Survival benefit of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: a nationwide cohort study

The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) is debated. We investigated whether the administration of ICS could lower the mortality risk in patients with COPD. We utilized the Korean National Health Insurance Service-National Sample Cohort database from 2002 to 2019. We included patients who had claim codes for COPD and inhalation respiratory medicine at least twice a year. A time-dependent Cox regression model was employed to estimate the association between ICS usage and survival. The cumulative dose of ICS was classified into three groups, and the mortality risk was compared among these groups. Of 16,463 included patients, there were 4395 (26.7%) deaths during the mean follow-up period of 5.0 years. The time-dependent Cox regression model demonstrated that ICS users had a significantly lower mortality risk compared to non-users (adjusted hazard ratio, 0.89; 95% CI, 0.83–0.94; p < 0.001), particularly among individuals aged ≥ 55 years, women, never smokers, and those with history of asthma or coronary heart disease. Higher cumulative dose groups were associated with a lower mortality risk compared to the lowest cumulative dose group. In conclusion, the administration of ICS seemed to be associated with a lower mortality risk in patients with COPD.


Study design
The following variables were assessed: demographic data, general health examinations, and medical treatments.General health examinations, including lifestyle and health behavior, were obtained through questionnaires from nationwide health examinations conducted by the NHIS.The cumulative dose of ICS was calculated by aggregating the total dose of ICS medication prescribed during each patient's follow-up and then applying a natural log transformed.The equivalent doses of ICS were 100 mg beclomethasone, 50 mg beclomethasone hydrofluoralkane, 80 mg budesonide, 200 mg triamcinolone, 32 mg ciclesonide, 50 mg fluticasone and 200 mg flunisolide.We compared the mortality risk depending on ICS usage.Moreover, the cumulative dose of ICS was classified into three groups: low (< 3937.5 μg), intermediate (3937.5 μg < and < 48,437.5 μg) and high (> 48,437.5 μg), based on the 33.3 percentile cut-off point, and the mortality risk was compared among these groups.For the covariates, we used demographic characteristics including age, sex, body mass index (BMI) and household income level.We also included smoking status and Charlson comorbidity index (CCI) as covariates.All covariates were considered as mortality risk factors, and these variables were assessed from the latest record of the national health examination from the year of COPD diagnosis.We performed subgroup analyses based on the patients' age, sex, and smoking status.Additionally, subgroup analyses based on the comorbidity status of asthma and coronary heart disease (CHD) diagnosed before inhaler initiation were performed.
All methods were performed in accordance with the relevant guidelines and were approved by the Institutional Review Board of Ewha Womans University Hospital, Seoul, Republic of Korea (IRB number: SEUMC 2023-03-002).Informed consent from participants was waived by IRB because NHIS-NSC does not contain any identifying information, and the study involved minimal risk to human subjects.

Statistical analysis
Categorical characteristics between survivors and non-survivors were compared by using the χ 2 test, and continuous characteristics were compared by using the t-test.The Kaplan-Meier curves were established based on the use of ICS, sex, cumulative dose of ICS, and smoking status, with significance determined by the log-rank test.A time-dependent Cox regression model was used to estimate the association between ICS usage and death in COPD patients, with the adjusted hazard ratio (aHR) and 95% confidence interval (CI) being calculated.For non-ICS users and ICS users prior to the first ICS prescription, the cumulative dose was considered zero.All analyses were conducted using SAS version 9.4 software (SAS Institute, Cary, NC, USA) and R Studio 1.0.136(R Studio, Inc).All p-values were two-sided, and those < 0.05 were considered statistically significant.

Baseline characteristics
The present study included 16,463 patients, with a mean age of 63.2 years.Of these, 55.9% were men, as detailed in Table 1.During the mean follow-up of 5.0 years from the date of first diagnosis of COPD to the date of death or censoring, there were 4395 (26.7%) deaths.The proportion of patients over 55 years of age was significantly higher in the non-survivor group (95.1%) compared with the survivor group (69.1%, p < 0.001).Survivors had significantly low CCI (2.1 ± 1.4 vs. 3.1 ± 2.0, p < 0.001) and used more ICS or LABA-containing inhaled therapy than non-survivors.A total of 35.4% of patients with COPD had been diagnosed with CHD, showing a significant difference in the prevalence of CHD between the two groups (42.0% vs. 33.0%,p < 0.001).

