31,
32] and asthmatic smokers are less responsive to ICS therapy [
33,
34]. Our findings support the concept that the tobacco smoke-drug particle interactions, which contribute to drug resistance, are less likely to occur in case of extra-fine formulations [
35]. Together, these results suggest that asthmatic smokers can particularly benefit from extrafine BDP/F combination. This is also supported by a recently published prospective real-life study showing significant improvements in pulmonary function and asthma control in patients treated with extrafine BDP/F combination with the same treatment benefits observed in former or current smokers compared with non-smoking asthmatics [
36].
Someone may argue that the level of asthma control detected in the present study is quite high compared to the GOAL study in which patients were stepped up for a 1-year period to the highest recommended dose of FP/S combination [
37]. However, this difference can be explained by the different patient population, definition of control and way of measuring it. In the GOAL study only patients with uncontrolled asthma were recruited and the definition of control as from asthma international guidelines included lung function. Moreover, the definition of “total control” used in the GOAL study was very stringent (defined by achievement of all specified criteria for 7 weeks in each 8-week period) and now abandoned [
1,
2]. By contrast, the ACT used in the present study is a validated patient reported outcome [
4,
5,
16,
17] and does not include lung function which has been shown having minimal impact on the reliability, responsiveness, and both cross-sectional and prospective validity of the instrument [
38].
Observational studies present some limitations such as the possibility of unmeasured or unrecognized confounding factors or influences on prescribing. These results should be interpreted in light of the inherent limitations of non-randomized, uncontrolled studies. However, these limits are balanced by the broader applicability of observational real life data on larger and more representative patient populations with common co-morbidities and that can identify clinically important differences among treatments [
39]. By contrast, RCTs have limited external validity as they have been performed on highly selected patient populations and most of the participants currently under asthma treatment in the community are not represented [
40].
In conclusion, the main findings from this prospective phase of the PRISMA study demonstrate that an improvement in asthma control can be achieved during a 1-year monitoring in a real life setting. Furthermore, patients have improved QoL and reduced hospital visits. Fixed combination of extrafine BDP/F was associated with significant benefit in terms of asthma control and QoL compared to large-particles combinations, this advantage likely being attributed to the extrafine formulation.
Acknowledgements
Best enrollers (more than 70 patients enrolled) for PRISMA study were: C. Terzano (Policlinico Umberto I, Roma), M. Sofia (AORN Monaldi, Napoli), P. Menna (Ospedale Cristo Re, Roma), F. Pezzuto (Ospedale "Amico Gaetano Fucito"Mercato San Severino, Slaerno), V. Dipietro (Ospedale G.F. Ingrassia, Palermo), G. Girbino (Policlinico G. Martino, Messina).
Participants with significant contribution (>69 enrolled patients >51) were: P. Bosco (Centro Catanese di Medicina e Chirurgia, Catania), M. Sforza (ASL BAT Andria, Andria), D. Ansalone (Ospedale G. da Procida, Salerno), D. De Sanctis (Ospedale di Atri, Atri), G. Failla (Ospedale Regina Apostolorum, Albano Laziale, Roma), V. Formisano (Ospedale Civile, Maddaloni, Caserta), A. Pennisi (Casa di Cura MUSUMECI Gecas, Gravina, Catania), W. Castellani (Ospedale Careggi, Firenze), M. Papale (I.F.O. Regina Elena, Roma), E. Giua Marassi (Ospedale Pneumologico R. Binaghi, Cagliari), R. Perra (I.N.R.C.A. Centro per le Broncopneumopatie IRCCS, Cagliari), E. Piccolini (Ospedale Santo Spirito, Casale Monferrato, Alessandria), S. Privitera (Centro per la Prevenzione e il Monitoraggio per l'insufficienza respiratoria, Giarre, Catania), R. Tazza (ASL4 Terni, Terni), M. Manzella (Servizio Territoriale di Pneumologia, San Severo, Foggia), G. Simon (Az. Osp. Villa Sofia CTO, Palermo), E. Marchi (I.N.R.C.A. Centro per le Broncopneumopatie, Casatenovo, Lecco), M. Nalin (Ospedale Santa Maria degli Angeli, Pordenone), V. Roncoroni (Ospedale Valduce, Como).
