www.nature.com/npjpcrm ARTICLE OPEN Prevalence of modifiable factors limiting treatment efficacy of poorly controlled asthma patients: EFIMERA observational study Paula Ribó 1,2,3 ✉, Jesús Molina 4 , Myriam Calle 5,6,7 , Luis Maiz8, Carlos Campo9, Paula Rytilä10, Vicente Plaza 3,11,12,13,14 and Antonio Valero1,2,3,14 Several modifiable factors leading to poor asthma control have been described. We aimed to determine the proportion of patients with inadequate treatment, adherence to it, or critical mistakes with inhaler technique, and their impact on asthma control. We conducted a cross-sectional multicenter observational study including asthma patients referred from primary to specialist care for the first time. Data collected were adequate prescription according to guidelines, treatment adherence, and disease control. Of the 1682 patients (age 45 ± 17 years, 64.6% men), 35.9% showed inadequate prescription, 76.8% low adherence, and 17% critical mistakes with inhaler technique, with significantly less critical mistakes among Easyhaler users versus other dry powder inhaler users (10.3 versus 18.4%; p < 0.05). Factors related to bad asthma control were inadequate prescription (OR: 3.65), non-adherence to treatment (OR: 1.8), and inhaler misuse (OR: 3.03). A higher number of risk factors were associated with a higher probability of 1234567890():,; having badly controlled asthma. npj Primary Care Respiratory Medicine (2020)30:33 ; https://doi.org/10.1038/s41533-020-00189-6 INTRODUCTION The same situation is reflected in primary care management of Asthma is a common disease and it accounts for considerable asthma. Several studies about asthma in primary care seem to healthcare costs and loss of work productivity1. Its prevalence is suggest that asthma control in clinical practice is suboptimal increasing worldwide: nearly 1000 people die from asthma every despite available therapies. During the past years, little apparent day according to a study published in 20152. Latest data about improvement in symptom control has been documented by asthma global prevalence estimate that it affects 334 million European publications10,11. people globally3. However, its prevalence varies greatly between The primary objectives of this study are to (1) determine the countries with the highest prevalence seen in developed ones1. appropriateness of prescribed treatment as well as the presence of High direct (medications, hospitalization, Emergency Department poor adherence and critical mistakes in the inhalation technique care, etc.) and indirect (school absenteeism, loss of work in patients referred from primary care to a specialist for the first productivity, etc.) costs are especially linked to exacerbations3. time; and (2) to study the relationship between these factors and Currently, asthma exacerbations are one of the most frequent poor asthma control. This real-life study may allow us to explore causes of Emergency Department4 visits emphasizing the poor whether asthma management in primary care has improved in control of asthma in affected patients. Many factors can trigger an terms of quality of prescription, inhaler technique, and patients’ exacerbation5: exposure to external factors, poor adherence to adherence to treatment, 30 years after the implementation of treatment, inadequate therapy, and poor inhaler technique are asthma guidelines in Spain. among the most important modifiable causes in the case of uncontrollable asthma6. Several studies have demonstrated poor treatment adherence in asthmatic patients: <50% in children and RESULTS 30–70% in adults, depending on the country, age, sex, and The number of patients enrolled in the study was 1682, of whom ethnicity7,8. The reasons for this variation were limited compre- 64.6% were men. The mean age was 45 ± 17 years. The hension or recognition (among patients and/or physicians), beliefs characteristics of the cohort are shown in Table 1. or side effect concerns, inhaler characteristics, and instructions for their use. Frequently, the key aspect of poor asthma control is that many patients, especially with mild to moderate asthma, are Modifiable factors associated with asthma control undertreated6. According to Global Initiative for Asthma (GINA) recommenda- Thus asthma control as a therapeutic goal, is far from being tions, 35.9% of patients had an insufficient or inadequate achieved9. Better control would improve not only cost effective- prescription (Table 2). In order to assess whether the prescription ness but also quality of life, reduce school absenteeism, and were adequate or not, GINA 1–5 steps were taken into account. increase work productivity as well3. Patients’ maintenance treatment were compared with their 1 Allergology Section, Pulmonology and Allergy Department, Hospital Clínic de Barcelona, Barcelona, Spain. 2Grup d’Inmunoal·lèrgia Respiratoria Clínica i Experimental (IRCE), Institut d’investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Barcelona, Spain. 3Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. 4Family Medicine Department, Centro de Salud Francia, Fuenlabrada, Madrid, Spain. 5Pulmonology Departament, Hospital Clínico San Carlos, Madrid, Spain. 6Medicine Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. 7Instituto de Investigación Biomédica, Hospital Clínico San Carlos (IdISSC), Madrid, Spain. 8Pulmonology Department, Hospital Ramón y Cajal, Madrid, Spain. 9Orion Pharma, Madrid, Spain. 10Orion Corporation Orion Pharma, Espoo, Finland. 11Respiratory Medicine Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Institut d’Investigació Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain. 13 Medicine Department, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. 