www.nature.com/npjpcrm ARTICLE OPEN Asthma control and COPD symptom burden in patients using fixed-dose combination inhalers (SPRINT study) Nicolas Roche1*, Vicente Plaza2, Vibeke Backer 3, Job van der Palen4,5, Isa Cerveri6, Chelo Gonzalez7, Guilherme Safioti 8 , Irma Scheepstra8, Oliver Patino8 and Dave Singh9 Previous studies have found suboptimal control of symptom burden to be widespread among patients with asthma and chronic obstructive pulmonary disease (COPD). The Phase IV SPRINT study was conducted in 10 countries in Europe to assess asthma disease control and COPD symptom burden in patients treated with a fixed-dose combination (FDC) of inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs). SPRINT included 1101 patients with asthma and 560 with COPD; all were receiving treatment with an FDC of ICS/LABA, delivered via various inhalers. Data were obtained over a 3-month period, during a single routine physician’s office visit. Asthma control was defined as Asthma Control Test (ACT) score >19. COPD symptom burden was assessed by COPD Assessment Test (CAT), with a CAT score <10 defining low COPD symptom burden. Among patients using any ICS/LABA FDC, 62% of patients with asthma had achieved disease control (ACT score >19) and 16% of patients with COPD had low symptom burden (CAT score <10). npj Primary Care Respiratory Medicine (2020)30:1 ; https://doi.org/10.1038/s41533-019-0159-1 1234567890():,; INTRODUCTION a different dry powder inhaler (DPI) mechanism with fewer Asthma and chronic obstructive pulmonary disease (COPD) are of preparation manoeuvres.14 significant concern worldwide owing to their high prevalence and The present real-world observational study was conducted to substantial clinical and economic burden.1 While asthma is the obtain a cross-sectional overview of asthma disease control and most prevalent respiratory disease in the world (and twice as COPD symptom burden among patients receiving treatment with common as COPD), the mortality rate associated with COPD is an FDC of ICS and LABA administered twice daily using a DPI. eight times higher than for asthma.1 The absolute number of Additional aims of the study were to evaluate patient adherence patients with these two conditions is increasing as the global in a real-world clinical practice population and to collect population grows.1 information on the patients’ background and their healthcare Inhaled medications are the mainstay of treatment for both utilisation, in order to assess the relationship between these COPD and asthma,2,3 but many patients with asthma and COPD factors and disease burden. Another purpose of the study was to have poor treatment adherence and/or inhaler technique.4,5 analyse clinical data among patients using the FDC budesonide/ Improvements in these patient factors have the potential to formoterol DuoResp Spiromax inhaler. The data on DuoResp substantially increase the effectiveness of therapy and help Spiromax adherence, satisfaction, and ease of use will be reported alleviate disease burden.6–9 separately. Combined inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) treatments play a central role in the management of persistent asthma (Step 3 and above)2 and have been RESULTS associated with beneficial effects on lung function, exacerbation Study population rates, and patient-reported outcomes compared with each A total of 1138 patients with asthma were enrolled in the study. treatment alone in patients with COPD.10–12 Several inhalers Enrolment by country is presented in Supplementary Table 1. containing a fixed-dose combination (FDC) and ICS and LABA are Among asthma patients receiving treatment with any ICS/LABA, commercially available in Europe for the delivery of maintenance 1101 completed the study. The 4 most frequently used ICS/LABA therapies for COPD and/or asthma. The convenience of having treatment devices (used by 72.0% of patients) were Symbicort both substances in a single inhaler may help improve treatment inhalers (298 patients), DuoResp Spiromax inhalers (235 patients), adherence and is often cost saving, compared with using two Seretide inhalers (174 patients), and Fostair inhalers (86 patients). separate inhalers.13 In April 2014, marketing authorisation was Other types of fixed-dose ICS/LABA inhalers were used by 28.0% granted for DuoResp® Spiromax®, a budesonide/formoterol of patients. combination treatment alternative to the existing Symbicort A total of 596 patients with COPD were enrolled in the study. Turbuhaler, which contains the same active substances but uses Enrolment by country is presented in Supplementary Table 1. Of 1 Respiratory Medicine, Cochin Hospital, APHP Centre University of Paris, Institut Cochin (UMR1016), Paris, France. 