Participants (>50 enrolled patients) were: F. Crismancich (Casa di Cura Pineta del Carso, Trieste), L. Ferramosca (Ospedale Civile Pispico, Poggiardo, Lecce), M. La Porta (Ospedale Ferro Branciforti Capra, Leonforte, Enna), N. Luzi (Ospedale Santo Spirito, Roma), B. Moscatelli (Ospedale San Giovanni Calibita FBF, Roma), S. Nardini (Ospedale Civile, Vittorio Veneto, Treviso), O. Resta (Policlinico Consorziale, Bari), P. Scavalli (Distretto 5 AUSL di Viterbo, Civita Castellana), A. Tubaldi (Ospedale di Macerata, Macerata), C. Zamprogna (Ospedale Amedeo di Savoia, Torino), A. Zedda (Ospedale S. Maria della Pietà Camilliani, Casoria, Napoli), V. Di Rienzo (ASL Frosinone, Frosinone), R. Numeroso (Casa di Cura Clinica San Carlo, Paderno Dugnano, Milano), E. Berardi (Ospedale M. Bufalini, Cesena), A. Scaramozzino (Policlinico Madonna della Consolazione, Reggio Calabria), G. Cremona (Istituto Scientifico San Raffaele, Milano), M. Torlasco (Ospedale Civile, Voghera), M. P. Foschino (Ospedale D'Avanzo, Foggia), O. Guarino (Ospedale S. Pietro Fatebenefratelli, Roma), G. Idotta (Ospedale Civile, Cittadella, Padova), R. Capra (Azienda Ospedaliera di Parma, Parma), L. Donateo (Azienda Unità Sanitaria Locale Lecce), M. Naldi (Ospedale San Donato, Arezzo), L. Bartolucci (Ospedale Narni-Amelia, Narni), V. Valenti (Policlinico San Donato, San Donato M.se), P. Rottoli (Az. Osp. Univ. Senese, Policlinico Le Scotte, Siena), P. Candoli (Ospedale Umberto I, Lugo, Ravenna), A. Moretti (Ospedale Sant' Andrea, La Spezia), M. Bevilacqua (Ospedale Civile CPO, Ostia, Roma), G. Cocco (A.O.R.N. A. Cardarelli, Napoli), R. Aquilina (Ospedale Unificato d'Imperia, Imperia).
The authors thank Medidata for data collection and analysis and Dr Selene Mogavero and Dr Colin G. Egan (Primula Multimedia) who provided skilful editorial assistance.
Competing interest
Giovanni Cremonesi: Employee of Chiesi Farmaceutici S.p.A, Eleonora Ingrassia: Employee of Chiesi Farmaceutici S.p.A, Gabriele Nicolini: Employee of Chiesi Farmaceutici S.p.A, Luigi Allegra: Consultant fees: GSK (I), Astrazeneca (I), Chiesi (I), Boehringer Mannheim (I), Zambon (I), IBSA (CH), Procter & Gamble (UK), Cotherix (USA). Reimbursements for attending a symposia: GSK (I), Astrazeneca (I), Chiesi (I), Boehringer Ingelheim (I), Eurodrug NL) Angelini (I). Fees for speaking: Menarini (I), Boehringer Ingelheim (I), IBSA (CH), Eurodrug (NL). Funds for research: Angelini (I). Funds for members of staff: Cotherix (USA) Exalee (USA), IBSA (CH). All other authors declare no competing interest.
Authors' contributions
All of the authors contributed to the definition of the study protocol, data interpretation and writing of the manuscript. All of the authors read and approved the final manuscript