14These authors contributed equally: Vicente Plaza, Antonio Valero. ✉email: ribo@clinic.cat Published in partnership with Primary Care Respiratory Society UK P Ribó et al. 2 Table 1. Baseline demographic and clinical characteristics. Table 2. Prevalence of modifiable factors associated with asthma control. Variable Results Number of patients Factor n (%) Number of patients evaluated evaluated Inadequate prescription (GINA) Age (years), mean ± SD (range) 45.2 ± 17.9 (18–90) 1681 Yes 604 (35.9) 1681 Females, n (%) 592 (35.4) 1670 No 1077 (64.1) 1681 Males, n (%) 1078 (64.6) 1670 Adherence according to Morisky–Green questionnaire Age at diagnosis (years), 33.8 ± 15.7 1682 Adherent 522 (31.5) 1658 mean ± SD Non-adherent 1136 (68.5) 1658 Disease duration (years), 14.9 ± 14.1 1682 mean ± SD Adherence according to TAI Time between treatment 1.1 ± 6.6 1677 Adherent 381 (23.2) 1639 initiation and diagnosis (years), Non-adherent 1258 (76.8) 1639 mean ± SD Critical inhaler mistakes Current smokers, n (%) 263 (15.7) 1678 No errors 1394 (83.0) 1680 Ex-smoker, n (%) 294 (20.8) 1414 ≥1 error 286 (17.0) 1680 Any allergy, n (%) 665 (39.8) 1671 GINA Global Initiative for Asthma, TAI Test of Adherence to Inhalers. Any comorbidity, n (%) 841 (50.4) 1668 Obesity, n (%) 242 (14.5%) 1668 Rhinosinusitis, n (%) 190 (11.4%) 1668 exacerbations in the past and their current symptoms, in order to Rhinitis/conjunctivitis, n (%) 313 (18.8%) 1668 decide whether the treatment was adequate or not, according to 1234567890():,; these 5 GINA steps. Among these patients with inadequate Gastroesophageal reflux 149 (8.9%) 1668 disease, n (%) prescription, 82.5% had a poorly controlled (partly/uncontrolled) asthma (according to the Asthma Control Test (ACT)), whereas Other comorbidities, n (%) 268 (16.1) 1668 56.3% of patients with adequate treatment had poorly controlled Predicted FEV1 (or personal best PEF value), n (%) asthma (odds ratio (OR) 3.65, 95% confidence interval (CI): ≥80% 1042 (62.3) 1673 2.87–4.65, p < 0.0001; Table 3). <80% 507 (30.3) 1673 Regarding adherence to treatment, 76.8% of patient had a low <60% 124 (7.4) 1673 adherence measured by the Test of Adherence to Inhalers (TAI) questionnaire and 68.5% by the Morisky–Green (MG) question- Categories of asthma severity (2015 GINA), n (%) naire (Table 2). Moreover, 68.8% of patients with poor adherence Mild 719 (42.9) 1674 had poorly controlled asthma (according to the ACT), whereas Moderate 780 (46.6) 1674 55.1% had poorly controlled asthma despite good adherence (OR Severe 175 (10.5) 1674 1.8, 95% CI: 1.42–2.27, p < 0.0001; Table 3). Level of asthma symptom control (2015 GINA) As measured by the extended TAI test, almost 17% of the patients had at least one of critical error (errors in the use of the Well controlled 474 (28.2) 1679 a device that compromise the effectiveness of inhaled treatment) in Partly controlled 635 (37.8) 1679 inhaler technique (Table 2); among patients with critical mistakes, a Uncontrolled 570 (33.9) 1679 83.2% had poorly controlled asthma (according to the ACT), versus Current treatments, n (%) 62.1% with poorly controlled asthma and no critical inhaler errors Only maintenance inhaler 492 (29.6) 1662 (OR 3.03, 95% CI: 2.18–4.21, p < 0.0001; Table 3). A different percentage of misuse depending on the device was a pressurized Only rescue inhaler 357 (21.5) 1662 metered-dose inhaler (pMDI) or dry powder inhaler (DPI) was Maintenance inhaler + rescue 468 (28.2) 1662 observed. Significantly less critical mistakes were found in inhaler Easyhaler (EH) users versus other DPI ones (Table 4), (EH: 10.3%; Maintenance inhaler + oral 78 (4.7) 1662 other DPI: 18.4%; p < 0.05): 10.3% of patients showed critical errors treatment with EH, 19.5% with Accuhaler, 16.0% with Nexthaler, and 17.5% Rescue inhaler + oral 40 (2.4) 1662 with Turbuhaler (p < 0.01). As a consequence (Table 4), a treatment significant lower need to technique adjustment was observed in Maintenance inhaler + rescue 206 (12.4) 1662 EH users compared to other DPI ones (p < 0.0001; Table 4). inhaler + oral treatment Monoclonal antibodies 23 (1.4) 1662 Asthma control Type of maintenance inhaler device, n (%) Regarding asthma control, 71.7% of patients had a poorly Multiple-dose DPI 935 (75.2) 1244 controlled asthma according to the GINA criteria and 65.7% pMDI 240 (19.3) 1244 according to ACT test. Several factors were shown to be related with poor asthma control according to the GINA criteria and the Single-dose DPI 26 (2.1) 1244 ACT test (Table 3): inadequate prescription (GINA: OR 8.05, 95% CI: pMDI + multiple-dose DPI 39 (3.1) 5.74–11.27; ACT: OR 3.65, 95% CI: 2.87–4.65), poor adherence to pMDI + single-dose DPI 4 (0.3) 1244 treatment (GINA: OR 1.58, 95% CI: 1.23–2.03; ACT: OR 1.8, 95% CI: DPI dry powder inhaler, FEV1 forced expiratory volume in 1 s, GINA Global 1.42–2.27), and inhaler misuse (GINA: OR 4.76, 95% CI: 3.08–7.34; Initiative for Asthma, PEF peak expiratory flow, pMDI pressurized metered- ACT: OR 3.03, 95% CI: 2.18–4.21). dose inhaler. Each one of these risk factors (inadequate prescription, poor a Poorly controlled. adherence, and inhaler misuse) has a statistically significant impact on poor asthma control (p < 0.0001; Table 3). npj Primary Care Respiratory Medicine (2020) 33 Published in partnership with Primary Care Respiratory Society UK P Ribó et al. 3 Table 3. Relation between asthma control by ACT criteria and modifiable factors associated with poor control. Modified factor Control (ACT criteria) OR (95% CI) n (%) p Poor Good Prescription Inadequate (A) 498 (82.5%) 106 (17.5%) 3.65 (2.87–4.65) 604 (36) <0.0001 Adequate 606 (56.3%) 471 (43.7%) 1077 (64) Adherence (TAI) Poor (B) 866 (68.8%) 392 (31.2%) 1.80 (1.42–2.27) 1258 (74.7) <0.0001 Good 210 (55.1%) 171 (44.9%) 381 (22.7) Critical mistakes One or more (C) 238 (83.2%) 48 (16.8%) 3.03 (2.18–4.21) 286 (17.0) <0.0001 None 865 (62.1%) 529 (37.9%) 1394 (83.0) A+B 399 (85.2%) 69 (14.8%) 4.16 (3.14–5.50) 468 (27.8) <0.0001 A+C 119 (90.1%) 13 (9.9%) 5.23 (2.92–9.36) 132 (7.8) <0.0001 B+C 202 (84.9%) 36 (15.1%) 3.36 (2.32–4.86) 238 (14.1) <0.0001 A+B+C 101 (93.5%) 7 (6.5%) 8.23 (3.80–17.83) 108 (6.4) <0.0001 ACT Asthma Control Test, TAI Test of Adherence to Inhalers. Table 4.Number of critical mistakes and need of technique these misconceptions on the adherence to treatment, when the adjustment according to DPI device. impact of asthma knowledge on asthma control was evaluated, it was found to be an independent predictor of asthma poor control DPI device Critical technique Need of technique Number of (Fig. 2) according to the ACT criteria. mistakes, n (%) adjustment, n (%) patients evaluated DISCUSSION Accuhaler 30 (19.5) 106 (68.8) 154 Despite years of asthma guidelines implementation, in this study Easyhaler 13 (10.3) 43 (34.4) 126 poor asthma control remained strongly associated with modifiable Nexthaler 17 (16.0) 52 (51.5%) 106 features related with therapy failure. Although many factors could Turbuhaler 36 (17.5) 120 (58.3%) 206 be involved in poor asthma control, three factors seem to be the main causes of poor asthma control in primary care, according to DPI dry powder inhaler. previous publications5,12: inadequate prescription, poor adherence to treatment, and poor inhaler technique6,9,13–15. Obesity has a negative impact in asthma, and there are preliminary data Moreover, a higher number of risk factors was related to a showing the benefit of weight reduction on asthma control and higher probability of having a poorly controlled asthma, reaching quality of life16. However, recommendation of diet-induced a maximum of 93% with the ACT and 100% with the GINA, if all weight loss in asthma patients is related with the plethora of three conditions were present, and 46% with the ACT and 54% general health benefits17, but it has insufficient evidence yet on with the GINA if none was present. asthma control18; for that reason, authors did not include this The control of asthma according to the GINA score compared to factor into the modifiable ones. the ACT questionnaire score showed a moderate concordance In our study, 71.7 and 65.7% of patients (according to the GINA (Kappa = 0.458; Rho = 0.709; r2 = 0.503). The corresponding tables and the ACT, respectively) showed a poor control of symptoms. for the GINA asthma control that are quite similar to the ACT Several studies have been conducted in primary care during the control are shown in Supplementary Tables 1 and 2 and past years, with different measurable variables and design16. Supplementary Figs 1 and 2. Despite their heterogeneity, all showed the same tendency toward poor asthma control. In a recent Spanish publication, Asthma knowledge questionnaire Calvo et al.19 found poor asthma control (ACT ≤ 20) ranging from Regarding the asthma knowledge questionnaire, the problematic 23.4 to 75.6% in 638 asthmatic patients, depending on the questions seemed to be related to asthma treatment during both patients’ medical consultation. On average, almost half of the exacerbation and remission periods (Fig. 1): only 17.8% of patients patients showed poor control. The authors of another study20 knew that bronchodilators are not the main asthma treatment, have estimated that 45% of asthmatic patients who received any and less than half of the patients knew that maintenance type of treatment in Spain had no controlled asthma (ACT ≤ 19). treatment must be continued during remission periods. Despite Asthma control in other European countries is also not encoura- less than half of the patients knew the correct use of anti- ging: a recent Swedish study in primary care calculated that 53.6% inflammatory drugs, >60% of them knew that it should be used of patients had no controlled asthma (≥600 doses of short-acting not only during crisis, because they knew that asthma is an beta agonists and/or ≥1 exacerbations/year)21. In the European inflammatory disease. More than 80% of patients knew that LIAISON study22, asthma control was assessed according to the asthma is a chronic disease, and 70% of them knew that they Asthma Control Questionnaire: the percentage of patients with could practice sports and could suffer no symptoms. But most of partly or not controlled asthma was 56.5 across 12 countries that them live with a poor controlled (and consequently symptomatic) participated in the study. In USA, the situation is similar: 50% of asthma (as discussed above). Despite the undoubted impact of patients who attended primary care for a non-respiratory Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2020) 33 P Ribó et al. 4 Bronchodilators are not the main treatment When you are asymptomac, you cannot stop an-inflammatory drugs An-inflammatory drugs should not be used only with crisis Inflammaon is asthma main feature It is a illness with no recovery You can suffer no symptoms You can pracce sports Every paent has different symptoms Asthma is a cronic illness You must always take along bronchodilator drugs 0 10 20 30 40 50 60 70 80 90 Fig. 1 Asthma knowledge questionnaire. Percentage of correct responses to asthma knowledge questionnaire (self-administered). consultation had non-controlled asthma (ACT < 19)23. Most of review frequently the inhaler usage technique as well as patient studies show slightly lower percentage of poorly controlled adherence in every visit. Also electronic reminders should be used patients compared with our study, which probably could be as they can be very effective29,30,32,33. In primary care, it has been related with selection bias as the patients referred to specialized established that an educational program could be effective in care are not expected to be asymptomatic. terms of improving adherence, controlling, and reducing costs. More than one-third of our patients, at the time of referral from The program should involve medical practitioners as well as primary care, had an inadequate treatment, which was associated nursing services, after an adequate training is given34. with a less adequate asthma control. Both providers and patients Regarding the third important