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Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study

Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world... www.nature.com/npjpcrm ARTICLE OPEN Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study 1 2 3 1 4 5 5 Karin Lisspers , Kjell Larsson , Christer Janson , Björn Ställberg , Ioanna Tsiligianni , Florian S. Gutzwiller , Karen Mezzi , 6 6 1 Bine Kjoeller Bjerregaard , Leif Jorgensen and Gunnar Johansson The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000–2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD. npj Primary Care Respiratory Medicine (2019) 29:45 ; https://doi.org/10.1038/s41533-019-0157-3 INTRODUCTION been higher for women than men (9.6% vs. 8.0% in 2016). However, in most countries, women smoke less than men, Chronic obstructive pulmonary disease (COPD) is a progressive suggesting that females may be more severely affected by COPD disorder characterized by airflow limitation and is a major cause of than males and are more susceptible to the harmful effects of chronic morbidity and mortality across the world. Approximately smoking, thereby developing COPD more easily than males. In a 65 million people suffer from COPD and 3 million deaths occur large population-based study, female gender was associated with from it annually, making it the third leading cause of death reduction in lung function and more severe disease among COPD globally. The importance and significance of COPD management patients with early onset of disease or low tobacco exposure. has been well documented. According to a systematic review, the annual decline in forced Until some years ago, COPD diagnosis has in many cases been expiratory volume in 1 s was faster in female smokers compared neglected in women as it was considered a disease that primarily with male smokers despite they smoke less. affects men. According to some of the earlier reports, there was Findings from mainly observational studies point to a gender- either no gender disparity in undiagnosed COPD or women were 4,5 specific susceptibility and morbidity, and it is important to at the greater risk of undiagnosed COPD. However, recent generate real-world evidence to better understand the gender studies demonstrated that the prevalence of COPD is similar 6–11 12 aspects of COPD. In Sweden, most patients with COPD are among men and women. A study by Mamary et al. reported managed in primary care. Therefore, the aim of this study was to that men were more prone to have underdiagnosis of COPD than provide real-world evidence on gender differences with respect to women. Furthermore, mortality among women due to COPD is diagnosis and outcomes among COPD patients in the Swedish higher than from many of the most commonly recognized forms primary care setting and to identify areas for improvement and of cancer. In a Swedish study, COPD mortality among women management of such patients. increased during 1999–2009, and life expectancy in the COPD population was 9.4 years lower for women (vs. 7.4 years lower in men) compared with that of the average Swedish population. RESULTS Several findings also suggested that health status and quality of 14–19 Patient demographics life is more impaired in women than in men with COPD. The above-mentioned findings reflect the increased incidence Of the identified 18,586 eligible patients with a COPD diagnosis of smoking among females over the past decades in several listed in electronic medical records (EMRs), 291 patients were countries. Although the smoking prevalence in Sweden has excluded because they were diagnosed with COPD before 40 decreased during the period of 2006–2016, since many years it is years of age. Following case–control matching, a total of 17,479 1 2 Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden. Department of Pulmonary Medicine, Work Environment Toxicology, Karolinska Institutet, Stockholm, Sweden. Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 4 5 6 Sweden. Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Crete, Greece. Novartis Pharma AG, Basel, Switzerland. IQVIA Solutions, Copenhagen, Denmark. *email: karin.lisspers@ltdalarna.se Published in partnership with Primary Care Respiratory Society UK 1234567890():,; K. Lisspers et al. Table 1. Patient demographics of the COPD and reference groups stratified by gender. Variable Females, COPD Males, COPD p value Females, ref. population Males, ref. population p Value (N = 9506) (N = 7973) (N = 47,744) (N = 36,711) Age (years), mean (SD) 68.19 (11.4) 68.87 (10.7) <0.0001 65.2 (12.5) 64.7 (11.1) <0.0001 Body mass index (kg/m ), 25.92 (5.9) 26.24 (5.0) 0.0744 27.47 (5.6) 27.23 (4.2) 0.1807 mean (SD) CCI value , mean 1.62 1.78 <0.0001 1.30 1.37 <0.0001 Healthcare utilization Outpatient visits per year, 1.74 1.82 0.17 1.54 1.44 <0.0001 mean ± SD Primary care visits per year, 10.39 9.46 0.0006 5.12 4.45 <0.0001 mean ± SD Overnight stays, n (%) 3148 (33.12) 2894 (36.30) <0.0001 10,869 (22.77) 8628 (23.50) 0.01 Patients with outpatient 5740 (60.38) 4835 (60.64) 0.73 28,290 (59.25) 20,367 (55.48) <0.0001 hospital visits, n (%) a,c Comorbidities , n (%) Respiratory diseases (including 3613 (38.01) 2769 (34.73) <0.0001 6774 (14.19) 4376 (11.92) <0.0001 COPD and asthma) Cardiovascular diseases 3417 (35.95) 3319 (41.63) <0.0001 10,257 (21.48) 9315 (25.37) <0.0001 Hypertensive diseases 2170 (22.83) 1849 (23.19) 0.57 6418 (13.44) 5275 (14.37) 0.0001 Asthma 1554 (16.35) 977 (12.25) <0.0001 2649 (5.55) 1428 (3.89) <0.0001 Any cancer 1180 (12.41) 1121 (14.06) 0.0013 5179 (10.85) 3875 (10.56) 0.1739 Other forms of heart diseases 1138 (11.97) 1366 (17.13) <0.0001 2539 (5.32) 2849 (7.76) <0.0001 Fractures 678 (7.13) 448 (5.62) <0.0001 2734 (5.73) 1335 (3.64) <0.0001 Depression 649 (6.83) 313 (3.93) <0.0001 1510 (3.16) 668 (1.82) <0.0001 Diabetes, type II 546 (5.74) 707 (8.87) <0.0001 1745 (3.65) 2114 (5.76) <0.0001 Anxiety 455 (4.79) 243 (3.05) <0.0001 956 (2.00) 439 (1.20) <0.0001 Rheumatoid arthritis 204 (2.15) 97 (1.22) <0.0001 624 (1.31) 184 (0.50) <0.0001 Diabetes, type I 160 (1.68) 180 (2.26) 0.006 677 (1.42) 743 (2.02) <0.0001 Kidney disease 114 (1.20) 209 (2.62) <0.0001 259 (0.54) 340 (0.93) <0.0001 Lung cancer 88 (0.93) 88 (1.10) 0.2404 99 (0.21) 82 (0.22) 0.6180 Polymyalgia rheumatica 81 (0.85) 40 (0.50) 0.0054 281 (0.59) 101 (0.28) <0.0001 Nasal polyps 39 (0.41) 53 (0.66) 0.0206 124 (0.26) 218 (0.59) <0.0001 Medication use , n (%) Inhaled corticosteroids 2623 (27.59) 1816 (22.78) <0.0001 5550 (11.62) 2892 (7.88) <0.0001 Oral steroids 1897 (19.96) 1219 (15.29) <0.0001 4028 (8.44) 2222 (6.05) <0.0001 ATC anatomical therapeutic chemical, CCI Charlson comorbidity index, COPD chronic obstructive pulmonary disease, ICD International Classification of Diseases, Ref. reference, SD standard deviation Age at index date; comorbidities and healthcare utilization and medication use 2 years before the index date CCI is a method of categorizing comorbidities of patients based on the ICD diagnosis codes found in administrative data, such as hospital abstracts data. Each comorbidity category has an associated weight (from 1 to 6) based on the adjusted risk of mortality or resource use, and the sum of all the weights resultsina single comorbidity score for a patient. The higher the score, the more likely the predicted outcome will result in mortality or higher resource use ICD-10 codes and ATC codes are reported in Supplementary Tables 1 and 2, respectively patients with COPD (International Classification of Diseases, tenth number of women used inhaled corticosteroids (ICSs) and oral revision [ICD-10] code: J44) were included under cases and they corticosteroids (OCSs) compared to men. However, no significant difference was observed with respect to body mass index were compared with 84,455 age- and gender-matched controls. between the genders in both COPD and reference population. The patients were followed for a mean (standard deviation) duration of 12.4 (4.6) years. Patient demographics of the COPD patients and the reference population stratified by gender are COPD incidence summarized in Table 1. In the COPD cohort, the mean age was COPD was more frequent among females than males during the 68.2 years for females and 68.9 years for males. The proportion of