2Department of Respiratory Medicine and Allergy, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomédica Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain. 3Department of Respiratory Medicine, Copenhagen University, Copenhagen, Denmark. 4Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, The Netherlands. 5Medical School Twente, Medisch Spectrum Twente, Enschede, The Netherlands. 6Unit of Respiratory Diseases, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy. 7Unit of Statistics and Data Management, Experior SL, 46139 La Pobla de Farnals, Valencia, Spain. 8Teva Pharmaceutical Industries Ltd, Amsterdam, The Netherlands. 9 Centre for Respiratory Medicine and Allergy, University of Manchester, and the Medicines Evaluation Unit, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. *email: nicolas.roche@aphp.fr Published in partnership with Primary Care Respiratory Society UK N Roche et al. 2 these, 560 COPD patients completed the study. The four most fact only one patient in five met the criteria for controlled frequently used ICS/LABA treatment devices (used by 74.5% of asthma.16 This underestimation of disease control probably has a patients) were Seretide inhalers (156 patients), Symbicort inhalers significant impact on asthma outcomes. A report by the Royal (113 patients), DuoResp Spiromax inhalers (107 patients), and College of Physicians in the UK estimated that >65% of asthma Fostair inhalers (41 patients). Other types of fixed-dose ICS/LABA deaths were associated with potentially preventable factors, inhalers were used by 25.5% of patients. including trigger avoidance, medication adherence, and regular Patient demographics are presented in Table 1a. The mean medical follow-up.17 (standard deviation [SD]) age of the asthma cohort was 53.8 (16.7) Comparatively few patients in the SPRINT study (15.5%) met the years, and asthma was less frequent in men (37.1%) than women pre-defined criterion for low COPD symptom burden (CAT score (62.9%). The mean (SD) age of the COPD cohort was 69.5 (9.0) <10). A recently reported multicentre, observational study in years. This group included more men (62.5%) than women Europe classified 21% of COPD patients as ‘controlled’, using the (37.5%). Disease characteristics for all patients are presented in same CAT score criteria.18 However, all patients classified had Table 1b (additional information regarding previous asthma/COPD mild-to-moderate COPD. Most patients in the SPRINT cohort were treatments is supplied in Supplementary Table 2). The mean (SD) elderly (median age 70 years). As symptoms become more difficult last known forced expiratory volume in 1 s (FEV1) % predicted was to manage as COPD progresses, the low rate of achievement of 81.7% (23.1) in the asthma cohort and 58.3% (23.6) in the COPD the pre-defined CAT score threshold in the SPRINT study COPD group. cohort is not unexpected. Taken together, these results suggest that a CAT threshold of 10 is probably too low to define low COPD Primary endpoints symptom burden.18,19 In view of the lack of reversibility that is typical of COPD, the threshold might need to be adapted to the In the overall asthma population, 684 patients (62.4%) had an baseline severity of the disease. Asthma Control Test (ACT) score >19 and were considered to have Significant negative effects of COPD on health-related quality of achieved disease control at the time of the assessment, after life are reflected in the health status scores reported among ≥3 months of FDC inhaler use (Fig. 1). In the overall COPD SPRINT study participants. For example, the mean EQ-5D-3L for a population, 85 patients (15.5%) had a COPD Assessment Test 70-year-old person (mean age of the COPD cohort) living in the 1234567890():,; (CAT) score <10, defining a low symptom burden at the time of European countries that were included in the SPRINT study is the assessment, after ≥3 months of FDC inhaler use (Fig. 2). between 69.0 and 81.5,20 whereas the mean EQ VAS in our COPD cohort was 62.8. Asthma appeared to have less effect on overall Secondary endpoints health status; the mean EQ VAS in our asthma cohort was 74.3, Table 2 shows an overview of patient adherence to treatment as which is within the average range for a 55-year-old person living assessed by Morisky Medication Adherence Scale (MMAS-8®) in these European countries (72.0–81.7).20 questionnaire. A greater proportion of patients in the COPD group The findings of the SPRINT study indicate that suboptimal had high adherence compared with patients in the asthma group adherence to inhaled treatment regimens is