factor responsible for poorly are prone to underestimate asthma severity, which can be the controlled asthma, inadequate inhaler technique, this study reason why many patients might be undertreated9. showed that 17% of the patients referred from primary care The lack of time and economical resources are some of the make critical mistakes, and it is directly related to bad asthma causes of not a fully satisfactory management of asthma in the control (GINA OR 4.76; ACT OR 3.03). Serious mistakes with inhaler primary care setting24, although it is well known that a bad technique can be defined as errors potentially limiting the drug diagnosis and treatment suppose a detriment to the patients’ uptake and its distribution to the lungs12. In some studies, the health25, which in turn increase care demand and health costs. In percentage of critical errors is higher than the one in our study this sense, the ACT was created as a tool to detect poorly (ranging from 50 to 90%)35; however, without a doubt this step controlled asthma and, as a consequence, to identify those remains crucial in order to achieve asthma control. It has been patients who require the most adequate treatment. It has been established that a poor inhaler technique is associated with more shown that it allows a better treatment adjustment when the symptoms36, more need for hospitalization12, and definitely a less physician uses it routinely26. effective asthma control. In a Dutch study, between 47.7 and The best strategy to evaluate adherence are electronic devices27 64.9% of patients referred to primary care presented inhaler that could be the gold standard8,28 (they are an objective method misuse; a pragmatic intervention showed a significant improve- to assess patients’ adherence), but they are expensive and difficult ment of this factor37. to use for many patients. Thus self-reports seem to be the most The percentage of serious errors differs significantly among cost-effective measure to assess it7, although patients are hesitant inhaler devices. In our study, patients showed a better perfor- to report poor adherence in some occasions29. In this study, two mance with the DPI devices versus the MDIs, as expected. Among adherence questionnaires were used, and the TAI questionnaire the DPIs, EH was associated with a lower number of critical errors seems to have more sensitivity than the MG one (76 and 68.5%, compared to other devices (Turbuhaler, Nexthaler, Accuhaler). This respectively, have a poor adherence). Also it is shown that the TAI finding is supported by previous studies that demonstrated better has a better correlation with patient real adherence30. Moreover, acceptance and satisfaction with the EH device38,39. In addition, when asthma control is compared according to the ACT several studies suggest that an explanation regarding the inhaler punctuation and the GINA criteria, a statistically significant use and a practical demonstration of patient skills with the relationship with poor adherence (ACT OR 1.8; GINA OR 1.58) is apparatus, as well as by taking into consideration patients’ found. Similarly, in the REcognise Asthma and LInk to Symptoms preferences, could improve satisfaction with the inhaler and and Experience (REALISE) study11, almost 50% of patients showed usage technique that consequently may result to a better asthma a poor adherence to treatment, and in the LIAISON study a higher control12,14,36,40,41. For instance, some publications advocate for rate of low adherence (according to the MG) was present in providing an explanation of inhaler technique at the Emergency patients with poorly controlled asthma, compared to the ones Department, before patient discharge42. with controlled asthma22. To stress the importance of a good Inadequate prescriptions, adherence to treatment, and inhaler adherence, it should be mentioned that its absence is linked to a technique overall contribute to the fact that 73.3% of patients higher risk of asthma exacerbations, increased use of oral have poorly controlled asthma (according to the GINA criteria) or corticosteroids, need of Emergency Department attendance and/ 65.7% according to the ACT questionnaire. As mentioned above, or hospitalization, deterioration of forced expiratory volume in 1 s these 3 parameters are essential for asthma control5,6,9,24, and this values29,31, and finally higher costs and poor quality of life7. control becomes worse as more risk factors are present, ranging Strategies to improve adherence have been explored, such as to from 58.4% of poor control (ACT ≤ 20) when one condition is npj Primary Care Respiratory Medicine (2020) 33 Published in partnership with Primary Care Respiratory Society UK P Ribó et al. 5 Female Older Inadequate/insuficient prescripon No adherence (TAI < 50) Inhaler technique mistakes Poor asthma knowledge Predicted FEV1 < 80% Predicted FEV1 < 60% Obesity Rhinosinusis Persistent mild asthma Persistent moderate asthma Persistent severe asthma 0.10 1 10 Favouring beer control Favouring poor control Fig. 2 Binary logistic regression model with poor asthma control (ACT < 21) as dependent variable. This figure represents factors associated with poor asthma control. implicated to 93.5% when all conditions are present (or 54–100% improve outcomes and cost-effectiveness as it was demonstrated with the GINA criteria). Our study seems to confirm such a by the Finnish program34. concordance between the ACT and the GINA criteria regarding There are several limitations in this study. No reason for asthma control, although the GINA could identify a higher number patients’ referral from primary care to pneumologist or allergol- of undercontrolled patients than the ACT. ogist was recorded, which could create a bias during patients’ Results regarding asthma knowledge and understanding are not selection. Furthermore, in primary care all tools of GINA treatment encouraging, and they are remarkable