observation period. The percentage of incident distribution for females (54.4%) was higher compared with males (45.6%). At females had been fairly constant at 53.8%. However, a small baseline, women were younger and had a lower Charlson downward trend was observed among females towards the later comorbidity index (CCI) value compared with men. Prevalence years of the observation period. of asthma was also significantly higher in women (p < 0.0001). Furthermore, although women had a higher number of primary Presence of asthma (ICD-10: J45/J46) care contacts, they had fewer overnight stays than men. The healthcare resource utilization data included both COPD and non- Of the 17,479 COPD patients, 6026 (34.5%) patients had a COPD, that is, comorbidity-related events. A significantly higher diagnosis code for asthma at any time point during the study. Of npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; K. Lisspers et al. Men Women 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Index year for COPD diagnosis Fig. 1 Calendar year trend in asthma before COPD diagnosis. COPD chronic obstructive pulmonary disease. these 6026 patients, 1924 (31.9%) patients had an asthma while no difference in severe exacerbations (p = 0.60) was observed on comparison with men (Fig. 3). diagnosis before the index date, while 1272 patients (21.1%) However, the mortality rate was found to be significantly higher had an asthma diagnosis 0 to 2 years after the index date and 417 in men compared to women (Fig. 2). Time from first COPD (6.92%) patients had an asthma and COPD diagnosis on the diagnosis to death is significantly longer for women than men (HR same date. [95% CI]: 0.78 [0.74–0.81], p < 0.0001). Before the index date, the asthma diagnosis showed marked It was observed that from COPD diagnosis to death, females live difference between genders; more females than males had an average of 2 years longer than males. Median survival time asthma (12.3% vs. 9.4%; p < 0.0001). Towards the later years of from COPD diagnosis to death in men (9.0 years, 95% CI: the observation period, the percentage of incident patients with 8.75–9.30) was shorter than that in women (11.1 years, 95% CI: the asthma had decreased significantly in both genders (Fig. 1). 10.8–11.5). Furthermore, no significant difference was observed between The five most common reasons of mortality among COPD males and females in the time period from the asthma diagnosis patients stratified by gender are shown in Fig. 4. During the study to the index date (difference: 3.1 years; p = 0.9284). period, it was seen that mortality due to neoplasms and circulatory system was significantly higher among males than Comorbidities females. However, no difference was observed for mortality due to The frequency of all comorbidities was higher in the COPD COPD between genders (males: n = 345 ± 4.01; females: n = 387 ± population compared with the reference population when 3.87; p = 0.62). The detailed results are reported in Supplementary analyzed 3 years before and 3 years after the index date. A Table 3. gender difference was observed in some of the comorbidities in both COPD and reference populations, and the magnitude of this Healthcare resource utilization difference was generally observed to be higher in the COPD Males had a higher number of hospitalizations, more nights at population compared with the reference population. hospital, and more outpatient visits to hospitals than females for The comorbidities that were more prevalent in females included all diseases (COPD and non-COPD, i.e., comorbidities). However, asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, when only COPD-related incidents were analyzed, females had a depression, and anxiety. The comorbidities that were more higher number of hospitalizations, more nights at hospital, and prevalent in males included type I and type II diabetes, kidney more outpatient visits to hospitals (Table 2). diseases, and cardiovascular diseases. The comorbidities where no There was no difference between genders for the number of gender difference was observed included respiratory diseases visits to primary care, neither for nurse visits (mean [95% CI]: men, (excluding COPD and asthma: ICD-10 code J41–J45), polymyalgia 8.30 [8.01–8.60]; women, 8.53 [8.26–8.81]; p = 0.2633) nor rheumatica, nasal polyps, any cancer, lung cancer, dementia, and physician visits (mean [95% CI]: men, 6.89 [6.58–7.20]; women, hyperlipidemia. 6.74 [6.45–7.03]; p = 0.4957). Data for primary care contacts cannot be stratified into COPD related and non-COPD related Exacerbations and mortality due to the structure of the primary care records. During the follow-up period, women exacerbated more frequently Annual direct healthcare utilization costs in 2013 were slightly than men as indicated by the significantly higher frequency of higher for men than for women (€11,054 vs. €10,173). The indirect exacerbations throughout the study period (Fig. 2). Time-to-first- cost (loss of income) was higher for the male patients (€13,995/ exacerbation analysis revealed that women had a 12% higher risk year) than for the female patients (8711/€year) compared with the of an earlier exacerbation than men (hazard ratio; HR [95% income in the reference population, with the difference between confidence interval; CI]: 1.12 [1.09–1.16], p < 0.0001). In terms of gender of €5284/year as a mean value for the 2006–2013 period, severity, women had more moderate exacerbations (p < 0.0001), mostly reflecting the higher income among men. Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 Percentage of patients with prior asthma K. Lisspers et al. Men Women 7.0 6.66 6.0 5.0 4.66 4.0 3.0 2.59 2.56 2.0 1.0 0.0 Moderate exacerbation Severe exacerbation Fig. 3 Number of moderate and severe exacerbations. Men Women P<0.0001 100% 88% 84% 80% 60% P<0.0001 45% 38% 40% 20% 0% Exacerbation Mortality Fig. 2 Mortality and exacerbations during the study period. COPD drug prescriptions In addition, the prevalence of asthma was significantly higher in women than in men, and these findings are concordant with Results suggested that females receive significantly higher 25,26 previously published studies. One reason for this might be number of COPD drug prescriptions (except long-acting β - due to the fact that women with COPD have been more likely to agonist [LABA]/long-acting muscarinic antagonist [LAMA] fixed be misdiagnosed with asthma than men. However, during the combinations) than males (Table 3). later years of the observation period, the proportion of incident patients with asthma had significantly decreased for both genders, which might be reflecting the improved precision in DISCUSSION COPD diagnosis over time. Moreover, no significant difference The results of this study suggested a closing of the gap in COPD among men and women was observed in terms of time period prevalence among both genders. Also, the burden of comorbid- from diagnosis of asthma to the index date, indicating no gender ities including asthma and the risk of exacerbations was higher in difference in the diagnostic procedure. In contrast to our results, a women. Furthermore, COPD-related hospital visits and use of 12 study by Mamary et al. reported that COPD was more likely to be COPD drug prescriptions were higher in women than in men. In underdiagnosed in men compared to women. The reason stated contrast, the survival rate was better among women compared to by the author was that women report symptoms earlier and are men, but no difference was observed for mortality due to COPD more likely to utilize healthcare resources than men. between genders. According to a Danish study, up to 28% variation in healthcare In alignment with these findings, a considerable number of expenditures can be caused by the presence of comorbidities, studies have indicated that COPD prevalence is now similar while only 5% of such variation can be caused by other 6–11 among men and women. This is likely due to dramatic increase demographic characteristics such as age and sex. Our findings in smoking rates among women in some regions of the world, suggest that the prevalence of comorbidities such as depression, including Sweden, where smoking rates are higher among women fracture, osteoporosis, rheumatoid