widespread among (51.0% vs 34.4%, respectively). Table 3 provides an overview of patients with asthma and COPD. In particular, only 34.4% of health status among SPRINT study participants, based on the patients with asthma had an MMAS-8 score indicative of high EuroQoL 5-dimensional 3-level (EQ-5D-3L) questionnaire findings. adherence, and >30% had a score indicative of low adherence. Mean (SD) visual analogue scale (VAS) score was greater in Poor adherence leading to poor outcomes in patients with asthma patients with asthma than in those with COPD (74.3 [18.3] vs 62.8 was also seen in the LIAISON study, which used the 4-item Morisky [18.5], respectively). The mean (SD) raw EQ-5D-3L index value was Medication Adherence Scale (MMAS-4) and found that patients also greater in asthma patients than in those with COPD (80.1 with uncontrolled asthma were more likely to have MMAS-4 [18.5] vs 70.7 [20.5], respectively). Table 4 shows correlations scores indicative of low adherence than those with controlled between adherence and health-related quality of life measures. asthma.15 Consistent with previous reports of relatively inferior Table 5 shows health-related quality of life measures according to adherence among younger vs older patients using inhaled achievement or otherwise of asthma disease control or COPD low medications,21 SPRINT study participants with COPD were more symptom burden. likely than those with asthma to be adherent, with more than half Healthcare resource utilisation in the 3 months preceding the having an MMAS-8 score indicative of high adherence. The rates study was determined. In the total cohort, asthma- or COPD- of adherence and asthma control among participants in the related visits to a physician (median 0, range 0–10) and SPRINT study were consistent with other recent reports of real- emergency department (median 0, range 0–6) and hospitalisa- world studies in both asthma and COPD cohorts.7,22 As expected, tions lasting >1 day (median 0, range 0–11) were rare events. adherence was markedly lower than is typically seen in clinical trials. Relationships between disease control and other variables were DISCUSSION explored for asthma patients using multiple regression. Although The results of this observational study of patients receiving no model could be found that could explain most of the variance inhaled maintenance treatment with ICS/LABA FDC showed that in the data, analysis findings suggested that male sex and higher almost two-thirds of asthma patients met the threshold for education may be positively associated, and body mass index asthma control (ACT score >19). The rate of asthma control in the (BMI) negatively associated, with disease control. These observa- SPRINT study (62.4%) was higher than the pan-European rate tions are consistent with previous findings.23,24 reported in the International Cross-Sectional and Longitudinal Previous research has linked adherence with clinical symptoms Assessment on Asthma Control (LIAISON) studies conducted in and outcomes.4,25–27 However, even in adherent patients, other 2012–2013 (43.5%)15 and the 2014 REcognise Asthma and LInk to factors may influence outcomes. For example, inhaler technique is Symptoms and Experience (REALISE) study conducted across an important determinant of outcome, as it influences the dose of Europe (20%).16 drug delivered to the lungs at each inhalation.6 Demographic Research has shown that asthma patients’ perceptions of factors may also influence disease control. For example, the disease control are often at odds with more objective measures LIAISON study found that females, those aged 40–64 years, and of disease control. For example, >80% of patients in the REALISE patients who were overweight or obese were less likely to achieve study considered their asthma to be controlled, and more than asthma control compared with males, other age groups, and those two-thirds did not consider their condition as serious, whereas in of normal weight, respectively.15 Other studies have confirmed the npj Primary Care Respiratory Medicine (2020) 1 Published in partnership with Primary Care Respiratory Society UK N Roche et al. 3 Table 1. (a) Patient demographic characteristics and (b) clinical characteristics, concomitant conditions, and prior medications. Asthma (N = 1101) COPD (N = 560) Total (N = 1661) p value (a) Gender, n (%) Female 693 (62.9) 210 (37.5) 903 (54.4) <0.001 Male 408 (37.1) 350 (62.5) 758 (45.6) Age at study visit, years Mean (SD) 53.8 (16.7) 69.5 (9.0) 59.1 (16.3) <0.001 BMI, kg/m2 Mean (SD) 28.1 (6.1) 27.8 (5.9) 28 (6.0) 0.258 Data unavailable 71 26 97 Obesity (BMI ≥30), n (%) Yes 315 (30.6) 161 (30.1) 