Health-related quality of life (HRQoL) in patients with moderate to severe chronic obstructive pulmonary disease (COPD) is often reduced by high symptom burden and frequent exacerbations. So far, data on therapeutic success in Swiss COPD patients receiving dual bronchodilation therapy as COPD maintenance treatment are limited. Data from a recently published, non-interventional study on clinical benefit after the start of combined tiotropium–olodaterol treatment were analyzed focusing on Swiss patients compared to the overall cohort including patients from various European countries. Demographic data on the changes in Clinical COPD Questionnaire (CCQ) for the assessment of HRQoL in correlation to symptoms and the number of exacerbations, as well as physician's global assessment (PGE), were evaluated 6 weeks after treatment start. In Switzerland (n = 61), significantly more patients had comorbidities and exacerbations but showed less symptoms compared to the overall cohort (n = 4639). HRQoL improved in both cohorts, with a negative correlation to symptom burden and number of exacerbations in the overall cohort. PGE scores improved after 6 weeks with a better general condition at baseline in Swiss patients (PGE score 4/5: 68.9% [Swiss cohort] vs. 49.0% [overall cohort]. Despite significant differences regarding the presence of symptoms and exacerbations, therapeutic success was similar in both patient groups. Highly symptomatic patients benefited mostly from tiotropium–olodaterol treatment.
Keywords: chronic obstructive pulmonary disease (COPD); Switzerland; Clinical COPD Questionnaire (CCQ); physicians global evaluation (PGE) score
Chronic obstructive pulmonary disease (COPD) is a common, treatable disease characterized by persistent respiratory symptoms, airflow limitation, and recurrent acute exacerbations [[
Key treatment in COPD includes maintenance bronchodilator therapy with oral inhaled long-acting muscarinic antagonists (LAMAs) and long-acting β
The Spiolto Respimat
The CCQ is a well-known, easy-to-use, and multi-lingual validated tool which can assess the clinical impact of COPD treatment on patients´ specific needs and their HRQoL [[
In most of the patients, disease control is achievable with dual bronchodilator therapy [[
This non-interventional study was an open-label, self-controlled, single-arm, observational study enrolling male and female patients aged ≥40 years with confirmed diagnosis of COPD receiving tiotropium–olodaterol delivered via Spiolto Respimat
The study was approved by country-specific independent ethic committees for each participating country and was carried out in accordance with the principles of the declaration of Helsinki. Identifiers: BASEC 2018-01259 (Switzerland); NCT03663569 (clinicaltrials.gov). Written informed consent was obtained from all individual participants prior to study enrollment.
Data were analyzed using SAS version 9.4 (Cary, NC, USA). All data were expressed as mean ± SD or as n and %.
Therapeutic success was defined as a change of −0.4 points in the CCQ score between visit 1 and visit 2. The correlation between the change in CCQ score and certain baseline characteristics were analysed by means of Pearson correlation coefficients. In this analysis, we extracted the data of the Swiss patient group and compared the results to the rest of the cohort, including patients from all other participating countries.
For comparison of continuous variables, the Wilcoxon rank sum test (Mann–Whitney U test) or Kruskal–Wallis test was used. Categorical variables were compared using the χ² test, and if the χ² test was not valid, the Fisher's exact test was used. All analyses were performed in descriptive manner and p-values were interpreted nominally. A p-value of p < 0.05 was considered as significant. Missing observations were not considered for analysis.