arthritis, rhinitis, and anxiety vs. men. was higher in women than in men. On the other hand, the npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK Percentage of patients Mean number of exacerbations K. Lisspers et al. Men Women 0.58 R – Symptoms, signs etc P =0.5821 0.52 0.88 K – Digestive system P = 0.4547 0.78 5.18 P = 0.1594 J – Respiratory system 4.73 6.42 P = 0.0010 C – Neoplasms 5.28 9.03 P <0.0001 I – Circulatory system 6.71 01 23 4 5 678 9 10 Percentage of patients Fig. 4 Five most common reasons of mortality among COPD patients. COPD chronic obstructive pulmonary disease. Table 2. Hospital visits per year for COPD patients during the study period. Variable Mean (95% CI) p Value Male Female All diagnosis No. of hospitalizations per year 1.43 (1.35–1.51) 1.17 (1.10–1.24) <0.0001 No. of outpatient visits per year 2.34 (2.24–2.44) 2.16 (2.07–2.25) 0.008 No. of nights at hospital per year, all diagnosis 9.62 (9.09–10.16) 8.92 (8.42–9.42) 0.06 COPD related No. of hospitalizations per year 0.14 (0.12–0.16) 0.17 (0.16–0.19) 0.007 No. of outpatient visits per year 0.12 (0.11–0.14) 0.14 (0.13–0.15) 0.15 No. of nights at hospital per year 0.85 (0.70–0.99) 1.21 (1.08–1.34) 0.0002 CI confidence interval, COPD chronic obstructive pulmonary disease lead to the vicious cycle of breathlessness and anxiety known as Table 3. COPD drug prescriptions . “dyspnea–anxiety–dyspnea cycle,” which means that patients’ emotional response to breathlessness result in intensification of Drug Mean no. of prescriptions per p Value their perception of breathlessness. Hence, it is very important for year (95% CI) healthcare professionals to be knowledgeable of and take into Male Female account gender differences regarding comorbidities when mana- ging patients with COPD. ICS 0.36 (0.33–0.39) 0.49 (0.46–0.52) <0.0001 In alignment with published literature, COPD exacerbations OCS 0.79 (0.73–0.86) 1.02 (0.95–1.08) <0.0001 occur more frequently among women. This can be attributed to SABA 1.05 (0.99–1.12) 1.39 (1.33–1.46) <0.0001 the greater prevalence of airway hyperresponsiveness in women, which is a significant predictor of lung function decline and also LAMA 1.42 (1.37–1.47) 1.62 (1.58–1.67) <0.0001 results in increased susceptibility to harmful effects of smoking LABA 0.30 (0.28–0.33) 0.40 (0.37–0.42) <0.0001 among women. As the risk of exacerbations is higher in women, LABA/LAMA fixed 0.01 (0.01–0.01) 0.01 (0.01–0.01) 0.6511 COPD-related healthcare resource utilization is also higher, combinations indicating that women may benefit from closer monitoring of LABA/ICS fixed 1.03 (0.99–1.07) 1.16 (1.13–1.20) <0.0001 their exacerbation risk. Therefore, healthcare professionals should combinations be more aware of these differences and try to be more prone to CI confidence interval, COPD chronic obstructive pulmonary disease, ICS investigate, treat, and follow-up women with COPD. inhaled corticosteroids, LABA long-acting β -agonist, LAMA long-acting 2 On the other hand, we found that survival in women was better muscarinic antagonist, OCS oral corticosteroids, SABA short-acting β - vs. men, which was consistent with findings from other agonist 21,35 studies. Findings from the PATHOS study conducted in ATC codes are reported in Supplementary Table 2 Sweden revealed that COPD mortality in women increased from 1999 to 2009, and life expectancy among COPD patients was 9.4 years lower in women (vs. 7.4 years lower in men) compared with incidence of type I and type II diabetes, kidney diseases, and the average Swedish population. Among the five most common cardiovascular diseases was higher among men. These observa- reasons of mortality, a significantly higher rate was observed for 15,16,28–31 tions are in alignment with earlier published literature. mortality due to neoplasms and circulatory system among males Depression and anxiety are among the strongest predictors of compared to females; however, there was no difference for impaired quality of life, and anxiety among COPD patients can mortality due to COPD between genders. Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 K. Lisspers et al. In general, women used more medications for COPD, and this Following ethical approval, EMR data for COPD patients between 2000 and 2014 from 52 primary care centers across Sweden were collected trend might be due to various reasons, including more exacerba- using an established software system (Pygargus Customized eXtraction tions, more respiratory symptoms and impaired quality of life, and Program) and included age and gender, prescriptions (according to the higher prevalence of asthma compared to men. As asthma is more World Health Organization Anatomic Therapeutic Chemical [ATC] codes), frequent in women, the study results demonstrated that women doctor’s diagnoses (according to the ICD-10 codes), spirometry measure- received significantly more prescriptions for ICS and LABA/ICS ments, laboratory tests, healthcare professional visits, and referrals. The fixed-dose combinations compared to men. It was also observed centers covered urban and rural sites of varying sizes across Sweden. EMR that significantly higher proportion of women are prescribed OCS data were linked by the Swedish National Board of Health and Welfare than men and this can be because of the higher exacerbation rate using individual patient identification (ID) numbers to National Registry data sources (patient IDs were pseudonymized). These data sources in women. Use of ICS is known to further increase the risk of included (i) the Longitudinal Integration Database for Health Insurance and fractures, particularly in women with COPD who are already at Labor Market Studies, which contains socio-demographic data, including higher risk of osteoporosis compared with men. The long course educational level, marital status and family situation, occupational status, use of OCS in patients with acute exacerbation of COPD is retirement and economic compensation, and social benefits; (ii) the associated with increased risk of pneumonia hospitalization and National Patient Register, which contains data related to diagnosis from all-cause mortality within 1-year period from the start of secondary care (ICD-10 code and associated position), including surgery, treatment. Hence, treatment with ICS and OCS in women with gender, age, region, hospital visits, specialty visits, hospital admissions, COPD should be carefully assessed. discharges, medical procedures, and surgeries performed in inpatient and The present study has several important strengths. The large outpatient specialist settings; (iii) the National Prescription Register (from 2005), which contains the full details of all dispensed medications (ATC sample size of the study comprised patients across the whole COPD codes) from both primary and secondary care, including brand name, classification spectrum. Moreover, the primary care setting and the prescription date, dose, strength, pack size, specialty of the prescriber, and real-world study design adequately reflects the general population costs associated with the drug prescription; and (iv) the Cause of Death and clinical practice in Sweden. Furthermore, measurement of the Register, which holds information related to sex, date of death, and the comprehensive range of outcomes over the extended assessment underlying cause of death. period (2000–2014) generated robust data on gender differences between COPD and non-COPD patients. Data quantification in this Study patients study can allow decision makers to identify gender-specific The study population consisted of patients aged ≥40 years who had differences in COPD risk and outcomes and analyze how integrated received either a physician’s diagnosis of COPD (ICD-10 code: J44) in screening and treatment strategies can be devised to achieve better primary care (EMR database) or a physician’s diagnosis of asthma (ICD-10 outcomes for millions of women with COPD worldwide. code: J45/J46) in primary care that was later verified as COPD, or COPD was Nevertheless, this study also has certain limitations. As this was added to the asthma diagnosis in the hospital setting according to the a retrospective study, the potential for bias and confounding National Patient Register. An age- and gender-matched reference