factors of asthma poor control: steps are not available, so patients with severe asthma hardly most patients believe that bronchodilators are the main treatment in would be well controlled at primary care. Patients were enrolled managing asthma and that the anti-inflammatory treatment can be during a relatively short period of time (from September to stopped during remission periods. When asthma understanding is December): patients with seasonal respiratory symptoms, due to a analyzed as predictive factor of asthma poor control through a binary specific allergy profile, were not enrolled in the study. In this study, logistic regression, it seems to be an independent predictor of asthma the ACT cut-off point was established at 21, while it was fixed at control. These concerns probably influence patients’ adherence: in the 19–20 in other studies. An overestimation of asthma poor control REALISE study11 half of the patients did not take correctly their could be present in this study. Regarding critical mistakes, maintenance medications, and among patients with poor control assessing inhaler technique may be challenging because some 50% did not take maintenance medication as prescribed because aspects of the technique are subjective, such as “synchronization they thought it was not necessary. In another study10, almost 50% of between actuation and inhalation” when evaluating pMDI devices patients believed that their asthma was well controlled, even when or “inhale deeply” when evaluating DPI devices. However, the they had severe and persistent symptoms. Educational interventions investigators who assessed inhaler technique were well trained could improve patients’ knowledge and consequently their adher- and had lots of experience educating patients; therefore, we think ence to treatment. that the reliability of inhaler technique evaluation is good. In This study aims to determine the proportion of patients with addition, the use of pMDI with spacer devices was not evaluated. inadequate treatment and offer an updated insight into modifi- However, the use of a spacer is generally recommended for able factors involved in asthma control at primary care level. children and older people, and its use is not common in adults43. Because results are different in clinical trials and real life, as it has Finally, study population is heterogeneous regarding comorbidity, been widely shown28, we tried to use modern tools to verify previous diagnostic and treatment, and habits. Although this whether recent advances in asthma management provided any heterogeneity lies closer to real life, it is s not easy to extrapolate changes in the preventable factors associated with asthma these results to a concrete population. Anyway, the aim of the control. The result is not especially encouraging: although current study is not to criticize primary care management of nowadays good recommendations for asthma control are asthmatic patients but to get a picture of referred asthmatic provided, in real life this aim is far from been achieved, and an patients’ condition. underestimation of risk appears critical between primary care Our results suggest that poor asthma management, adherence physicians and their patients. Maybe educational programs with to treatment, inhaler technique, and poor asthma knowledge the aim to improve recognition of the importance of adherence to constitute, at primary care level, critical factors resulting in a proper, early, and sustained therapy and good inhaler technique reduced asthma control. Many patients do not receive adequate for improving asthma control, as well as knowledge of asthma as treatment and adherence to therapy is poor when referred to a chronic illness, should be taken into consideration. The mean Specialist. In addition, patients showing critical mistakes in the problem about improving asthmatic patients’ education by inhaler technique is a frequent finding. physicians and nurses is probably the lack of time addressed to This study demonstrates that there is yet room for improvement this aim, especially in some Health Care Systems. This is a common by acting on these modifiable factors that appear as key problem in chronic diseases. Probably, the first step could be the opportunities for the improvement of asthma management at obligatory establishment of a time addressed only to education to primary care level by optimizing therapy, retraining on inhaler the knowledge of asthma disease and the correct use of the technique and asthma knowledge, and developing new tools to devices for its treatment. These kinds of interventions could improve adherence to treatment. Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2020) 33 P Ribó et al. 6 METHODS REFERENCES Study design and participants 1. To, T. et al. Global asthma prevalence in adults: findings from the cross-sectional A cross-sectional multicenter observational study was conducted in world health survey. BMC Public Health 12, 204 (2012). patients aged ≥18 years who made use of any type of inhaler device 2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and and were referred from primary care to a pneumologist or allergologist for national age-sex specific all-cause and cause-specific mortality for 240 causes of the first time for every kind of reason. Data were collected from September death, 1990-2013: a systematic analysis for the Global Burden of Disease Study to December 2016. Exclusion criteria were the lack of a signed informed 2013. Lancet 385, 117–171 (2015). consent and incapacitating illness or mental disease, making the 3. Nguyen, H. V. et al. Association between asthma control and asthma cost: Results participation to the study, according to the research criteria, difficult. All from a longitudinal study in a primary care setting. Respirology 22, 454–459 patients were undergone to a spirometry and a bronchodilator test in (2017). order to confirm/exclude asthma diagnose. 