The total cohort consists of 4700 patients, including 61 patients from Switzerland. Table 1 gives an overview about patients´ demographics and baseline characteristics. Significant differences between the Swiss cohort and the patients from other countries were observed in terms of gender distribution, disease characteristics, concomitant diseases and medication, and exacerbation history. In contrast to the other countries, in Switzerland, both genders were represented almost equally, more patients had a Modified British Medical Research Council (mMRC) Grade of 0–1, and the proportion of patients belonging to GOLD group C was larger. Additionally, in the Swiss cohort, a higher proportion of patients had ≥1 exacerbation in the last 12 months prior to study inclusion, and the mean number of exacerbations was higher than in the total cohort excluding Switzerland. Furthermore, Swiss patients had a higher proportion of concomitant diseases and concomitant medication compared with the larger cohort. Most frequently reported comorbidities of the Swiss cohort were (multiple answers possible) cardiovascular diseases (n = 38), metabolic/endocrinological diseases (n = 29), gastrointestinal/hepatobiliary diseases (n = 22, including 17 patients with gastroesophageal reflux disease (GERD)), and psychiatric diseases (n = 14).
The mean change in the total CCQ score following therapy with tiotropium–olodaterol was stratified according to the mMRC grade at baseline and study cohort (Figure 1). Results indicated no significant differences in the mean change between patients from Switzerland in comparison to patients from the other countries, irrespective of the degree of breathlessness at baseline (Figure 1).
The mean change in the total CCQ score was additionally compared between the patients from Switzerland and the patients from the other countries with respect to the number of exacerbations within the last 12 months (Figure 2). Results showed no significant differences between both cohorts in general (p-value = 0.1026). Additionally, there were no statistically significant differences between patients from both cohorts with no exacerbations in the last 12 months prior study inclusion, as well as between patients from both cohorts with ≥1 exacerbations.
The results of the Pearson correlation analysis between the changes in the total CCQ score, the mMRC score, and exacerbation frequency within the last 12 months prior to study inclusion in patients from Switzerland and from the other countries are shown in Figure 3 and Table 2. Results indicate a significant negative correlation between the mMRC score at baseline and the changes in total CCQ score in the larger cohort (p-value < 0.0001) but not in Switzerland, independently (p-value = 0.1068). A similar result was observed for the correlation between the number of exacerbations and the CCQ score change with a significant negative correlation in the other countries (p-value < 0.0001). Again, in the Swiss cohort, no significant correlation between both variables was observed (p-value = 0.4543).
At baseline, Swiss patients mostly documented a satisfactory-to-good general condition since most of the patients had a PGE score of 4 (41.0%, n = 25) or 5 (27.9%, n = 17, Figure 4A). This represented a distribution differently to the other countries, where most of the patients had a PGE of 3 (25.2%, n = 1171) or 4 (30.2%, n = 1403, Figure 4B). After 6 weeks of treatment, the PGE score improved in both cohorts, with a majority of patients in both cohorts reporting PGE scores of 5 (Switzerland: 31.2%, n = 19; other countries: 26.0%, n = 1208) or 6 (Switzerland: 31.2%, n = 19; other countries: 31.2%, n = 1449, Figure 4A,B). Details regarding the PGE scores in both cohorts are shown in Figure 4.
In the current analysis, HRQoL in COPD patients was markedly improved after onset of dual therapy with tiotropium–olodaterol without significant differences between patients from Switzerland and the pooled cohort of patients from the other countries. This is an important outcome as the results indicate that the LAMA/LABA combination tiotropium–olodaterol adequately reduces respiratory symptoms in a wide range of different patient populations. In a real-world environment, COPD patients are faced with quite different conditions in terms of health care systems, treatment management, and socio-economic circumstances. It is widely considered that such diversities can influence patients´ responsiveness to therapeutic approaches, although the reasons are still unknown [[