cannot be excluded. Although all patients had physician- population was selected from the primary care centers, excluding those who had a diagnosis of COPD and/or asthma. The age and gender were diagnosed COPD, the accuracy of COPD diagnosis and the severity matched for overall population and not at the subgroup level. Therefore, of disease could not be verified. In addition, use of medications differences in age could be observed when analyzed by gender subgroups. was based on prescription claims, while patients’ actual adherence to treatment remains unknown. Moreover, this study was Outcomes conducted only in Swedish patients, and it is therefore uncertain whether these findings can be extrapolated to a more diverse Difference between genders was evaluated with respect to the incidence of COPD; prevalence of asthma and comorbidities; risk of exacerbations group of patients and to other healthcare systems. Furthermore, and severity of exacerbations; mortality rate, duration from the index date the reference population was identified from primary care centers to death and reason for mortality, healthcare resource use and costs; and rather than from healthy individuals in the general population. the number of COPD drug prescriptions. An overall measure of In conclusion, our findings demonstrated that COPD is now comorbidities was calculated by the CCI. CCI is a method of categorizing equally prevalent among men and women, thus imposing a comorbidities of patients based on the ICD diagnosis codes found in significant healthcare disease burden among women. Despite a primary care medical records and register data from secondary care. Each lower mortality rate, women had higher prevalence comorbidities comorbidity category has an associated weight (from 1 to 6), based on the including asthma and a higher risk of exacerbations, leading to adjusted risk of mortality or resource use, and the sum of all the weights more utilization of COPD drugs and COPD-related healthcare results in a single comorbidity index for a patient. The higher the index, the more likely the predicted outcome will result in mortality or higher resources. In daily clinical practice, healthcare professionals in resource use. Prevalence of the most common comorbidities at 3 years primary care play a pivotal role and should consider all these before and after the first COPD diagnosis was compared between genders parameters in order to properly diagnose and treat women with for both COPD patients and non-COPD patients (reference population). COPD. Additional research is warranted to understand the gender- “Moderate exacerbations” were defined as treatment with systemic specific differences and to formulate gender-targeted strategies corticosteroids (H02AB) or antibiotics (J01AA, J01CA) or both (but no for prevention and treatment of COPD in both women and men. hospitalization). “Severe exacerbations” were defined as COPD-related The focus should also be on recognizing and treating comorbid- hospitalizations (J44 in primary position or J44.0/J44.1 in secondary) or ities together with interventions that directly target COPD. emergency visits (J44.0/J44.1 in outpatient hospital care). Recurrent exacerba- tions occurring within 14 days were considered as one unique event. “Hospital nights” was defined as the sum of overnight stays at a hospital per patient. “Hospitalizations” was the number of times that a patient has METHODS been admitted to a hospital regardless of the length of stay. “Outpatient Study design visit” was defined as the visit to a hospital that did not include an overnight ARCTIC was a large, real-world, retrospective, Swedish cohort study stay. Comorbidities were defined based on diagnosis codes in the primary conducted in 18,586 eligible, primary care, COPD patients. Ethical approval or secondary care setting and by medications according to the National for the study was obtained from the local Ethical Regional Board in Prescription Register. The study index date constituted the time of the first Uppsala, Sweden, on 11 December 2014 (number: 2014-397), for accessing recorded physician’s diagnosis of COPD during the enrollment timeframe. the National Health Register and for recruiting primary care centers to the study. An amendment specifying additional analysis was approved by the Statistical analysis Ethical Regional Board in Uppsala on 6 October 2017. Data from all records were de-identified, and therefore, patient consent was not required by the A sample size calculation conducted prior to the study indicated that ethics committee. 13,800 patients were required to detect a 4% difference between groups, npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK K. Lisspers et al. with a power of 80% and an α level of 5% in the two-tailed test. The 12. Mamary, A. J. et al. 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Thorax 66, 699–708 (2011). primary care. Br. J. Gen. Pract. 59, 927–933 (2009). 37. Sivapalan, P. et al. COPD exacerbations: the impact of long versus short courses 9. Rycroft, C. E., Heyes, A., Lanza, L. & Becker, K. Epidemiology of chronic obstructive of oral corticosteroids on mortality and pneumonia: nationwide data on 67000 pulmonary disease: a literature review. Int. J. Chron. Obstruct. Pulmon. Dis. 7, patients with COPD followed for 12 months. BMJ Open Respir. Res. 6, e000407 457–494 (2012). (2019). 10. Tsiligianni, I., Rodriguez, M. R., Lisspers, K., LeeTan, T. & Infantino, A. Call to action: 38. University of Manitoba – Community of Health Sciences – Manitoba Center for improving primary care for women with COPD. NPJ Prim. Care Respir. Med. 27,11 (2017). Health Policy. Concept Description: Charlson Comorbidity Index [updated 17 Jan 2019]. Available from: http://mchp-appserv.cpe.umanitoba.ca/viewConcept.php? 11. Waatevik, M. et al. Increased prevalence of chronic obstructive pulmonary dis- printer=Y&conceptID=1098 (2019). Accessed 22 Feb 2019. ease in a general population. Respir. Med. 107, 1037–1045 (2013). Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 K. Lisspers et al. ACKNOWLEDGEMENTS this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk, and Takeda. This study was funded by Novartis Pharma AG, Basel, Switzerland. We would like to thank Harneet Kaur (Novartis) for managing and providing writing assistance in the development of this manuscript. ADDITIONAL INFORMATION Supplementary information is available for this paper at https://doi.org/10.1038/ AUTHOR CONTRIBUTIONS s41533-019-0157-3. All authors participated equally in the study conception, design, statistical analysis Correspondence and requests for materials should be addressed to K.L. planning, analyzed, and interpreted the data and have reviewed and approved the manuscript. Reprints and permission information is available at http://www.nature.com/ reprints COMPETING INTERESTS Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims K.L. has, during the past 5 years, received honoraria for educational activities and in published maps and institutional affiliations. lectures from AstraZeneca, GlaxoSmithKline, TEVA, and Novartis and has served on advisory boards arranged by Novartis and Boehringer Ingelheim. She has also participated in the steering committee for this study funded by Novartis. K. Larsson has, during the past 5 years, on one or more occasion served in an advisory board, served as a speaker, and/or participated in education activities arranged by Open Access This article is licensed under a Creative Commons AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion, Attribution 4.0 International License, which permits use, sharing, and Teva. C.J. has received honoraria for educational activities and lectures from adaptation, distribution and reproduction in any medium or format, as long as you give Novartis, AstraZeneca, GlaxoSmithKline, TEVA, and Boehringer Ingelheim outside the appropriate credit to the original author(s) and the source, provide a link to the Creative submitted work. B.S. has received honoraria for educational activities and lectures Commons license, and indicate if changes were made. The images or other third party from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, MEDA, and TEVA material in this article are included in the article’s Creative Commons license, unless and has served on advisory boards arranged by AstraZeneca, Novartis, GSK, indicated otherwise in a credit line to the material. If material is not included in the Boehringer Ingelheim, and MEDA. I.T. has received honoraria for lectures and article’s Creative Commons license and your intended use is not permitted by statutory participation in advisory boards from Novartis, GlaxoSmithKline, Boehringer regulation or exceeds the permitted use, you will need to obtain permission directly Ingelheim, and Menarini. The authors report no other competing interest related from the copyright holder. To view a copy of this license, visit http://creativecommons. to this manuscript. F.S.G. and K.M. are employees of Novartis Pharma AG. B.K.B. and org/licenses/by/4.0/. 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Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study

