Introduction
Chronic obstructive pulmonary disease (COPD) is a representative small airway obstructive disease with major impact on chronic morbidity and mortality worldwide. The global burden is expected to rise due to ongoing exposure to risk factors and aging populations [1]. The guidelines for COPD treatment assist physicians in selecting appropriate therapeutic medications. While several guidelines exist for COPD management, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report is regarded as the most representative. Additionally, some domestic thoracic societies such as the American Thoracic Society have published guidelines for the pharmacological treatment of COPD [2-5]. However, there is scant information on the percentage of COPD patients who have received treatment according to the GOLD or domestic guidelines [3,6-8].
Since its inaugural publication in 2001, there have been five major revisions to the GOLD report, reflecting emerging insights and the results of ongoing clinical studies. The 2023 edition, marking the fifth major revision, introduces several pivotal changes: a new definition of COPD, a terminological reorganization that includes categories such as early COPD, mild COPD, young COPD, pre-COPD, and preserved ratio impaired spirometry, a new taxonomy, and detailed criteria for classifying acute exacerbation of COPD [1]. A significant modification is the transition of the combined assessment tool from ‘ABCD’ to ‘ABE.’ Since the 2011 revisions, the GOLD guidelines have proposed a combined assessment of COPD patients by categorizing them into four groups (A, B, C, and D) based on symptoms (modified Medical Research Council [mMRC] or COPD assessment test [CAT]), exacerbation risk, and spirometric results (forced expiratory volume in 1 second [FEV1]) [9]. In the 2017 revision, the spirometric result was omitted from the combined assessment [10]. The 2023 GOLD guidelines further refine this approach by eliminating the distinguishing between groups with more frequent symptoms and those with fewer, introducing group E, which combines the former groups C and D [1]. Notably, this updated classification closely resembles the 2018 Korean COPD guideline [4]. In Korea, the Korean Academy of Tuberculosis and Respiratory Diseases COPD guideline committee has issued four revised guidelines, with the latest in 2018 dividing patients into three groups (Ga, Na, and Da) based on symptoms (mMRC or CAT), exacerbation risk, and spirometric results (FEV1) [4].
The Korea COPD Subtype Study (KOCOSS) is a comprehensive multicenter, observational study involving COPD patients and encompassing detailed data on clinical parameters and medication use, collected by pulmonology specialists across South Korea. For this study, we classified Korean COPD patients according to the 2018 Korean guideline, the 2019 GOLD guideline, and the 2023 GOLD guideline, using the KOCOSS cohort. These patients were then subdivided into two groups based on their enrollment before and after 2019, correlating with the application of the 2018 Korean and 2019 GOLD guidelines, respectively. Additionally, we aim to evaluate the real-world prescription patterns of medications by respiratory specialists, their adherence to each guideline, and ascertain which guideline most effectively aligns with the stable management of COPD in South Korea.
Materials and Methods
1. Study subjects and data collection
The KOCOSS cohort is a prospective cohort that has been enrolling COPD patients from 54 hospitals across South Korea since 2011. From this cohort, we selected 3,477 patients between 2011 and 2022. The inclusion criteria included a diagnosis of COPD by a pulmonologist, age ≥40 years, and symptoms such as cough, sputum, dyspnea, as well as a post-bronchodilator FEV1/forced vital capacity (FVC) ratio less than 70% of the predicted normal value [11]. Demographic and medical data were collected through self-administered questionnaires by physicians and trained nurses during the initial visit, and patients underwent evaluation at regular 6 month intervals. The presence of comorbidities, including asthma, was ascertained based on self-reported disease history via questionnaires.
The major exclusion criteria included other obstructive lung diseases such as bronchiectasis, tuberculosis destroyed lung, inability to complete a pulmonary function test, myocardial infarction or cerebrovascular events within the prior 3 months, pregnancy, rheumatoid disease, malignancy, irritable bowel disease, and steroid use for conditions other than COPD exacerbation within the 8 weeks preceding enrollment [11]. Patients meeting the inclusion criteria and with a history of asthma were considered to have asthma-COPD overlap and were included in this cohort.
We obtained written informed consent from all study participants. Ethics approval was secured from the ethics committee at each participating center (Jeonbuk National University Hospital IRB No. 2011-12-018). Furthermore, we received authorization from each center to access their patients’ clinical records for this study, while ensuring data confidentiality.