476 (30.4) 0.906 No 715 (69.4) 373 (69.9) 1088 (69.6) Data unavailable 71 26 97 (b) Years since disease diagnosis Median (P25, P75) 11 (4, 23) 7 (4, 12) 9 (4, 18) <0.001 Data unavailable 14 4 18 FEV1, L Mean (SD) 2.5 (0.9) 1.5 (0.6) 2.1 (1.0) <0.001 Data unavailable 186 36 222 1234567890():,; % predicted FEV1, % Mean (SD) 81.7 (23.1) 58.3 (23.6) 73.1 (25.9) <0.001 Data unavailable 224 50 274 Concomitant disease presence, n (%) Yes 792 (73.1) 459 (83.5) 1251 (76.6) <0.001 No 292 (26.9) 91 (16.5) 383 (23.4) Data unavailable 17 10 27 Concomitant diseasea, n (%) (N = 1084) (N = 550) (N = 1634) Cardiovascular disease 267 (24.6) 269 (48.9) 536 (32.8) <0.001 Depression or anxiety disorder 126 (11.6) 79 (14.4) 205 (12.5) 0.133 Allergy 304 (28) 26 (4.7) 330 (20.2) <0.001 Osteoporosis 33 (3.0) 37 (6.7) 70 (4.3) <0.001 Diabetes 91 (8.4) 84 (15.3) 175 (10.7) <0.001 Cancer 42 (3.9) 53 (9.6) 95 (5.8) <0.001 Other 430 (39.7) 276 (50.2) 706 (43.2) <0.001 Any previous asthma/COPD treatment, n (%) Yes 575 (56.3) 283 (55.1) 858 (55.9) 0.679 No 446 (43.7) 231 (44.9) 677 (44.1) Data unavailable 80 46 126 Previous asthma/COPD treatment description, n (%) (n = 575) (n = 283) (n = 858) ICS monotherapy 191 (33.2) 23 (8.1) 214 (24.9) <0.001 LABA monotherapy 20 (3.5) 21 (7.4) 41 (4.8) Fixed-dose combination (different from current) 287 (49.9) 147 (51.9) 434 (50.6) Long-acting muscarinic antagonists 13 (2.3) 60 (21.2) 73 (8.5) Leukotriene modifier 28 (4.9) 0 (0) 28 (3.3) Methylxanthine (theophylline) 1 (0.2) 5 (1.8) 6 (0.7) Other 35 (6.1) 27 (9.5) 62 (7.2) Data unavailable 0 0 0 Duration (months) of use of the patient’s current FDCb Median (P25, P75) 18.7 (8.6, 47.2) 22.4 (10.1, 55.1) 19.7 (9, 50.4) 0.144 Data unavailable 225 130 355 Disease control (asthma)/Low symptom burden (COPD), n (%) Yes 684 (62.4) 85 (15.5) 769 (46.7) <0.001 No 412 (37.6) 464 (84.5) 876 (53.3) Data unavailable 5 11 16 BMI body mass index, COPD chronic obstructive pulmonary disease, FDC fixed-dose combination, FEV1 forced expiratory volume in 1 s, ICS inhaled corticosteroid, LABA long-acting beta agonist, SD standard deviation a Every patient may present several concomitant diseases. Thus percentages have been calculated based on the number of patients b Patients were eligible for the study if they had received a stable dose of ICS/LABA FDC for the 3 months prior to enrolment. One COPD patient who had received treatment for 12 weeks was accepted onto the study by the sponsor Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2020) 1 N Roche et al. 4 Asthma control among patients using FDC ICS/LABA COPD symptom burden among patients using FDC ICS/LABA N = 1096* N = 549* 15.5% Achieved control Had low symptom burden 37.6% (ACT score >19) (CAT score <10) Did not achieve control Did not have low symptom 62.4% (ACT score ≤19) burden (CAT score ≥10) 84.5% Fig. 1 Proportion of asthma patients with disease control, Fig. 2 Proportion of COPD patients with low symptom burden, defined as ACT score >19, at the time of assessment after at defined as CAT score <10, at the time of assessment, after at least least 3 months of FDC inhaler use. *Data were unavailable for 5 3 months of FDC inhaler use. *Data were unavailable for 11 patients. ACT Asthma Control Test, FDC fixed-dose combination. patients. CAT COPD Assessment Test, COPD chronic obstructive pulmonary disease, FDC fixed-dose combination. Table 2. Adherence to ICS/LABA treatment among SPRINT study participants with asthma and COPD, as assessed by MMAS-8 score and adherence classification. Asthma (N = 1101) COPD (N = 560) Total (N = 1661) p value MMAS-8 score All ICS/LABA (n = 1101) (n = 560) (n = 1661) Median (P25, P75) 7.0 (5.8, 8.0) 8.0 (7.0, 8.0) 7 (5.8, 8) <0.001 Data unavailable 21 9 30 MMAS-8 adherence classification, n (%) All ICS/LABA (n = 1101) (n = 560) (n = 1661) High (score = 8) 371 (34.4) 281 (51.0) 652 (40) <0.001 Medium (6 ≤ score < 8) 382 (35.4) 182 (33.0) 564 (34.6) Low (score < 6) 327 (30.3) 88 (16.0) 415 (25.4) Data unavailable 21 9 30 COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroid, LABA long-acting beta agonist, MMAS-8 8-item Morisky Medication Adherence Scale Note: Use of the ©MMAS is protected by US copyright laws. Permission for use is required. A license agreement is available from: Donald E. Morisky, ScD, ScM, MSPH, Professor, Department of Community Health Sciences, UCLA School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA, 90095-1772 interaction between obesity and disease control in asthma. Scott higher than is typical for large randomised COPD studies, for et al. showed that, among asthma patients who are adherent to which Kruis and colleagues reported a mean