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Medicine & Public Health; Medicine/Public Health, general; Primary Care Medicine; Internal Medicine; Pneumology/Respiratory System; Thoracic Surgery
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Abstract

www.nature.com/npjpcrm ARTICLE OPEN Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retrospective cohort study 1 2 3 1 4 5 5 Karin Lisspers , Kjell Larsson , Christer Janson , Björn Ställberg , Ioanna Tsiligianni , Florian S. Gutzwiller , Karen Mezzi , 6 6 1 Bine Kjoeller Bjerregaard , Leif Jorgensen and Gunnar Johansson The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000–2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD. npj Primary Care Respiratory Medicine (2019) 29:45 ; https://doi.org/10.1038/s41533-019-0157-3 INTRODUCTION been higher for women than men (9.6% vs. 8.0% in 2016). However, in most countries, women smoke less than men, Chronic obstructive pulmonary disease (COPD) is a progressive suggesting that females may be more severely affected by COPD disorder characterized by airflow limitation and is a major cause of than males and are more susceptible to the harmful effects of chronic morbidity and mortality across the world. Approximately smoking, thereby developing COPD more easily than males. In a 65 million people suffer from COPD and 3 million deaths occur large population-based study, female gender was associated with from it annually, making it the third leading cause of death reduction in lung function and more severe disease among COPD globally. The importance and significance of COPD management patients with early onset of disease or low tobacco exposure. has been well documented. According to a systematic review, the annual decline in forced Until some years ago, COPD diagnosis has in many cases been expiratory volume in 1 s was faster in female smokers compared neglected in women as it was considered a disease that primarily with male smokers despite they smoke less. affects men. According to some of the earlier reports, there was Findings from mainly observational studies point to a gender- either no gender disparity in undiagnosed COPD or women were 4,5 specific susceptibility and morbidity, and it is important to at the greater risk of undiagnosed COPD. However, recent generate real-world evidence to better understand the gender studies demonstrated that the prevalence of COPD is similar 6–11 12 aspects of COPD. In Sweden, most patients with COPD are among men and women. A study by Mamary et al. reported managed in primary care. Therefore, the aim of this study was to that men were more prone to have underdiagnosis of COPD than provide real-world evidence on gender differences with respect to women. Furthermore, mortality among women due to COPD is diagnosis and outcomes among COPD patients in the Swedish higher than from many of the most commonly recognized forms primary care setting and to identify areas for improvement and of cancer. In a Swedish study, COPD mortality among women management of such patients. increased during 1999–2009, and life expectancy in the COPD population was 9.4 years lower for women (vs. 7.4 years lower in men) compared with that of the average Swedish population. RESULTS Several findings also suggested that health status and quality of 14–19 Patient demographics life is more impaired in women than in men with COPD. The above-mentioned findings reflect the increased incidence Of the identified 18,586 eligible patients with a COPD diagnosis of smoking among females over the past decades in several listed in electronic medical records (EMRs), 291 patients were countries. Although the smoking prevalence in Sweden has excluded because they were diagnosed with COPD before 40 decreased during the period of 2006–2016, since many years it is years of age. Following case–control matching, a total of 17,479 1 2 Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden. Department of Pulmonary Medicine, Work Environment Toxicology, Karolinska Institutet, Stockholm, Sweden. Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 4 5 6 Sweden. Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Crete, Greece. Novartis Pharma AG, Basel, Switzerland. IQVIA Solutions, Copenhagen, Denmark. *email: karin.lisspers@ltdalarna.se Published in partnership with Primary Care Respiratory Society UK 1234567890():,; K. Lisspers et al. Table 1. Patient demographics of the COPD and reference groups stratified by gender. Variable Females, COPD Males, COPD p value Females, ref. population Males, ref. population p Value (N = 9506) (N = 7973) (N = 47,744) (N = 36,711) Age (years), mean (SD) 68.19 (11.4) 68.87 (10.7) <0.0001 65.2 (12.5) 64.7 (11.1) <0.0001 Body mass index (kg/m ), 25.92 (5.9) 26.24 (5.0) 0.0744 27.47 (5.6) 27.23 (4.2) 0.1807 mean (SD) CCI value , mean 1.62 1.78 <0.0001 1.30 1.37 <0.0001 Healthcare utilization Outpatient visits per year, 1.74 1.82 0.17 1.54 1.44 <0.0001 mean ± SD Primary care visits per year, 10.39 9.46 0.0006 5.12 4.45 <0.0001 mean ± SD Overnight stays, n (%) 3148 (33.12) 2894 (36.30) <0.0001 10,869 (22.77) 8628 (23.50) 0.01 Patients with outpatient 5740 (60.38) 4835 (60.64) 0.73 28,290 (59.25) 20,367 (55.48) <0.0001 hospital visits, n (%) a,c Comorbidities , n (%) Respiratory diseases (including 3613 (38.01) 2769 (34.73) <0.0001 6774 (14.19) 4376 (11.92) <0.0001 COPD and asthma) Cardiovascular diseases 3417 (35.95) 3319 (41.63) <0.0001 10,257 (21.48) 9315 (25.37) <0.0001 Hypertensive diseases 2170 (22.83) 1849 (23.19) 0.57 6418 (13.44) 5275 (14.37) 0.0001 Asthma 1554 (16.35) 977 (12.25) <0.0001 2649 (5.55) 1428 (3.89) <0.0001 Any cancer 1180 (12.41) 1121 (14.06) 0.0013 5179 (10.85) 3875 (10.56) 0.1739 Other forms of heart diseases 1138 (11.97) 1366 (17.13) <0.0001 2539 (5.32) 2849 (7.76) <0.0001 Fractures 678 (7.13) 448 (5.62) <0.0001 2734 (5.73) 1335 (3.64) <0.0001 Depression 649 (6.83) 313 (3.93) <0.0001 1510 (3.16) 668 (1.82) <0.0001 Diabetes, type II 546 (5.74) 707 (8.87) <0.0001 1745 (3.65) 2114 (5.76) <0.0001 Anxiety 455 (4.79) 243 (3.05) <0.0001 956 (2.00) 439 (1.20) <0.0001 Rheumatoid arthritis 204 (2.15) 97 (1.22) <0.0001 624 (1.31) 184 (0.50) <0.0001 Diabetes, type I 160 (1.68) 180 (2.26) 0.006 677 (1.42) 743 (2.02) <0.0001 Kidney disease 114 (1.20) 209 (2.62) <0.0001 259 (0.54) 340 (0.93) <0.0001 Lung cancer 88 (0.93) 88 (1.10) 0.2404 99 (0.21) 82 (0.22) 0.6180 Polymyalgia rheumatica 81 (0.85) 40 (0.50) 0.0054 281 (0.59) 101 (0.28) <0.0001 Nasal polyps 39 (0.41) 53 (0.66) 0.0206 124 (0.26) 218 (0.59) <0.0001 Medication use , n (%) Inhaled corticosteroids 2623 (27.59) 1816 (22.78) <0.0001 5550 (11.62) 2892 (7.88) <0.0001 Oral steroids 1897 (19.96) 1219 (15.29) <0.0001 4028 (8.44) 2222 (6.05) <0.0001 ATC anatomical therapeutic chemical, CCI Charlson comorbidity index, COPD chronic obstructive pulmonary disease, ICD International Classification of Diseases, Ref. reference, SD standard deviation Age at index date; comorbidities and healthcare utilization and medication use 2 years before the index date CCI is a method of categorizing comorbidities of patients based on the ICD diagnosis codes found in administrative data, such as hospital abstracts data. Each comorbidity category has an associated weight (from 1 to 6) based on the adjusted risk of mortality or resource use, and the sum of all the weights resultsina single comorbidity score for a patient. The higher the score, the