4. Rui, P., Kang, K. & Ashman, J. J. National Hospital Ambulatory Medical Care Survey: 2016 emergency department summary tables. https://www.cdc.gov/nchs/data/ nhamcs/web_tables/2016_ed_web_tables.pdf (2016). Study measurements 5. Dougherty, R. H. & Fahy, J. V. Acute exacerbations of asthma: epidemiology, The following main variables were assessed: appropriate asthma treatment biology and the exacerbation-prone phenotype. Clin. Exp. Allergy 39, 193–202 according to the GINA recommendations44 (GINA treatment steps 1–5 (2009). were used to assess the appropriateness of current patients’ treatment, 6. Menzies-Gow, A. & Chiu, G. Perceptions of asthma control in the United Kingdom: according to asthma control at the visit time. For this evaluation, GINA a cross-sectional study comparing patient and healthcare professionals’ per- criteria of asthma control were used, as explained below), treatment ceptions of asthma control with validated ACT scores. NPJ Prim. Care Respir. Med. adherence according to the MG questionnaire (patients were classified into 27, 48 (2017). reliable or not reliable according to a punctuation from 0 to 4, in which 7. Engelkes, M., Janssens, H. M., de Jongste, J. C., Sturkenboom, M. C. J. M. & Ver- 0 = reliable and ≥1 = not reliable), adherence to inhalers (TAI ≥ 50 reliable; hamme, K. M. C. Medication adherence and the risk of severe asthma exacer- <50 not reliable)45,46, and critical errors with patient inhaler technique46 bations: a systematic review. Eur. Respir. J. 45, 396–407 (2015). identified through item 12 of the TAI questionnaire. Only the main inhaler 8. Boulet, L.-P., Vervloet, D., Magar, Y. & Foster, J. M. Adherence: the goal to control for maintenance therapy was evaluated. This item consists of a practical asthma. Clin. Chest Med. 33, 405–417 (2012). demonstration of patients’ inhaler technique, in addition to discover 9. Lang, D. M. Severe asthma: epidemiology, burden of illness, and heterogeneity. critical errors by the physician. This item shows 2 categories of patients: Allergy Asthma Proc. 36, 418–424 (2015). with ≥1 or without critical errors. Additional patient knowledge about 10. Rabe, K. F., Vermeire, P. A., Soriano, J. B. & Maier, W. C. Clinical management of asthma was evaluated through a questionnaire from the GEMA educa- asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur. tional material47 (Supplementary Table 3). Respir. J. 16, 802–807 (2000). The following clinical data were collected: asthma severity according to 11. Price, D., Fletcher, M. & van der Molen, T. Asthma control and management in the 2015 GINA criteria44, comorbidities (allergy, occupational exposure to 8,000 European patients: the REcognise Asthma and LInk to Symptoms and allergens or irritants, smoking, etc.), and asthma control according to both Experience (REALISE) survey. NPJ Prim. Care Respir. Med. 24, 14009 (2014). GINA and ACT criteria44,48. According to GINA, these items were taken into 12. Westerik, J. A. M. et al. Characteristics of patients making serious inhaler errors account: patients’ day/nighttime symptoms (<2 times/week daytime with a dry powder inhaler and association with asthma-related events in a pri- symptom and no nighttime symptoms), treatment to relieve symptoms mary care setting. J. Asthma 53, 321–329 (2016). (<2 times/week), and no activity limitations in the past 4 weeks. Thus 13. Van Ganse, E. & Price, D. Respiratory medication adherence: toward a common patients were classified into 2 categories: well controlled (with all previous language and a shared vision. J. Allergy Clin. Immunol. Pract. 4, 799–801 (2016). items), partially/not controlled (with 1–4 of previous items). According to 14. Walia, M. et al. Assessment of inhalation technique and determinants of incorrect the ACT, patients were classified into the same 2 categories, but in this performance among children with asthma. Pediatr. Pulmonol. 41, 1082–1087 case established through 5 items of the ACT validated Spanish version (2006). (≥21: well controlled, <21: partially/not controlled). Patients having a body 15. Boulet, L.-P. et al. Benefits of an asthma education program provided at primary mass index >30 were diagnosed as obese. care sites on asthma outcomes. Respir. Med. 109, 991–1000 (2015). All data were collected in a single visit, through an online patient 16. Peters, U., Dixon, A. E. & Forno, E. Obesity and asthma. J. Allergy Clin. Immunol. notebook, proportioned to the needs of the study. Ethics Committee 141, 1169–1179 (2018). permission (Hospital Clinic de Barcelona, Registration number HCB/2016/ 17. Özbey, Ü. et al. The effects of diet-induced weight loss on asthma control and 0647) was obtained, and the study was performed according to the Helsinki quality of life in obese adults with asthma: a randomized controlled trial. J. Declaration (1964). Informed consent was obtained from all participants. Asthma 57, 618–626 (2020). 18. Stoodley, I., Williams, L., Thompson, C., Scott, H. & Wood, L. Evidence for lifestyle interventions in asthma. Breathe (Sheff.) 15, e50–e61 (2019). Statistical analysis 19. Calvo, E., Trigueros, J. A., López, A. & Sánchez, G. [Asthma control in patients attending Statistical inference was analyzed with the Pearson’s chi-squared test (χ2) primary care in Spain (Actis study)]. Aten. Primaria 49, 586–592 (2017). for categorical data and with analysis of variance test for continuous data. 20. Demoly, P. et al. Prevalence of asthma control among adults in France, Germany, A binary logistic regression was used in order to establish the Italy, Spain and the UK. Eur. Respir. Rev. 18, 105–112 (2009). independence of detected factors (OR). Relationship and concordance 21. Larsson, K. et al. Prevalence and management of severe asthma in primary between ACT/GINA about asthma control were expressed through Cohen’s care: an observational cohort study in Sweden (PACEHR). Respir. Res. 19, 12 k coefficient, Spearman’s correlation coefficient, and R square (R2). All data (2018). were analyzed with SPSS 20.0 version. 