Although no differences regarding treatment response were observed between patients from Switzerland and patients from the other participating countries, some varieties between both cohorts were still present. In Switzerland, the proportion of patients belonging to GOLD group C was significantly higher in comparison to the other countries. This suggested that, in Switzerland, more patients suffer from COPD clinically present with less symptoms but with a higher risk for exacerbations in contrast to patients from the other countries, where most of the patients belonged to GOLD group B or D and, therefore, with an overall higher symptom burden. The high proportion of Swiss patients in GOLD group C and D was in line with data regarding exacerbation rates in the Swiss cohort. In the current study, a higher percentage of Swiss patients had ≥1 exacerbations within the previous 12 months in comparison to the other countries. Additionally, the number of exacerbations per patient was significantly higher in the Swiss group than in the overall cohort. However, reasons for the higher proportion of exacerbators in the Swiss cohort remain unclear. Acute exacerbations in COPD are mainly caused by respiratory infections (50% to 70%) [[
The general condition at baseline was slightly better in the Swiss than in the overall cohort which could be reasoned by the higher proportion of GOLD group C patients in Switzerland, since those patients experience less COPD related symptoms. However, the share of patients with concomitant diseases was significantly higher in the Swiss cohort than in the overall cohort. This seems to be contradictory to their good general condition. A possible explanation can be the well-established healthcare system in Switzerland enabling an excellent medical service to Swiss citizens [[
Our analysis has some limitations. It was performed as a post-hoc analysis to generate data on COPD patients from Switzerland and to compare those results to a large international patient cohort. The absolute number of Swiss patients was indeed small, and therefore, the results may not entirely reflect the differences between Switzerland and the other participating countries. However, since patients were included from the whole country without regional restrictions, the Swiss cohort can be considered as representative for the total Swiss COPD patient cohort. Further, data were generated during a non-interventional, observational study without having a comparison group to detect treatment efficacy in COPD as the primary effectiveness outcome in the overall population. It is discussed in the literature that real-life data (RLD) are more relevant for routine practice since they represent a real-world setting rather than an experimental setting. Usually, RLD study groups are heterogenous, involving many practitioners, and represent many alternative interventions. Another limitation represents the observational period which was rather short with 6 weeks after treatment onset. Therefore, long-lasting therapeutic effects could not be evaluated. Nevertheless, the current study was performed on a large, representative sample size in a real-world setting, including different kinds of healthcare systems and various COPD stages with mixed comorbidities and different previous treatment regimens. Therefore, results can be considered as valuable data comprehensively reflecting clinical practice in Switzerland in comparison to other European countries.
To summarize, the current analysis revealed no significant differences between COPD patients from Switzerland and from the other participating countries in treatment response based on an improvement in HRQoL, despite different healthcare systems and differences in the socio-economic environment. In both cohorts, the response to combined tiotropium–olodaterol treatment was good, and the general condition of the patients improved during the observational period. Our findings confirm the results of clinical trials, and other non-interventional, observational studies that combined tiotropium–olodaterol therapy represents an appropriate treatment option in COPD patients of GOLD group B, C, and D and should, thus, be administered in accordance with GOLD recommendations as the primary maintenance therapy in eligible patients.
Graph: Figure 1 The mean change in the total CCQ score at visit 2 according to baseline mMRC grade. n: Number of patients. * Kruskal–Wallis test.
Graph: Figure 2 The mean change in the total CCQ score at visit 2 according to number of exacerbations within the last 12 months before study inclusion. n: number of patients. * Kruskal–Wallis test.
Graph: Figure 3 Pearson Correlation between CCQ score and mMRC at baseline and number of exacerbations within the last 12 months. (A) Pearson Correlation between CCQ score and mMRC at baseline in Switzerland; (B) Pearson Correlation between CCQ score and mMRC at baseline in other countries; (C) Pearson Correlation between CCQ score and number of exacerbations within the last 12 months in Switzerland; (D) Pearson Correlation between CCQ score and number of exacerbations within the last 12 months in other countries.
Graph: Figure 4 Distribution of PGE Score at visit 1 and at visit 2 in Switzerland (A) and in other countries (B). * one patient was excluded.
Table 1 Demographic data and baseline characteristics of the Swiss cohort and the other countries.