more likely the predicted outcome will result in mortality or higher resource use ICD-10 codes and ATC codes are reported in Supplementary Tables 1 and 2, respectively patients with COPD (International Classification of Diseases, tenth number of women used inhaled corticosteroids (ICSs) and oral revision [ICD-10] code: J44) were included under cases and they corticosteroids (OCSs) compared to men. However, no significant difference was observed with respect to body mass index were compared with 84,455 age- and gender-matched controls. between the genders in both COPD and reference population. The patients were followed for a mean (standard deviation) duration of 12.4 (4.6) years. Patient demographics of the COPD patients and the reference population stratified by gender are COPD incidence summarized in Table 1. In the COPD cohort, the mean age was COPD was more frequent among females than males during the 68.2 years for females and 68.9 years for males. The proportion of observation period. The percentage of incident distribution for females (54.4%) was higher compared with males (45.6%). At females had been fairly constant at 53.8%. However, a small baseline, women were younger and had a lower Charlson downward trend was observed among females towards the later comorbidity index (CCI) value compared with men. Prevalence years of the observation period. of asthma was also significantly higher in women (p < 0.0001). Furthermore, although women had a higher number of primary Presence of asthma (ICD-10: J45/J46) care contacts, they had fewer overnight stays than men. The healthcare resource utilization data included both COPD and non- Of the 17,479 COPD patients, 6026 (34.5%) patients had a COPD, that is, comorbidity-related events. A significantly higher diagnosis code for asthma at any time point during the study. Of npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; K. Lisspers et al. Men Women 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Index year for COPD diagnosis Fig. 1 Calendar year trend in asthma before COPD diagnosis. COPD chronic obstructive pulmonary disease. these 6026 patients, 1924 (31.9%) patients had an asthma while no difference in severe exacerbations (p = 0.60) was observed on comparison with men (Fig. 3). diagnosis before the index date, while 1272 patients (21.1%) However, the mortality rate was found to be significantly higher had an asthma diagnosis 0 to 2 years after the index date and 417 in men compared to women (Fig. 2). Time from first COPD (6.92%) patients had an asthma and COPD diagnosis on the diagnosis to death is significantly longer for women than men (HR same date. [95% CI]: 0.78 [0.74–0.81], p < 0.0001). Before the index date, the asthma diagnosis showed marked It was observed that from COPD diagnosis to death, females live difference between genders; more females than males had an average of 2 years longer than males. Median survival time asthma (12.3% vs. 9.4%; p < 0.0001). Towards the later years of from COPD diagnosis to death in men (9.0 years, 95% CI: the observation period, the percentage of incident patients with 8.75–9.30) was shorter than that in women (11.1 years, 95% CI: the asthma had decreased significantly in both genders (Fig. 1). 10.8–11.5). Furthermore, no significant difference was observed between The five most common reasons of mortality among COPD males and females in the time period from the asthma diagnosis patients stratified by gender are shown in Fig. 4. During the study to the index date (difference: 3.1 years; p = 0.9284). period, it was seen that mortality due to neoplasms and circulatory system was significantly higher among males than Comorbidities females. However, no difference was observed for mortality due to The frequency of all comorbidities was higher in the COPD COPD between genders (males: n = 345 ± 4.01; females: n = 387 ± population compared with the reference population when 3.87; p = 0.62). The detailed results are reported in Supplementary analyzed 3 years before and 3 years after the index date. A Table 3. gender difference was observed in some of the comorbidities in both COPD and reference populations, and the magnitude of this Healthcare resource utilization difference was generally observed to be higher in the COPD Males had a higher number of hospitalizations, more nights at population compared with the reference population. hospital, and more outpatient visits to hospitals than females for The comorbidities that were more prevalent in females included all diseases (COPD and non-COPD, i.e., comorbidities). However, asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, when only COPD-related incidents were analyzed, females had a depression, and anxiety. The comorbidities that were more higher number of hospitalizations, more nights at hospital, and prevalent in males included type I and type II diabetes, kidney more outpatient visits to hospitals (Table 2). diseases, and cardiovascular diseases. The comorbidities where no There was no difference between genders for the number of gender difference was observed included respiratory diseases visits to primary care, neither for nurse visits (mean [95% CI]: men, (excluding COPD and asthma: ICD-10 code J41–J45), polymyalgia 8.30 [8.01–8.60]; women, 8.53 [8.26–8.81]; p = 0.2633) nor rheumatica, nasal polyps, any cancer, lung cancer, dementia, and physician visits (mean [95% CI]: men, 6.89 [6.58–7.20]; women, hyperlipidemia. 6.74 [6.45–7.03]; p = 0.4957). Data for primary care contacts cannot be stratified into COPD related and non-COPD related Exacerbations and mortality due to the structure of the primary care records. During the follow-up period, women exacerbated more frequently Annual direct healthcare utilization costs in 2013 were slightly than men as indicated by the significantly higher frequency of higher for men than for women (€11,054 vs. €10,173). The indirect exacerbations throughout the study period (Fig. 2). Time-to-first- cost (loss of income) was higher for the male patients (€13,995/ exacerbation analysis revealed that women had a 12% higher risk year) than for the female patients (8711/€year) compared with the of an earlier exacerbation than men (hazard ratio; HR [95% income in the reference population, with the difference between confidence interval; CI]: 1.12 [1.09–1.16], p < 0.0001). In terms of gender of €5284/year as a mean value for the 2006–2013 period, severity, women had more moderate exacerbations (p < 0.0001), mostly reflecting the higher income among men. Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 Percentage of patients with prior asthma K. Lisspers et al. Men Women 7.0 6.66 6.0 5.0 4.66 4.0 3.0 2.59 2.56 2.0 1.0 0.0 Moderate exacerbation Severe exacerbation Fig. 3 Number of moderate and severe exacerbations. Men Women P<0.0001 100% 88% 84% 80% 60% P<0.0001 45% 38% 40% 20% 0% Exacerbation Mortality Fig. 2 Mortality and exacerbations during the study period. COPD drug prescriptions In addition, the prevalence of asthma was significantly higher in women than in men, and these findings are concordant with Results suggested that females receive significantly higher 25,26 previously published studies. One reason for this might be number of COPD drug prescriptions (except long-acting β - due to the fact that women with COPD have been more likely to agonist [LABA]/long-acting muscarinic antagonist [LAMA] fixed be misdiagnosed with asthma than men. However, during the combinations) than males (Table 3). later years of the observation period, the proportion of incident patients with asthma had significantly decreased for both genders, which might be reflecting the improved precision in DISCUSSION COPD diagnosis over time. Moreover, no significant difference The results of this study suggested a closing of the gap in COPD among men and women was observed in terms of time period prevalence among both genders. Also, the burden of comorbid- from diagnosis of asthma to the index date, indicating no gender ities including asthma and the risk of exacerbations was higher in difference in the diagnostic procedure. In contrast to our results, a women. Furthermore, COPD-related hospital visits and use of 12 study by Mamary et al. reported that COPD was more likely to be COPD drug prescriptions were higher