age of 63.7 years.31 therapy, those who are obese (BMI >30 mg/m2) have difficulty Strengths of the SPRINT study include the pan-European achieving asthma control.28 Thirty percent of patients in the context, involving 10 countries from across Europe, and the SPRINT cohort had a BMI >30 kg/m2, and the proportion of obese generalisability to the population of patients seen in everyday patients was similar in the asthma (30.6%) and COPD (30.1%) clinical practice. The study included all patients with asthma or cohorts. This is slightly higher than the proportion of obese COPD receiving twice-daily ICS/LABA FDC and did not exclude patients reported in the LIAISON study of European asthma anyone on demographic or clinical grounds. Another strength is patients (26.1%).15 the inclusion of patient-reported outcome measures that are COPD patient demographics showed that participants receiving widely used and validated in COPD and asthma populations.33 an ICS/LABA FDC in this study covered the range of COPD However, the SPRINT study also has some limitations. As an subtypes encountered in routine clinical practice (elderly, former observational study, it is subject to confounders and potential bias. For example, assessments by patients were subject to recall or current smokers, high incidence of comorbidity).29,30 Owing to bias and reporting bias (e.g. with regard to adherence). Wherever the stringent selection criteria that are typically applied, rando- possible, attempts were made to minimise recall bias by using mised clinical trial cohorts are poorly representative of the broader patient records to assess preceding medical visits. In addition, this COPD population, most of whom are treated in primary care.31,32 study was not designed to assess the comparative effectiveness of Comorbidities, which may be a reason to exclude patients from different ICS/LABA FDC inhalers, and the findings likely describe a randomised clinical trials,32 were present in 83.5% of COPD class effect rather than the effect of any specific type of inhaler. patients in the SPRINT study. This is higher than the prevalence of The results of this observational clinical study showed that the significant comorbidity reported in a Norwegian study of COPD majority (62%) of asthma patients using ICS/LABA FDC inhalers patients seen in primary care or hospital outpatient clinics meet the threshold for asthma control in real-world clinical (60.7%)32 but lower than the prevalence reported in US COPD practice and that the burden of symptoms for COPD in real-world patients (96.4%), according to the National Health and Nutrition clinical practice is high. Adult patients with asthma and COPD Examination Survey, 1999–2008.30 Furthermore, the mean age of have a high rate of comorbidities, but adherence to ICS/LABA COPD patients in the SPRINT study, 69.5 years, was markedly therapy in real-world asthma and COPD patients is low. npj Primary Care Respiratory Medicine (2020) 1 Published in partnership with Primary Care Respiratory Society UK N Roche et al. 5 Table 3. Health-related quality of life and healthcare utilisation among SPRINT study participants with asthma and COPD. Asthma COPD Total p value (N = 1101) (N = 560) (N = 1661) VAS score Mean (SD) 74.3 (18.3) 62.8 (18.5) 70.4 (19.1) <0.001 Data unavailable 26 7 33 Mean EQ-5D-3L index value Mean (SD) 0.80 (0.21) 0.69 (0.23) 0.76 (0.23) <0.001 Data unavailable 17 4 21 Number of visits to the doctor/GP due to asthma or COPD Mean (SD) 0.4 (0.8) 0.7 (1.2) 0.5 (1) <0.001 Data unavailable 0 0 0 Number of emergency department visits due to asthma or COPD Mean (SD) 0 (0.2) 0.1 (0.5) 0.1 (0.3) 0.006 Data unavailable 0 0 0 Number of hospital stays (>1 day) due to asthma or COPD Mean (SD) 0 (0.2) 0.1 (0.8) 0.1 (0.5) <0.001 Data unavailable 0 0 0 COPD chronic obstructive pulmonary disease, EQ-5D-3L EuroQoL 5-dimensional 3-level, SD standard deviation, VAS visual analogue scale In conclusion, this large, observational study in adult patients aged ≥40 years and/or a current or ex-smoker with a smoking history of with asthma and COPD across 10 countries in Europe found that >10 pack-years. In addition, all participants had to agree to participate in more than half of asthma patients using any ICS/LABA FDC inhaler the study and to disclose any medical events to the treating physician and met the threshold for asthma disease control. The pre-defined to be willing and able to provide written informed consent and complete threshold for low symptom burden was met by few patients with the questionnaires. The only exclusion criterion was that patients could not currently be, or plan to be, enrolled in an interventional