2. Assessment of medication use
Data on medication use were collected through inquiries concerning drug utilization. The classes of medications investigated included inhalers such as inhaled corticosteroids (ICS), long-acting beta 2 agonists (LABA), long-acting muscarinic antagonists (LAMA), LABA/LAMA (dual bronchodilators [DBD]), ICS/LABA, and ICS/LABA/LAMA, as well as oral agents like methylxanthine and phosphodiesterase-4 (PDE4) inhibitors. Short-acting bronchodilators were not evaluated in this study.
3. Adherence to the guideline recommendations
Patients were divided into two groups based on their registration dates relative to 2019. Those registered before 2019 were enrolled before the implementation of the 2018 Korean guideline and the 2019 GOLD guideline, whereas those registered after 2019 were enrolled following the publication of these guidelines. Adherence to three guidelines (the 2019 and 2023 GOLD reports, as well as the 2018 Korean guideline) was evaluated for patients registered during the entire period. Furthermore, alignment with these guidelines was assessed for participants registered before and after 2019. Appropriate treatment was defined as the use of drugs recommended as initial pharmacological treatment in the guidelines (Tables 1-3). Inappropriate treatment was classified as either over-treatment or under-treatment.
4. Statistical analysis
Categorical data are expressed as numbers (percentages) and were assessed using the chi-square test or Fisher’s exact test for intergroup comparisons. Numerical data were analyzed using the independent t-test or, if they did not satisfy the normality test, the Mann-Whitney test for intergroup comparisons. The level of significance was set at p-values less than 0.05. Data were analyzed using SPSS for Windows version 26.0 (IBM Co., Armonk, NY, USA).
Results
1. Patient characteristics
A total of 3,477 eligible patients were identified from the KOCOSS database and divided into two subgroups. Patients registered before 2019 were enrolled from 2011 to 2018 (n=2,534), and those registered after 2019 were enrolled from 2019 to 2022 (n=943) (Figure 1). Table 4 presents the baseline characteristics. The mean age of all patients was 68.4±8.0; the majority of the patients were male (92.3%) and had a history of smoking (90.5%). Compared to patients registered before 2019, those registered after 2019 were older (68.3±8.0 years vs. 68.9±8.1 years, p=0.029) and had a lower pack-year smoking history (38.7±26.6 pack-years vs. 36.6±27.5 pack-years, p=0.046). Additionally, patients registered after 2019 exhibited higher body mass indexs, improved lung function (FEV1 and FEV1/FVC values), and higher St. George's Respiratory Questionnaire (SGRQ) scores (28.5±20.8 vs. 31.9±19.9, p<0.001). However, mMRC and CAT scores were comparable between the two groups. The group registered after 2019 exhibited significantly higher proportions of patients with moderate exacerbations at baseline (16.3% vs. 20.5%, p<0.001). Regarding comorbidities, hypertension, dyslipidemia, and cerebral infarction occurred more prevalent among patients registered after 2019, whereas bronchial asthma, allergic rhinitis, and gastroesophageal reflux disease were more common in patients registered before 2019.
When patients were classified according to the GOLD document, the majority of patients (94%) fell into GOLD groups A and B. Patients with low FEV1 (<60%) and no history of exacerbations were classified in groups A or B according to the GOLD criteria, but as group Da in the Korean guideline (Figure 2). This phenomenon was termed ‘domestic patient shifting.’ The proportion of patients classified as group Da by the Korean guideline was 53.6%.
2. Prescribed medications
Of the total patients, 2,975 (85.6%) received drug treatment, and 2,838 (81.6%) were prescribed inhalers. Additionally, the proportions of treated patients and inhaler prescriptions increased in those enrolled after 2019 compared to those registered before 2019 (84.3% vs. 89.1% with p<0.001; and 80.5% vs. 84.6% with p=0.005, respectively) (Figure 3, Supplementary Table S1). Furthermore, the percentage of patients using oral agents (methylxanthine or PDE4 inhibitor) without inhalers decreased in patients enrolled after 2019 (3.2% vs. 1.0 %, p<0.001; and 0.6% vs. 0.1%, p=0.085, respectively). The most frequently prescribed medication overall was DBD. Among the prescribed inhalers, the rates of LABA, LAMA, ICS/LABA, and ICS/LABA/LAMA decreased (6.2% vs. 1.4%, p<0.001; 21.4% vs. 8.2%, p<0.001; 12.1% vs. 7.5%, p<0.001; and 21.7% vs. 9.7%, p<0.001, respectively). Notably, the rate of LABA/LAMA significantly increased in patients enrolled after 2019 (11.5% vs. 49.7%, p<0.001).