in women than in men. In underdiagnosed in men compared to women. The reason stated contrast, the survival rate was better among women compared to by the author was that women report symptoms earlier and are men, but no difference was observed for mortality due to COPD more likely to utilize healthcare resources than men. between genders. According to a Danish study, up to 28% variation in healthcare In alignment with these findings, a considerable number of expenditures can be caused by the presence of comorbidities, studies have indicated that COPD prevalence is now similar while only 5% of such variation can be caused by other 6–11 among men and women. This is likely due to dramatic increase demographic characteristics such as age and sex. Our findings in smoking rates among women in some regions of the world, suggest that the prevalence of comorbidities such as depression, including Sweden, where smoking rates are higher among women fracture, osteoporosis, rheumatoid arthritis, rhinitis, and anxiety vs. men. was higher in women than in men. On the other hand, the npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK Percentage of patients Mean number of exacerbations K. Lisspers et al. Men Women 0.58 R – Symptoms, signs etc P =0.5821 0.52 0.88 K – Digestive system P = 0.4547 0.78 5.18 P = 0.1594 J – Respiratory system 4.73 6.42 P = 0.0010 C – Neoplasms 5.28 9.03 P <0.0001 I – Circulatory system 6.71 01 23 4 5 678 9 10 Percentage of patients Fig. 4 Five most common reasons of mortality among COPD patients. COPD chronic obstructive pulmonary disease. Table 2. Hospital visits per year for COPD patients during the study period. Variable Mean (95% CI) p Value Male Female All diagnosis No. of hospitalizations per year 1.43 (1.35–1.51) 1.17 (1.10–1.24) <0.0001 No. of outpatient visits per year 2.34 (2.24–2.44) 2.16 (2.07–2.25) 0.008 No. of nights at hospital per year, all diagnosis 9.62 (9.09–10.16) 8.92 (8.42–9.42) 0.06 COPD related No. of hospitalizations per year 0.14 (0.12–0.16) 0.17 (0.16–0.19) 0.007 No. of outpatient visits per year 0.12 (0.11–0.14) 0.14 (0.13–0.15) 0.15 No. of nights at hospital per year 0.85 (0.70–0.99) 1.21 (1.08–1.34) 0.0002 CI confidence interval, COPD chronic obstructive pulmonary disease lead to the vicious cycle of breathlessness and anxiety known as Table 3. COPD drug prescriptions . “dyspnea–anxiety–dyspnea cycle,” which means that patients’ emotional response to breathlessness result in intensification of Drug Mean no. of prescriptions per p Value their perception of breathlessness. Hence, it is very important for year (95% CI) healthcare professionals to be knowledgeable of and take into Male Female account gender differences regarding comorbidities when mana- ging patients with COPD. ICS 0.36 (0.33–0.39) 0.49 (0.46–0.52) <0.0001 In alignment with published literature, COPD exacerbations OCS 0.79 (0.73–0.86) 1.02 (0.95–1.08) <0.0001 occur more frequently among women. This can be attributed to SABA 1.05 (0.99–1.12) 1.39 (1.33–1.46) <0.0001 the greater prevalence of airway hyperresponsiveness in women, which is a significant predictor of lung function decline and also LAMA 1.42 (1.37–1.47) 1.62 (1.58–1.67) <0.0001 results in increased susceptibility to harmful effects of smoking LABA 0.30 (0.28–0.33) 0.40 (0.37–0.42) <0.0001 among women. As the risk of exacerbations is higher in women, LABA/LAMA fixed 0.01 (0.01–0.01) 0.01 (0.01–0.01) 0.6511 COPD-related healthcare resource utilization is also higher, combinations indicating that women may benefit from closer monitoring of LABA/ICS fixed 1.03 (0.99–1.07) 1.16 (1.13–1.20) <0.0001 their exacerbation risk. Therefore, healthcare professionals should combinations be more aware of these differences and try to be more prone to CI confidence interval, COPD chronic obstructive pulmonary disease, ICS investigate, treat, and follow-up women with COPD. inhaled corticosteroids, LABA long-acting β -agonist, LAMA long-acting 2 On the other hand, we found that survival in women was better muscarinic antagonist, OCS oral corticosteroids, SABA short-acting β - vs. men, which was consistent with findings from other agonist 21,35 studies. Findings from the PATHOS study conducted in ATC codes are reported in Supplementary Table 2 Sweden revealed that COPD mortality in women increased from 1999 to 2009, and life expectancy among COPD patients was 9.4 years lower in women (vs. 7.4 years lower in men) compared with incidence of type I and type II diabetes, kidney diseases, and the average Swedish population. Among the five most common cardiovascular diseases was higher among men. These observa- reasons of mortality, a significantly higher rate was observed for 15,16,28–31 tions are in alignment with earlier published literature. mortality due to neoplasms and circulatory system among males Depression and anxiety are among the strongest predictors of compared to females; however, there was no difference for impaired quality of life, and anxiety among COPD patients can mortality due to COPD between genders. Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 K. Lisspers et al. In general, women used more medications for COPD, and this Following ethical approval, EMR data for COPD patients between 2000 and 2014 from 52 primary care centers across Sweden were collected trend might be due to various reasons, including more exacerba- using an established software system (Pygargus Customized eXtraction tions, more respiratory symptoms and impaired quality of life, and Program) and included age and gender, prescriptions (according to the higher prevalence of asthma compared to men. As asthma is more World Health Organization Anatomic Therapeutic Chemical [ATC] codes), frequent in women, the study results demonstrated that women doctor’s diagnoses (according to the ICD-10 codes), spirometry measure- received significantly more prescriptions for ICS and LABA/ICS ments, laboratory tests, healthcare professional visits, and referrals. The fixed-dose combinations compared to men. It was also observed centers covered urban and rural sites of varying sizes across Sweden. EMR that significantly higher proportion of women are prescribed OCS data were linked by the Swedish National Board of Health and Welfare than men and this can be because of the higher exacerbation rate using individual patient identification (ID) numbers to National Registry data sources (patient IDs were pseudonymized). These data sources in women. Use of ICS is known to further increase the risk of included (i) the Longitudinal Integration Database for Health Insurance and fractures, particularly in women with COPD who are already at Labor Market Studies, which contains socio-demographic data, including higher risk of osteoporosis compared with men. The long course educational level, marital status and family situation, occupational status, use of OCS in patients with acute exacerbation of COPD is retirement and economic compensation, and social benefits; (ii) the associated with increased risk of pneumonia hospitalization and National Patient Register, which contains data related to diagnosis from all-cause mortality within 1-year period from the start of secondary care (ICD-10 code and associated position), including surgery, treatment. Hence, treatment with ICS and OCS in women with gender, age, region, hospital visits, specialty visits, hospital admissions, COPD should be carefully assessed. discharges, medical procedures, and surgeries performed in inpatient and The present study has several important strengths. The large outpatient specialist settings; (iii) the National Prescription Register (from 2005), which contains the full details of all dispensed medications (ATC sample size of the study comprised patients across the whole COPD codes) from both primary and secondary care, including brand name, classification spectrum. Moreover, the primary care setting and the prescription date, dose, strength, pack size, specialty of the prescriber, and real-world study design adequately reflects the general population costs associated with the drug prescription; and (iv) the Cause of Death and clinical practice in Sweden. Furthermore, measurement of the Register, which holds information related to sex, date of death, and the comprehensive range of outcomes