study. COPD; however, this is probably to be expected in a chronic disease with an overall more advanced patient population than for asthma. Suboptimal adherence was widespread, particularly Assessments among asthma patients. Both patient populations had a high Demographic and clinical characteristics (including medical history, rate of comorbidities, and many of the patients would have been previous and concomitant respiratory medications, number of exacerba- ineligible to participate in recent randomised controlled trials of tions in the previous year, and healthcare utilisation in the past 3 months) asthma and COPD medications. The findings of the SPRINT study were collected from the patient’s medical records by the investigational highlight the need for more attention by European physicians on centres. During the study visit, the patient’s respiratory disease burden was evaluated by a series of paper questionnaires, completed by patients in patient-reported symptoms and adherence in the asthma and their local language. Asthma disease control was assessed using the ACT COPD patients they see in clinical practice. questionnaire.34 The burden of COPD symptoms was evaluated using CAT.35 Patients rated their own adherence to therapy using the MMAS-8 questionnaire.36–38 Patients also rated their general health status using the METHODS EQ-5D-3L questionnaire.39 The two-part questionnaire is comprised of the Study design and participants EQ-5D descriptive system and the EQ VAS, which measure 5 dimensions This was a Phase IV, multi-country, observational, prospective study in (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) on patients with asthma or COPD who were on a stable dose of ICS/LABA FDC a 3-point scale and self-rated health on a VAS, respectively. administered by DPI twice daily. The study was performed between May 2015 and April 2017 at 140 centres in Croatia (15 sites), Denmark (7), Endpoints Ireland (7), Italy (25), The Netherlands (7), Norway (4), Portugal (10), Spain (39), Sweden (2), and the UK (24). Prior to study initiation, Independent The primary endpoint was the percentage of patients whose respiratory Ethics Committee approval was obtained from all relevant national or disease was well controlled, which was defined as having an ACT score >19 regional bodies. in patients with asthma and low symptom burden (defined as CAT score Data were collected for the whole population of patients receiving any <10) in patients with COPD. Secondary endpoints were self-reported ICS/LABA treatment in a routine setting (on a single occasion during an adherence based on the MMAS-8 score, health status defined by the EQ- otherwise normal visit to a physician’s office or clinic). Participating 5D-3L, and recent healthcare resource utilisation in terms of physician physicians did not perform any additional medical procedures, other than visits, emergency room visits, and hospitalisations lasting >1 day for those that were part of routine practice. All treatment decisions were at the asthma or COPD. sole discretion of participating physicians. Statistical analyses Patients A target sample size of approximately 792 patients with asthma and 648 Patients were eligible to participate if they had a diagnosis of persistent patients with COPD was planned. Based on the calculated sample size, the asthma or COPD in accordance with the GINA or GOLD reports, half-width of the 95% confidence interval for the proportion of patients respectively, and were receiving treatment with a stable dose of an ICS/ with asthma with controlled disease is 0.035 for all patients treated with LABA FDC, administered twice daily by DPI for 3 months prior to ICS/LABA. Similarly, based on this sample size, the half-width of the 95% enrolment. Dose stability was defined as no change in dose by >50% in the confidence interval for the proportion of patients with COPD with low past 3 months. Patients with asthma were eligible to participate if they symptom burden (considered controlled disease) is 0.032 for all patients were aged ≥18 years, and those with COPD could participate if they were treated with ICS/LABA. Statistical analysis was based on the Safety Set, Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2020) 1 N Roche et al. 6 differences were also performed in a post hoc exploratory analysis). No Table 4. Correlation between adherence and health-related quality- imputation was made for missing data. of-life measures. Correlation analyses Correlation estimate p valuea Ethics approval The study protocol was approved by the Hospital Universitario de Canarias, Adherence (MMAS-8 score) and (N = 1603) Spain; Lakemedelsverket and the