ICS usage and mortality
A total of 10,759 patients (65.4%) used inhaled therapy containing ICS.The Kaplan-Meier curves indicated that the use of ICS and the cumulative dose of ICS did not violate the proportional assumption.As a result, the Kaplan-Meier curves showed that ICS users (Fig. 2a) and the intermediate and high dose ICS groups (Fig. 2b) had significantly improved survival compared with non-ICS users and low dose ICS group, respectively.Moreover, men (Fig. 2c) and current smokers (Fig. 2d) had a significantly lower survival probability compared with women and former or never smokers, respectively.
The crude models of time-dependent Cox regression model showed that the use of ICS was associated with a lower risk of mortality in the overall population (HR, 0.69; 95% CI, 0.65-0.73,p < 0.001, Table 2).The adjusted models performed by adjusting for age, sex, BMI, household income level, CCI, and smoking status revealed that the use of ICS was associated with a lower risk of mortality in the overall population (aHR, 0.89; 95% CI, 0.83-0.94,p < 0.001).Especially, patients aged ≥ 55 years, women, never smokers, and those with history of asthma or CHD showed a lower risk of mortality.www.nature.com/scientificreports/ In the analysis with three groups of the cumulative dose of ICS, the intermediate (HR, 0.79; 95% CI, 0.74-0.86,p < 0.001) and high dose groups (HR, 0.91; 95% CI, 0.84-0.99,p = 0.03, Fig. 3) showed significantly lower mortality risk in the overall population.In subgroup analysis using the adjusted models, the intermediate dose group showed significantly lower mortality risk in patients aged ≥ 55 years, women, never smokers, and those with history of asthma or CHD, compared with the low dose group.The adjusted models of time-dependent Cox regression showed that a cumulative dose of ICS was associated with a lower risk of mortality in the overall population (HR, 0.991; 95% CI, 0.985-0.997,p = 0.004, eTable 2 in supplement 1).