22. Braido, F. et al. Determinants and impact of suboptimal asthma control in Europe: The INTERNATIONAL CROSS-SECTIONAL AND LONGITUDINAL ASSESSMENT ON ASTHMA CONTROL (LIAISON) study. Respir. Res. 17, 51 (2016). Reporting summary 23. Mintz, M. et al. Assessment of asthma control in primary care. Curr. Med. Res. Opin. Further information on research design is available in the Nature Research 25, 2523–2531 (2009). Reporting Summary linked to this article. 24. Rank, M. A., Bertram, S., Wollan, P., Yawn, R. A. & Yawn, B. P. Comparing the Asthma APGAR system and the Asthma Control TestTM in a multicenter primary care sample. Mayo Clin. Proc. 89, 917–925 (2014). DATA AVAILABILITY 25. Pakhale, S., Sumner, A., Coyle, D., Vandemheen, K. & Aaron, S. (Correcting) mis- The data that support the findings of this study are available from CLEVER RESEARCH diagnoses of asthma: a cost effectiveness analysis. BMC Pulm. Med. 11, 27 (2011). but restrictions apply to the availability of these data, which were used under license 26. García-Giralda, L., Quiralte Enríquez, J., Sánchez Herrero, M. G., López Peral, J. C. & for the current study, and so are not publicly available. Data are, however, available Aracil, J. [Impact of administering the Asthma Control Test questionnaire on from the authors upon reasonable request and with permission of ORION PHARMA. rating asthma control in primary health care]. Aten. Primaria 45, 522–527 (2013). 27. Weinstein, A. G. Improving adherence to asthma therapies. Curr. Opin. Pulm. Med. 21, 86–94 (2015). Received: 24 June 2019; Accepted: 7 July 2020; 28. Vrijens, B. et al. What we mean when we talk about adherence in respiratory medicine. J. Allergy Clin. Immunol. Pract. 4, 802–812 (2016). npj Primary Care Respiratory Medicine (2020) 33 Published in partnership with Primary Care Respiratory Society UK P Ribó et al. 7 29. Anderson, W. C. Incorporating technology to advance asthma controller adher- Guerra Ramos, Jose Antonio Gutierrez Lara, Helena Hermida Clarena, Francisco Javier ence. Curr. Opin. Allergy Clin. Immunol. 17, 153–159 (2017). Hernandez Arbeiza, Miguel Angel Hernandez Mezquita, Rosana Hernando Salvador, 30. Bidwal, M., Lor, K., Yu, J. & Ip, E. Evaluation of asthma medication adherence rates Miguel Herrerias Peña, Maria Belen Herrero Gonzalez, Hemily Katerine Izaguirre and strategies to improve adherence in the underserved population at a Fed- Flores, Maria del Mar Jimenez Lara, Jesus Jimenez Lopez, Gema Jorro Martinez, Jordi erally Qualified Health Center. Res. Soc. Adm. Pharm. RSAP 13, 759–766 (2017). Juanola Pla, Laura Juez Garcia, Lyam Lamrribi Laarbi, Pedro Landete Rodriguez, 31. Dima, A. L. et al. Asthma inhaler adherence determinants in adults: systematic Milagros Lazaro Sastre, Alberto Levy Naon, Francisco Linde De Luna, Juan Jose Liñana review of observational data. Eur. Respir. J. 45, 994–1018 (2015). Santafe, María Belén López Muñiz Ballesteros, Aurora Losada Peña, Ildefonso Luna 32. Mokoka, M. C. et al. In patients with severe uncontrolled asthma, does knowledge Ortiz, Hernan Abraham Manrique Chavez, Pedro Jorge Marcos Rodriguez, Alejandra of adherence and inhaler technique using electronic monitoring improve clinical Marín Arguedas, Nuria Marina Mallanda, Ramon Maria Marrades Sicardt, Pilar Martin decision making? A protocol for a randomised controlled trial. BMJ Open 7, Martinez, Carlos Martin Carrasco, Miguel Angel Martin Perez, Carlos Martinez Rivera, e015367 (2017). Gema Martinez Hernandez, Manuel Martinez Muñoz, Maria Martinez Ceres, Albert 33. Foster, J. M. et al. Inhaler reminders improve adherence with controller treatment in Martos Velasco, Luis Mateos Caballero, Isabel Molero Sancho, Susana Monzon primary care patients with asthma. J. Allergy Clin. Immunol. 134, 1260–1268.e3 (2014). Ballarin, Alvaro Moreno Ancillo, Ricardo Moreno Borque, Maria Dolores Mota Godoy, 34. Haahtela, T. et al. The Finnish experience to save asthma costs by improving care in 1987–2013. J. Allergy Clin. Immunol. 139, 408–414.e2 (2017). Virginia Moya Álvarez, Pilar Mur Jimeno, Luis Angel Navarro Seisdedos, Silvia Navarro 35. Melani, A. S. et al. Inhaler mishandling remains common in real life and is Moreno, Jose Antonio Navarro Echeverria, David Nieto Sanchez, Iñigo Ojanguren associated with reduced disease control. Respir. Med. 105, 930–938 (2011). Arranz, Alicia Padilla Galo, Clara Padro Casas, Merce Palau Benavent, Abel Pallares 36. Bartolo, K. et al. Predictors of correct technique in patients using pressurized Sanmartin, Raquel Pascual Cascon, Leopoldo Pau Casanova, Maria Pavon Masa, Alicia metered dose inhalers. BMC Pulm. Med. 17, 47 (2017). Pérez Rodríguez, Jose Perez Ronchel, Jesus Pola Pola, Paloma Poza Guedes, Patricia 37. Metting, E. I. et al. Feasibility and effectiveness of an asthma/COPD service for Prieto Montaño, Daniel Pujadas Clar, Miguel Angel Racionero Casero, Angela Ramos primary care: a cross-sectional baseline description and longitudinal results. NPJ Pinedo, Maria Luisa Rivera Ortun, Jose Luis Rojas Box, Ana Dolores Romero Ortiz, Mª Prim. Care Respir. Med. 25, 14101 (2015). Auxiliadora Romero Falcon, Juan María Rubio Sanchez, Lirios Sacristan Bou, Sergio 38. Chrystyn, H. & Price, D. Not all asthma inhalers are the same: factors to consider Salgado Aranda, Iran Sanchez Ramos, Ana Sanchez Fernandez, Dan Sanchez when prescribing an inhaler. Prim. Care Respir. J. 18, 243–249 (2009). Berenguer, Juan Miguel Sanchez Nieto, Raquel Sanchez Juez, Ignacio Sánchez 39. Giner, J. et al. [Patient preference in the choice of dry powder inhalers]. Arch. Hernández, Anselmo Sanchez Palacios, German Sanchez López, Alejandro Sanchez Bronconeumol. 