3. Adherence to GOLD and domestic guidelines
We evaluated adherence to GOLD and Korean guidelines using data from patients prescribed medications. To facilitate visual understanding, appropriate treatment is marked green, under-treatment as blue, and over-treatment as red (Tables 5-7). Among all treated patients, the overall adherence rate was 56.9% for the 2018 Korean guideline, 31.3% for the 2019 GOLD, and 28.0% for the 2023 GOLD. ICS-containing agents were overprescribed, leading to a decrease in overall adherence rate and a relative increase in adherence among higher-risk groups. The adherence rates to the 2018 Korean guideline were 56.6% in patients registered before 2019 and 57.7% in patients registered after 2019. The adherence rate to the 2019 GOLD guideline decreased from 37.8% to 14.0%, and that to the 2023 GOLD guideline increased from 24.0% to 38.6% in the cohort registered after 2019 compared to the cohort registered before 2019.
Discussion
To our knowledge, this is the first comprehensive, well characterized cohort study examining adherence rates to domestic and GOLD guidelines in Korea. In this analysis of a large cohort of individuals with COPD, 85.6% received drug treatments, and 81.6% used inhalation therapies. Compared to those registered before 2019, there was a notable increase in inhaler prescriptions among patients enrolled after 2019, with DBDs being the most commonly prescribed medication. Among the treated patients, adherence rates to the 2018 Korean, 2019 GOLD, and 2023 GOLD guidelines were 56.9%, 31.3%, and 28.0%, respectively. Our study finds that in patients registered before 2019, adherence rates to the 2018 Korean, 2019 GOLD, and 2023 GOLD guidelines were 56.6%, 37.8%, and 24.0%, respectively, while in those registered after 2019, the rates were 57.7%, 14.0%, and 38.6%.
In the current study, the adherence rates to GOLD guidelines were lower (31.3% and 28.0%) compared to previous studies. Among 999 primary care physicians in Mexico, 72.5% had read a COPD guideline and 59.4% had utilized one in their practice [7]. A recent study in India reported adherence to the 2015 GOLD guideline by stratifying patients into GOLD stages: stage I (18.18%), II (15.75%), III (82.6%), and IV (79.7%) [8]. The Study of Economics in COPD (EconCOPD) study in Norway revealed adherence rates to pharmacological treatment guidelines of 10.0% in population-based cases and 35.5% in hospital-recruited cases [12]. Other studies have reported adherence to the GOLD report as follows: 40.4% in Turkey [13], 58.1% in Spain [14], and 47.7 to 58.1% in Hong Kong [15]; in earlier KOCOSS data surveys, adherence ranged from 49.6% to 61.5% [11]. The relatively lower adherence rates to the GOLD guidelines in our study are likely due to the definition of appropriate treatment as only based on the initial recommendation.
In this study, adherence was higher to the Korean guideline than to the GOLD recommendation. Many countries have their own national guidelines for COPD management, which often differ significantly in terms of definitions, combined assessments, and detailed recommendations. In a survey conducted by the Asia-Pacific Society of Respiratory from 2013 to 2020, adherence rates to each domestic guideline were as follows: Australia 64%, Japan 74%, Korea 54%, and Taiwan 70% [16]. For the Korean guideline, group Da included more than half of the patients and broad appropriate criteria. Due to the domestic patients shifting, a considerable portion of the GOLD groups A and B are re-classified as Korean group Da. If an individual categorized as GOLD A with low FEV1 were prescribed LABA/LAMA, they would be considered inappropriate according to GOLD guidelines but appropriate based on the 2018 Korean guideline. Consequently, a high appropriateness rate for the Korean guideline was achieved in group Da (70.5% overall, 65.1% in patients registered before 2019, and 90.9% in patients registered after 2019), primarily due to the frequent prescription of DBD. In group Na, the most commonly prescribed inhaler was LAMA for patients registered before 2019 and LABA/LAMA for those registered after 2019, with both regimens deemed appropriate. This resulted in a relatively higher appropriateness rate in group Na (65.4% overall, 62.4% in patients registered before 2019, 73.1% in patients registered after 2019). We propose that the early recommendation of LABA/LAMA for group Na in the Korean guideline significantly influenced the increased adherence rate. Previous studies have demonstrated that DBD enhances pulmonary function, dyspnea, and health-related quality of life more effectively than either a single long-acting bronchodilator (LABD) or an ICS/LABA combination [16-20]. In Korea, the price differential between single LABD and DBD is negligible; therefore, DBD is recommended as the initial treatment for patients experiencing severe breathlessness in group Na.