over the extended assessment underlying cause of death. period (2000–2014) generated robust data on gender differences between COPD and non-COPD patients. Data quantification in this Study patients study can allow decision makers to identify gender-specific The study population consisted of patients aged ≥40 years who had differences in COPD risk and outcomes and analyze how integrated received either a physician’s diagnosis of COPD (ICD-10 code: J44) in screening and treatment strategies can be devised to achieve better primary care (EMR database) or a physician’s diagnosis of asthma (ICD-10 outcomes for millions of women with COPD worldwide. code: J45/J46) in primary care that was later verified as COPD, or COPD was Nevertheless, this study also has certain limitations. As this was added to the asthma diagnosis in the hospital setting according to the a retrospective study, the potential for bias and confounding National Patient Register. An age- and gender-matched reference cannot be excluded. Although all patients had physician- population was selected from the primary care centers, excluding those who had a diagnosis of COPD and/or asthma. The age and gender were diagnosed COPD, the accuracy of COPD diagnosis and the severity matched for overall population and not at the subgroup level. Therefore, of disease could not be verified. In addition, use of medications differences in age could be observed when analyzed by gender subgroups. was based on prescription claims, while patients’ actual adherence to treatment remains unknown. Moreover, this study was Outcomes conducted only in Swedish patients, and it is therefore uncertain whether these findings can be extrapolated to a more diverse Difference between genders was evaluated with respect to the incidence of COPD; prevalence of asthma and comorbidities; risk of exacerbations group of patients and to other healthcare systems. Furthermore, and severity of exacerbations; mortality rate, duration from the index date the reference population was identified from primary care centers to death and reason for mortality, healthcare resource use and costs; and rather than from healthy individuals in the general population. the number of COPD drug prescriptions. An overall measure of In conclusion, our findings demonstrated that COPD is now comorbidities was calculated by the CCI. CCI is a method of categorizing equally prevalent among men and women, thus imposing a comorbidities of patients based on the ICD diagnosis codes found in significant healthcare disease burden among women. Despite a primary care medical records and register data from secondary care. Each lower mortality rate, women had higher prevalence comorbidities comorbidity category has an associated weight (from 1 to 6), based on the including asthma and a higher risk of exacerbations, leading to adjusted risk of mortality or resource use, and the sum of all the weights more utilization of COPD drugs and COPD-related healthcare results in a single comorbidity index for a patient. The higher the index, the more likely the predicted outcome will result in mortality or higher resources. In daily clinical practice, healthcare professionals in resource use. Prevalence of the most common comorbidities at 3 years primary care play a pivotal role and should consider all these before and after the first COPD diagnosis was compared between genders parameters in order to properly diagnose and treat women with for both COPD patients and non-COPD patients (reference population). COPD. Additional research is warranted to understand the gender- “Moderate exacerbations” were defined as treatment with systemic specific differences and to formulate gender-targeted strategies corticosteroids (H02AB) or antibiotics (J01AA, J01CA) or both (but no for prevention and treatment of COPD in both women and men. hospitalization). “Severe exacerbations” were defined as COPD-related The focus should also be on recognizing and treating comorbid- hospitalizations (J44 in primary position or J44.0/J44.1 in secondary) or ities together with interventions that directly target COPD. emergency visits (J44.0/J44.1 in outpatient hospital care). Recurrent exacerba- tions occurring within 14 days were considered as one unique event. “Hospital nights” was defined as the sum of overnight stays at a hospital per patient. “Hospitalizations” was the number of times that a patient has METHODS been admitted to a hospital regardless of the length of stay. “Outpatient Study design visit” was defined as the visit to a hospital that did not include an overnight ARCTIC was a large, real-world, retrospective, Swedish cohort study stay. Comorbidities were defined based on diagnosis codes in the primary conducted in 18,586 eligible, primary care, COPD patients. Ethical approval or secondary care setting and by medications according to the National for the study was obtained from the local Ethical Regional Board in Prescription Register. The study index date constituted the time of the first Uppsala, Sweden, on 11 December 2014 (number: 2014-397), for accessing recorded physician’s diagnosis of COPD during the enrollment timeframe. the National Health Register and for recruiting primary care centers to the study. An amendment specifying additional analysis was approved by the Statistical analysis Ethical Regional Board in Uppsala on 6 October 2017. Data from all records were de-identified, and therefore, patient consent was not required by the A sample size calculation conducted prior to the study indicated that ethics committee. 13,800 patients were required to detect a 4% difference between groups, npj Primary Care Respiratory Medicine (2019) 45 Published in partnership with Primary Care Respiratory Society UK K. Lisspers et al. with a power of 80% and an α level of 5% in the two-tailed test. The 12. Mamary, A. J. et al. 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Increased prevalence of chronic obstructive pulmonary dis- printer=Y&conceptID=1098 (2019). Accessed 22 Feb 2019. ease in a general population. Respir. Med. 107, 1037–1045 (2013). Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2019) 45 K. Lisspers et al. ACKNOWLEDGEMENTS this study and served on advisory boards arranged by AstraZeneca, Novo Nordisk, and Takeda. This study was funded by Novartis Pharma AG, Basel, Switzerland. We would like to thank Harneet Kaur (Novartis) for managing and providing writing assistance in the development of this manuscript. ADDITIONAL INFORMATION Supplementary information is available for this paper at https://doi.org/10.1038/ AUTHOR CONTRIBUTIONS s41533-019-0157-3. All authors participated equally in the study conception, design, statistical analysis Correspondence and requests for materials should be addressed to K.L. planning, analyzed, and interpreted the data and have reviewed and approved the manuscript. Reprints and permission information is available at http://www.nature.com/ reprints COMPETING INTERESTS Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims K.L. has, during the past 5 years, received honoraria for educational activities and in published maps and institutional affiliations. lectures from AstraZeneca, GlaxoSmithKline, TEVA, and Novartis and has served on advisory boards arranged by Novartis and Boehringer Ingelheim. She has also participated in the steering committee for this study funded by Novartis. K. Larsson has, during the past 5 years, on one or more occasion served in an advisory board, served as a speaker, and/or participated in education activities arranged by Open Access This article is licensed under a Creative Commons AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, Chiesi, Orion, Attribution 4.0 International License, which permits use, sharing, and Teva. C.J. has received honoraria for educational activities and lectures from adaptation, distribution and reproduction in any medium or format, as long as you give Novartis, AstraZeneca, GlaxoSmithKline, TEVA, and Boehringer Ingelheim outside the appropriate credit to the original author(s) and the source, provide a link to the Creative submitted work. B.S. has received honoraria for educational activities and lectures Commons license, and indicate if changes were made. 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