40, 106–109 (2004). Acosta, Fernando Sanchez Toril Lopez, Juan Carlos Santana Astudillo, Alberto Saura 40. Plaza, V. et al. Impact of patient satisfaction with his or her inhaler on adherence Vinuesa, Marta Seoane Rodriguez, Ana Sogo Sagardia, Enrique Javier Soto Hurtado, and asthma control. Allergy Asthma Proc. 39, 437–444 (2018). Lorena Soto Retes, Margarita Tomás Pérez, Deyanira Vanessa Tovar Flores, Jose Maria 41. Valero, A. et al. Asthma patient satisfaction with different dry powder inhalers. Vega Chicote, Xavier Vila Giralte, Cristina Zapata Jimenez. Expert Rev. Respir. Med. 13, 133–138 (2019). 42. Schatz, M. et al. Recommendations for the management and follow-up of asthma exacerbations. Introduction. J. Emerg. Med. 37, S1–S5 (2009). AUTHOR CONTRIBUTIONS 43. Vincken, W. et al. Spacer devices for inhaled therapy: why use them, and how? ERJ Open Res. 4, 00065-2018 (2018). V. Plaza., A. Valero., C. Campo., and P. Rytilä make substantial contributions to the 44. The Global Initiative for Asthma (GINA). Pocket guide for asthma management conception and design of the work; P. Ribó, J. Molina, M. Calle., and L. Maiz. were and prevention. https://ginasthma.org/wp-content/uploads/2016/10/WMS- involved in data acquisition. Finally, all authors have contributed in the analysis and Spanish-Pocket-Guide-GINA-2016-v1.1.pdf (2015). interpretation of data and revising the work critically and approved it for publication. 45. Morisky, D. E., Green, L. W. & Levine, D. M. Concurrent and predictive validity of a self-reported measure of medication adherence. Med. Care 24, 67–74 (1986). 46. Plaza, V. et al. Validation of the ‘Test of the Adherence to Inhalers’ (TAI) for asthma COMPETING INTERESTS and COPD patients. J. Aerosol Med. Pulm. Drug Deliv. 29, 142–152 (2016). P. Ribó has received honoraria from LETIPharma, AstraZeneca, Allergy Therapeutics, and 47. GEMA Educadores. Manual del educador en asma. Grupo español para el manejo Diater. J. Molina. states that for the past 3 years he has received fees for drafting del asma. http://www.seicap.es/gema-educadores_30428.pdf (2012). documents, being on board an expert committee, and lectures from AstraZeneca, 48. Nathan, R. A. et al. Development of the asthma control test: a survey for assessing Boehringer-Ingelheim, GlaxoSmithKline, Menarini, Novartis, Orion Pharma, Pfizer, Roche, asthma control. J. Allergy Clin. Immunol. 113, 59–65 (2004). semFYC, SOMAMFYC and SERMAS. He has received funding for research projects from different government agencies, from scientific societies, as well as from Boehringer- Ingelheim, AstraZeneca, Chiesi, and Novartis, and is a consultant for AstraZeneca and ACKNOWLEDGEMENTS Sanofi. M. Calle. has received speaker fees from Boehringer Ingelheim, AstraZeneca, Editorial assistance was provided by Content Ed Net, Madrid, Spain, with funding GlaxoSmithKline, Menarini, and Novartis and has received consulting fees from from Orion Pharma. The authors would also like to acknowledge Dr. Sarah Micozzi GlaxoSmithKline, Gebro Pharma, and Novartis. L.M. has participated in advisory and and Dr. Pablo Rivas who provided medical writing support. The authors thank the training activities for Zambon, Esteve, Orion Pharma, GSK, TEVA, and ROVI. C.C. and P. EFIMERA study investigators for their contribution: Angel Abellan Aleman, Irene Rytilä are employed by Orion Pharma. V.P. previously received honoraria for speaking at Alaejos Pascua, Maria Pilar Alba Jorda, Bernardino Alcazar Navarrete, Eva Alcoceba sponsored meetings by AstraZeneca, Chiesi, GlaxoSmithKline and Novartis. He also Borras, África Alcorta Mesas, Ismael Ali García, Miguel Angel Alonso Fernandez, Jose received assistance in traveling to meetings from Chiesi and Novartis. He acted as a Antonio Alvarez Fernandez, Marta Alvariño Martin, Michael Alwakil Olpah, Carlos consultant for ALK, AstraZeneca, Boehringer, MundiPharma, and Sanofi. He has also Antonio Amado Diago, Blanca Andres Lopez, Ruben Andujar Espinosa, Ascension received funding/grant support for research projects from a variety of government Aranzabal Soto, Aurelio Arnedillo Muñoz, M. Teresa Audicana Berastegui, Juan Bauza agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and Menarini. A.V. Deroulede, Roberto Bernabeu Mora, Ana Boldova Loscertales, Juan Manuel Bravo has previously received honoraria for speaking at sponsored meetings by AstraZeneca, Santervas, Noemi Burgos Guadix, Alfonso Carreño Rojo, Santiago Carrizo Sierra, Pablo Chiesi, and Novartis and is a consultant for AstraZeneca and Sanofi. Catalan Serra, Ernesto Centeno Echebarrieta, Eusebi Chiner Vives, Mercedes Cimarra Álvarez- Lovell, Carlos Colas Sanz, Jose Antonio Compaired Villa, Pedro Cordero Rodriguez, Astrid Crespo Lessmann, Andrea Crespo Sedano, Jose Maria Cruz Molina, José Ángel Cumplido Bonny, Manuel De Las Heras Gonzalo, Felix Del Campo Matias, ADDITIONAL INFORMATION Nathalie Depreux Niño, Rocio Diaz Campos, Juan Manuel Diez Piña, Esperanza Doña Supplementary information is available for this paper at https://doi.org/10.1038/ Diaz, Silvia Dorronsoro Quintana, Susana Echechipia Madoz, Abdulkader El Hachem s41533-020-00189-6. Debek, José Félix Esteban Gomez, Olga Esteso Hontoria, Ana Fernandez Tena, Cleofe Fernandez Aracil, Luis Fernandez Pellon, Mar Fernandez Nieto, Monica Fernandez Correspondence and requests for materials should be addressed to P.Ribó Rodriguez, Sara Fernandez Cortes, David Ferrando Garcia, Angel Ferrer Torres, Gloria Francisco Corral, Lelia Gacías Pedrós, Gaspar Gala Ortiz, Javier Gallego Borrego, Reprints and permission information is available at http://www.nature.com/ Alfonso Garcia Guisado, Juan Luis Garcia Rivero, Victoria Garcia Mugica, Cayo Javier reprints Garcia Polo, César Garcia De Llanos, Ignacio García Talavera Martin, Jordi Giner Donaire, Armando Gonzalez Lopez, Jose Fernando Gonzalez Torralba, Francisco Javier Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims Gonzalez Barcala, Emma Gonzalez Seco, Jose Vicente Greses Giner, Francisco Javier in published maps and institutional affiliations. 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