Demographic Data and Baseline Characteristics Switzerland Other Countries Age at registration (years) 61 4639 0.9247 Mean 65.15 65.34 SD 11.50 9.31 Min 42.00 40.00 Median 66.00 66.00 Max 87.00 93.00 Age at registration ( ≤65 years 30 (49.18) 2294 (49.45) 0.9666 >65 years 31 (50.82) 2345 (50.55) Gender [ Male 32 (52.46) 3256 (70.19) 0.0027 Female 29 (47.54) 1383 (29.81) COPD degree of severity (spirometric) ( 1 3 (4.92) 150 (3.23) 0.6674 2 31 (50.82) 2578 (55.57) 3 24 (39.34) 1547 (33.35) 4 3 (4.92) 315 (6.79) Missing 0 (0.00) 49 (1.06) mMRC Questionnaire ( Grade 0–1 16 (26.23) 244 (5.26) <0.0001 Grade ≥2 45 (73.77) 4395 (94.74) GOLD Group ( A 0 (0.00) 0 (0.00) <0.0001 B 16 (26.23) 2426 (52.30) C 16 (26.23) 244 (5.26) D 29 (47.54) 1969 (42.44) Patients with concomitant diseases ( No 9 (14.75) 1568 (33.80) 0.0017 Yes 52 (85.25) 3071 (66.20) Patients with concomitant medication ( No 15 (24.59) 2405 (51.84) <0.0001 Yes 46 (75.41) 2234 (48.16) Smoking status ( Smoker 31 (50.82) 2232 (48.11) 0.2659 Ex-Smoker 28 (45.90) 1973 (42.53) Non-Smoker 2 (3.28) 434 (9.36) Patients with exacerbations in the last 12 months prior to study ( ≥1 51 (83.61) 3321 (71.59) 0.0383 0 10 (16.39) 1318 (28.41) Number of exacerbations in the last 12 months prior to study Patients with available data ( 61 4639 0.0023 Mean 1.70 1.20 SD 1.43 1.13 Min 0.00 0.00 Median 1.00 1.00 Max 8.00 12.00
Table 2 Pearson correlation between the CCQ score and mMRC at baseline, and the number of exacerbations within the last 12 months.
Switzerland Other Countries mMRC at Baseline Number of Exacerbations within the Last 12 Months mMRC at Baseline Number of Exacerbations within the Last 12 Months Change in CCQ-Score Correlation coefficient r −0.21 −0.10 −0.26 −0.19 0.1068 0.4543 <0.0001 <0.0001 61 61 4639 4639
Conceptualization, M.S., S.S. and J.P.D.; methodology, M.S., J.P.D.; formal analysis, M.S. and A.V.; investigation, M.S. and A.V.; writing—original draft preparation, M.S., S.S. and J.P.D. All authors have read and agreed to the published version of the manuscript.
This research: the medical writing assistance and the APC was funded by Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland.
The study was conducted according to the guidelines of the Declaration of Helsinki and in accordance to country-specific regulatory requirements, such as formal ethics committee approval or ethics committee notification where appropriate (date of first approval: 19 January 2016).
Informed consent was obtained from all subjects involved in the study.
The authors confirm that the data supporting the findings of this study are available within the article. To ensure independent interpretation of clinical study results, Boehringer Ingelheim grants all external authors access to relevant material, including participant-level clinical study data, as needed by them to fulfill their role and obligations as authors under the ICMJE criteria. Clinical study documents and participant clinical study data are available to be shared on request from the corresponding author.
Marc Spielmanns reports personal fees and non-financial support from Boehringer Ingelheim. Sebastian Schildge and Jens Diedrich are employees of Boehringer Ingelheim. Arschang Valipour reports personal fees, non-financial support from Boehringer Ingelheim, personal fees from Novartis, Chiesi, and AstraZeneca, during the conduct of the study. The funder was involved in the design of the study and in writing the manuscript, but had no role in the collection, analyses, or interpretation of the data, or in the decision to publish the results.
The authors would like to thank Katharina Bakhaus, Alcedis GmbH, Giessen, Germany for medical writing assistance.
By Marc Spielmanns; Sebastian Schildge; Jens Peter Diedrich and Arschang Valipour
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