When comparing the initial recommended treatment in GOLD guidelines across the 2019 and 2023 versions, no modification was observed in group A. The transition from group C and D in the 2019 GOLD to group E in the 2023 GOLD did not result in a significant impact due to the limited patient numbers, thereby rendering group B the most influential in the adherence assessment. Within group B, the shift of a single LABD from appropriate treatment in 2019 GOLD to under-treatment in 2023 GOLD, and the reclassification of LABA/LAMA from over-treatment in 2019 GOLD to appropriate treatment in 2023 GOLD, reversed the adherence rates between the two reports (from 37.8%, 24.0% to 14.0%, 38.6%, respectively). The adherence rate was higher according to the 2019 GOLD guidelines for patients enrolled before 2019, and higher per the 2023 GOLD guidelines for those registered after 2019.
A significant observation from our study is the favorable progression in COPD management, marked by decreased oral agent use, increased inhaler prescriptions, reduced ICS-containing agent utilization, and heightened LABA/LAMA adoption. Consistent with prior studies [3,6,11,13,14] our data indicated that the excessive use of ICS-containing agents led to diminished adherence rates. Nevertheless, the utilization of ICS-containing inhalers significantly declined in patients enrolled after 2019, with LABA/LAMA constituting the majority of prescriptions. Consequently, adherence to the 2023 GOLD increased for patients enrolled post-2019 compared to those pre-2019. Moreover, despite basing the standard for appropriate prescription in our study, adherence to both the GOLD and domestic guidelines remains notably low in Korea [13-16]. Addressing this requires robust promotion and education about the latest guidelines at the academic level, alongside educating patients about diseases and inhalers to enhance prescription compliance.
The over-treatment in groups A and Ga consistently surpassed 50%, irrespective of the guidelines and subgroups due to the utilization of LABA/LAMA, ICS/LABA, and ICS/LABA/LAMA combinations. Although a significant number of patients fall within group A and Ga, the evidence level supporting bronchodilator use is low, owing to the scarcity of clinical studies targeting this cohort. In line with previous observations [6,11,13,14], excessive employment of ICS-containing inhalers was noted in these groups. Moreover, a substantial number of patients in group A or Ga were prescribed LABA/LAMA inhalers.
This paper possesses several strengths. Our study encompasses a substantial cohort of COPD patients, spanning over 10 years in Korea, enabling the assessment of evolving prescription patterns and adherence rates to guideline recommendations over time. Furthermore, this study concurrently examines the alignment of medication use with both domestic and GOLD guidelines. Nevertheless, certain limitations warrant consideration. Firstly, the accuracy of the data may be compromised, as the definition of appropriate treatment relies on the use of drugs recommended as initial pharmacological interventions in the guidelines. Generally, treatment may be escalated or de-escalated based on the patient's symptoms and exacerbations. Secondly, our interpretation of appropriateness was partially broadened. In groups A and Ga, observing or prescribing only oral agents without an inhaler was deemed appropriate, given the low level of evidence [1,4]. In groups D and Da, we classified initial triple therapy as appropriate, taking into account clinical conditions such as blood eosinophilia [21-24] and the prevention of exacerbation by ICS [25-32]. Thirdly, as our cohort largely comprised patients from tertiary hospitals treated by pulmonology specialists, the severity of COPD may be more pronounced than in the general patient population. Consequently, our data might not accurately represent the broader populace. Fourthly, we evaluated the prescription pattern at the time of enrollment, meaning that patients enrolled prior to the issuance of three guidelines were essentially assessed by subsequent guidelines. While this approach provided insights into the clinical implementation of guidelines, careful interpretation is necessary. Fifthly, it was not assessed whether treatment outcomes, such as symptom severity and exacerbation frequency, improved in accordance with guideline adherence.
In conclusion, this study shows that adherence to the 2018 Korean guideline is higher compared to the GOLD recommendation. Additionally, the proportion of patients aligning with both the 2018 Korean and 2023 GOLD guidelines has increased among those enrolled from 2019 onwards compared to those enrolled earlier. These findings indicate that physicians adjust their treatment strategies to align with either domestic or current international guidelines.
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