Discussion
The present study demonstrated that inhaled therapy containing ICS was associated with a reduction in all-cause mortality risk in patients with COPD.To the best of our knowledge, this is the first study to show the benefits of ICS in improving survival in COPD, using nationwide cohort data from real-world practice.In subgroup analysis, an intermediate cumulative dose of ICS showed the most significant improvement in survival and a pronounced reduction in mortality risk among patients aged ≥ 55 years, women, never smokers, and those with history of asthma or CHD.
The specific mechanism by which ICS reduces the risk of all-cause mortality in patients with COPD remains unclear.ICSs are anti-inflammatory drugs that have been proven to reduce symptoms, the rate of decline in forced expiratory volume in one second and the AE rate when used with bronchodilators 4,[13][14][15][16][17][18] .AE is one of the most common causes of death in patients with COPD, with in-hospital mortality rates after hospitalization for a COPD AE ranging from 2.5 to 15% [19][20][21][22] .Because inflammation plays an important role in the development of AE, the anti-inflammatory effect of ICS may reduce mortality by preventing AEs.Additionally, the anti-inflammatory effect of ICS might also favorably affect airway remodeling, as demonstrated by the decline in forced expiratory volume in one second over time 4,23 .We demonstrated that ICS was less effective in current and former smokers who might have a high inflammatory burden and a high risk of ongoing airway remodeling compared to never smokers.Even if ICSs are used, inflammation will inevitably persist if patients are exposed to continuous   stimulation such as smoking.On the other hand, delaying the deterioration of lung function might reduce the pulmonary vascular burden, especially in patients with severe COPD who usually suffer from frequent AEs or comorbidities 24 .
In the present study, patients with concomitant CHD showed more benefit from ICS.The post hoc analysis of TORCH (Towards a Revolution in COPD Health) showed similar results, indicating that the ICS/LABA combination had a beneficial effect on reducing CHD events in subgroups who had previously had a myocardial infarction 25 .Several studies showed that ICS was associated with a reduction in CHD events and CHD-related mortality in patients with COPD [26][27][28] .It is known that the risk of CHD increases after an AE of COPD 29 .Corticosteroids not only prevent AE but also upregulate beta2-adrenoreceptors and can prevent or reverse down-regulation of beta2-adrenoreceptors in response to agonists [30][31][32] .Dransfield et al. reported that ICS/LABA may reduce aortic pulse wave velocity in those with elevated arterial stiffness 33 .Rabe et al. reported that a high cumulative dose of ICS was associated with a greater effect in reducing CHD risk compared with a low cumulative dose of ICS 24 .Although inhaled delivery of corticosteroids provides minimized systemic anti-inflammatory effects, ICS might also have a cardio-protective effect because cardiovascular disease is provoked by chronic inflammation 34 .
The most concern regarding the use of ICS is the increased risk of pneumonia.High-dose ICSs have been associated with a high pneumonia risk, which offsets its anti-inflammatory effect [35][36][37] .The meta-analysis showed that the use of ICS increases the incidence of pneumonia and serious pneumonia, but not pneumonia-related mortality 8 .Some studies have shown that the incidence of pneumonia depends on the type of ICS; budesonide was found to cause less pneumonia compared with fluticasone 36 .Chen et al. reported that medium-and low-dose ICSs, rather than high-dose ICSs, were associated with a significant reduction in all-cause mortality 8 .Consistent with this result, the present study showed that intermediate-dose ICS had the lowest mortality, although highdose ICS showed a decrease in mortality risk.
The present study has several limitations.First, although we defined the diagnosis and outcome using a structural definition, the possibility of over-diagnosis or misdiagnosis could not be totally excluded.This is because www.nature.com/scientificreports/ the database does not include pulmonary function tests, respiratory symptoms, and laboratory tests, leading us to define COPD using claim data.Second, the proportions of women and never smokers were relatively high compared to the known epidemiologic characteristics of COPD patients in Korea 38 .This may be due to the diagnosis of COPD using claim codes.In addition, we excluded people who did not receive a national examination, which is generally known that smokers have lower interest in healthcare and therefore have lower rates of national examinations compared with never smokers.However, the relatively high proportions of women and never smokers can be considered a positive reflection of the characteristics of Korean COPD patients, especially since many women with COPD suffer from conditions caused by tuberculosis-destroyed lung or bronchiectasis.Furthermore, women and never smokers are more likely to have COPD-asthma overlap, which may have resulted in a more pronounced effect of ICS 39 .Third, the effect of ICS alone cannot be fully investigated because ICS was mainly used with other bronchodilators.However, since bronchodilators are the mainstay of treatment for COPD, the additive effect of ICS with LABA or LAMA/LABA is clinically significant.Fourth, smoking status and age may be important prognostic factors for death or a natural course of COPD.More patients in the non-survivors were former-or current smokers which may mean that they had poorer lung function or that COPD progressed more quickly.In a subgroup analysis based on smoking status, never smokers showed a higher survival rate.Therefore, smoking status might have influenced mortality rate.Age factor may also be associated with poor lung function or a short remaining lifespan.
In conclusion, the present study demonstrated that inhaled therapy containing ICS improved all-cause mortality, particularly in individuals aged ≥ 55 years, women, never smokers, and those with history of asthma or CHD.A cumulative dose of ICS was associated with improved survival, especially at an intermediate dose.Further well-designed studies providing all-cause mortality and dose and type of ICS on varied patient subgroups are needed to guide clinical practice better.

Figure 1 .
Figure 1.Study design.Population selection diagram of the study (a) and study design over time (b).NHIS DB National Health Insurance Service database, COPD chronic obstructive lung disease.

Figure 2 .
Figure 2. Kaplan-Meier curves of study population.Survival according to use of inhaled corticosteroids (a), cumulative dose of inhaled corticosteroids (b), sex (c), and smoking status (d) among patients with chronic obstructive pulmonary disease.

Figure 3 .
Figure 3. Association among three cumulative dose of inhaled corticosteroids exposure groups and the mortality risk.Models were adjusted for age, sex, body mass index, household income level, Charlson comorbidity index, and smoking status.Inhaled corticosteroids usage was converted to μg, and analyzed as a time-dependent covariate.

Table 1 .
Baseline characteristics of the study subjects.Data are shown as means ± standard deviations or n (%) per each group.BMI body mass index, CCI Charlson comorbidity index, ICS inhaled corticosteroids, LABA long-acting beta-2 agonists, LAMA long-acting muscarinic antagonists, SABA short-acting beta-2 agonists, SAMA short-acting muscarinic antagonists, CHD coronary heart disease.

Table 2 .
Result of time-dependent Cox regression between use of inhaled corticosteroids and mortality risk in patients with chronic obstructive pulmonary disease.a Adjusted hazard ratios were adjusted for age, sex, body mass index, household income level, Charlson comorbidity index, and smoking status.
b Adjusted hazard ratios were adjusted for age, body mass index, household income level, Charlson comorbidity index, and smoking status.c Adjusted hazard ratios were adjusted for age, sex, body mass index, household income level and Charlson comorbidity index.