National Ethics Committee, Sweden; 25 VAS score local Ethics Committees in Italy; The Foundation for the Code for Spearman correlation −0.081 0.001b Pharmaceutical Advertising, Netherlands; 10 local Ethics Committees in Portugal; one National Ethics Committee in the UK; one National Ethics Kendall correlation −0.061 0.001 Committee in Ireland; and one National Ethics Committee in Croatia. Adherence (MMAS-8 score) and EQ- (N = 1616) 5D-3L index value Reporting summary Spearman correlation −0.085 0.001 Further information on research design is available in the Nature Research Kendall correlation −0.065 0.001 Reporting Summary linked to this article. Note: Use of the ©MMAS is protected by US copyright laws. Permission for use is required. A license agreement is available from: Donald E. Morisky, ScD, ScM, MSPH, Professor, Department of Community Health Sciences, DATA AVAILABILITY UCLA School of Public Health, 650 Charles E. Young Drive South, Los Data are available upon reasonable request; please contact oliver.patino@tevaeu.com Angeles, CA, 90095-1772 with any enquiries regarding data access. MMAS-8 8-item Morisky Medication Adherence Scale a For hypothesis contrast, null hypothesis was correlation = 0 and Received: 14 January 2019; Accepted: 4 November 2019; alternative hypothesis was correlation different from 0 b p value for Spearman correlation could not be computed exact due to ties REFERENCES Table 5. Health-related quality of life and disease control. 1. GBD 2015 Chronic Respiratory Disease Collaborators. 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Med. 16, 42 (2016). npj Primary Care Respiratory Medicine (2020) 1 Published in partnership with Primary Care Respiratory Society UK N Roche et al. 7 15. Braido, F. et al. Determinants and impact of suboptimal asthma control in Europe: ACKNOWLEDGEMENTS the international cross-sectional and longitudinal assessment on asthma control Medical writing support was provided by Ian Grieve of Ashfield Healthcare (LIAISON) study. Resp. Res. 17, 51 (2016). Communications, part of UDG Healthcare plc, and was funded by Teva Pharmaceu- 16. Price, D., Fletcher, M. & van der Molen, T. Asthma control and management in ticals. The authors were fully responsible for all content and editorial decisions, were 8,000 European patients: the REcognise Asthma and LInk to Symptoms and involved at all stages of manuscript development, and have approved the final Experience (REALISE) study. Npj Prim. Care Resp. Med. 24, 14009 (2014). version. This study was sponsored by Teva Pharmaceuticals. 17. RCP. Why asthma still kills: The National Review of Asthma Deaths (NRAD). https://www.asthma.org.uk/globalassets/campaigns/nrad-full-report.pdf (2014). Accessed 11 Oct 2019. AUTHOR CONTRIBUTIONS 18. Miravitlles, M. et al. Evaluation of criteria for clinical control in a prospective, N.R., V.P., V.B., J.v.d.P., I.C., G.S., O.P. and D.S. contributed to data interpretation. N.R., V. international, multicenter study of patients with COPD. Resp. Med. 136, 8–14 (2018). P., V.B., J.v.d.P., I.C., O.P. and D.S. contributed to the plan and design of the study. C.G. 19. Nibber, A. et al. Validating the concept of COPD control: a real-world cohort study and I.S. contributed to data acquisition. C.G. and G.S. contributed to data analysis. All from the United Kingdom. COPD 14, 504–512 (2017). authors contributed to draft versions of the manuscript, read and approved the final 20. Szende, A., Janssen, B. & Cabasés, J. (eds). Self-Reported Population Health: An manuscript, and are accountable for the accuracy and integrity of this work. International Perspective Based on EQ-5D (Springer, Dordrecht, 2014). 21. Mäkelä, M. J., Backer, V., Hedegaard, M. & Larsson, K. Adherence to inhaled therapies, health outcomes and costs in patients with asthma and COPD. Respir. Med. 107, 1481–1490 (2013). COMPETING INTERESTS 22. Plaza, V. et al. Validation of the ‘Test of the Adherence to Inhalers’ (TAI) for asthma N.R. reports grants and personal fees from Boehringer Ingelheim, and Novartis and and COPD patients. J. Aerosol Med. Pulm. Drug Deliv. 29, 142–152 (2016). personal fees from Teva, GSK, AstraZeneca, Chiesi, Mundipharma, Cipla, Sanofi, 23. Lavoie, K. L., Bacon, S. L., Labrecque, M., Cartier, A. & Ditto, B. Higher BMI is Sandoz, 3M, Pfizer, and Zambon outside of the published work. V.B., I.C., J.v.d.P., and associated with worse asthma control and quality of life but not asthma severity. C.G. declare no conflicts of interest. D.S. received grants and/or personal fees from Respir. Med. 100, 648–657 (2006). AstraZeneca, Apellis, Boehringer Ingelheim, Chiesi, Cipla, Genetech, GlaxoSmithKline, 24. Temprano, J. & Mannino, D. M. The effect of sex on asthma control from the Glenmark, Menarini, Merck, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, National Asthma Survey. J. Asthma Clin. Immunol. 123, 854–860 (2009). Skyepharma, Teva, Theravance, and Verona. V.P. in the last three years has received 25. Chiu, K. C. et al. Patients’ beliefs and behaviors related to treatment adherence in honoraria for speaking at sponsored meetings from Astrazeneca, Chiesi, and Novartis; patients with asthma requiring maintenance treatment in Asia. J. Asthma 51, received help assistance to meeting travel from Astrazeneca, Chiesi, and Novartis; 652–659 (2014). acts as a consultant for ALK, Astrazeneca, Boehringer, MundiPharma, and Sanofi; and 26. Blais, L. et al. Assessing adherence to inhaled corticosteroids in asthma patients has received funding/grant support for research projects from a variety of using an integrated measure based on primary and secondary adherence. Eur. J. Government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, Clin. Pharmacol. 73, 91–97 (2017). and Menarini. G.S. and O.P. are employees of Teva Pharmaceuticals. I.S. was an 27. Laforest, L. et al. Long-term inhaled corticosteroid adherence in asthma patients employee of Teva Pharmaceuticals at the time the study was conducted. with short-term adherence. J. Allergy Clin. Immunol. Pract. 4, 890–899 (2016). 28. Scott, L. et al. Factors affecting ability to achieve asthma control in adult patients with moderate to severe persistent asthma. J. Asthma 53, 644–649 (2016). ADDITIONAL INFORMATION 29. European Respiratory Society (ERS) White Book. 2013. Chapter 13: Chronic Supplementary information is available for this paper at https://doi.org/10.1038/ obstructive pulmonary disease. http://www.erswhitebook.org/chapters/chronic- s41533-019-0159-1. obstructive-pulmonary-disease/ (2013). Accessed 11 Oct 2019. 30. Schnell, K. et al. The prevalence of clinically-relevant comorbid conditions in Correspondence and requests for materials should be addressed to N.R. patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999-2008. BMC Pulm. Med. 12, 26 (2012). Reprints and permission information is available at http://www.nature.com/ 31. Kruis, A. L. et al. Primary care COPD patients compared with large reprints pharmaceutically-sponsored COPD studies: an UNLOCK validation study. PLoS ONE 9, e90145 (2014). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 32. Herland, K., Akselsen, J. P., Skjønsberg, O. H. & Bjermer, L. How representative are in published maps and institutional affiliations. clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir. Med. 99, 11–19 (2005). 33. Kocks, J. W. H., Seys, S. F., van Duin, T. S., Diamant, Z. & Tsiligianni, I. G. Assessing patient-reported outcomes in asthma and COPD patients: which can be recommended in clinical practice. Curr. Opin. Pulm. Med. 24, 18–23 (2018). Open Access This article is licensed under a Creative Commons 34. Nathan, R. A. et al. Development of the asthma control test: a survey for assessing Attribution 4.0 International License, which permits use, sharing, asthma control. J. Allergy Clin. Immunol. 113, 59–65 (2004). adaptation, distribution and reproduction in any medium or format, as long as you give 35. Jones, P. W. et al. Development and first validation of the COPD assessment test. appropriate credit to the original author(s) and the source, provide a link to the Creative Eur. Respir. J. 34, 648–654 (2009). Commons license, and indicate if changes were made. The images or other third party 36. Morisky, D. E., Ang, A., Krousel-Wood, M. & Ward, H. J. Predictive validity of a material in this article are included in the article’s Creative Commons license, unless medication adherence measure for hypertension control. J. Clin. Hypertens. 10, indicated otherwise in a credit line to the material. If material is not included in the 348–354 (2008). article’s Creative Commons license and your intended use is not permitted by statutory 37. Krousel-Wood et al. New medication adherence scale versus pharmacy fill rates in regulation or exceeds the permitted use, you will need to obtain permission directly seniors with hypertension. Am. J. Manag. Care 15, 59–66 (2009). from the copyright holder. To view a copy of this license, visit http://creativecommons. 38. Morisky, D. E. & DiMatteo, M. R. Improving the measurement of self-reported org/licenses/by/4.0/. medication nonadherence: response to authors. J. Clin. Epidemiol. 64, 258–263 (2011). 39. Brooks, R. EuroQol: the current state of play. Health Policy 37, 53–72 (1996). © The Author(s) 2020 Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2020) 1