Adherence to Inhaled Therapy in Patients with COPD Associated to Pneumoconiosis

Introduction

COPD is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.¹ Cigarette smoking is recognized as the most common and important cause of COPD.² Besides tobacco smoke, occupational exposures are important factors in COPD and other lung diseases.^2,3 Patients exposed to silicosis or coal have increased risk of COPD, our previous study⁴ and other’s study⁵ have shown that the prevalence of COPD was up to 40% in pneumoconiosis in China. Notably, our group first reported that patients with COPD who suffered from occupational exposure developed more severe dyspnea than those exposed to tobacco alone.⁶ Moreover, COPD patients exposed to occupational dust have distinct exposure pattern and different imaging and pathology features compared to those exposed to cigarette smoke.^2,7,8 The effect of dust on emphysema is small⁷ but on opacity profusion and fibrosis⁸ is prominent when compared to the effect of tobacco smoking. However, owing to the limited research on COPD patients exposed to occupational dust with or without cigarette smoke, relevant clinical characteristics and the prognosis is unclear. Recently, a large retrospective cohort study showed there is excess risk of death from COPD among workers with silicosis in Hong Kong, with smoking-adjusted standardized mortality ratio (SMR) of 2.03.⁹ These drive us to pay attention to COPD patients with occupation dust exposure.

The first-line drug treatment for COPD are inhaled bronchodilators or in combination with corticosteroids. There have been several studies which have explored adherence to inhaled therapy in COPD with varying results.¹⁰ The levels of adherence among COPD patients are ranging from as low as 20% to over 60% in different studies.^11,12 Amongst others, some factors found to be associated with non-adherence to inhaled therapy in COPD include age, gender, education, race, disease severity, smoking status, and disease knowledge.^13–18And non-adherence to prescribed inhaled therapy contributes to exacerbations, patient mortality, and health care costs in COPD.^19–21

The availability of an accurate method to measure inhaled therapy adherence in COPD patients is essential for detecting patients with poor adherence. Depending on the environment and type of treatment, the methods of assessing adherence to medication include electronic monitoring methods (smart-inhaler), pharmacy refill methods, inhaled drug device remaining counts, patient and caregiver report measures or questionnaires, but they are all burdened with important limitations. Electronically monitored inhalers are suitable for intervention studies and pharmacy refill highly relies on the National Medical Record System. While self-reporting of treatment compliance could introduce recall bias by either over-reporting or under-reporting depending on patient’s behavior in the recent past.²² To date, there is no “gold standard” self-report questionnaire to assess treatment adherence in COPD patients.

In the clinic, we found COPD patients with only tobacco smoke have a higher diagnosis rate, have more opportunities to take smoking cessation and other education programs, and receive more active treatments compared to COPD patients with other risk factors. We hypothesize that COPD patients with occupational dust exposure are different from the rest of COPD. Despite compelling evidence on non-adherence to long-term inhaled medications in COPD and its consequences elsewhere, there is paucity of information on adherence of this hard-to-reach population of pneumoconiosis with COPD. Therefore, this analysis, set within a prospective observational study of pneumoconiosis complicated with COPD prescript with inhaled therapy, aims to: describe patient characteristics; describe rates and reasons of non-adherence to inhaled therapy; and access main risk factors of non-adherence to inhaled therapy.

Methods

Setting and Participants

The study was performed in the Second Xiangya Hospital and Hunan Prevention and Treatment Institute for Occupational Diseases. This study was registered on the Chinese Clinical Trial Registry (ChiCTRPOC-17010431, http://www.chictr.org.cn/). This study was performed following the ethics principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University in Changsha, Hunan (NO. 2016032).

Patients with International Classification of Diseases (ICD)-10 diagnosis code for pneumoconiosis and COPD and receiving inhaled therapy between March 2017 and May 2019 were recruited and observed for 2 years. Individuals were excluded if they were seriously ill or refused to participate. In baseline, participants completed a questionnaire detailing demographic data, self-reported smoking index, and dust exposure duration. Smoking index was calculated as pack×year. Dust exposure duration was calculated as hour×year. A smoker was defined as continuous smoking exposure of more than 10 pack-years. Patients who had sustained abstinence for more than 6 months were former smokers. The impact of COPD on health status was assessed using the 8-item CAT score.²³ The level of breathlessness experienced by the patient was assessed via the mMRC dyspnea scale.²⁴ The number of AE referred in the last year was also evaluated. Meanwhile, spirometric measurements were performed by experienced and skilled technicians and met the standards of the American Thoracic Society and the European Respiratory Society.²⁵ Patients were also classified into one of four Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 categories (ABCD) based on the intensity of respiratory symptoms and previous exacerbations.¹

Assessment of Adherence

During the 2 years of follow-up, telephone contact follow-ups were arranged every 6 months following the first visit at the outpatient clinic through a follow-up questionnaire, including months of inhaled drug use in the past 6 months, reasons for withdrawal, and change in therapies. Adherence to inhaler therapy, based on the 2-year follow-up periods, was defined by the proportion of reported total months of inhaled drug usage to 24 months. The 80% cut-off has been shown to offer the optimal balance between specificity and sensitivity for self-reported and prescription refill adherence measures.²⁶ Adherence was classified as follows: adherent (≥80%), non-adherent (<80%).

For each visit, patients gave us reasons for poor-adherence behaviors and reasons for good-adherence behaviors in their own words, answering open questions. This new information obtained from patients themselves was then classified and re-written. We defined eight potential causes for non-adherence, based on the WHO proposal,¹⁰ previous studies,²⁷ and the patient’s answer in our study: 1) high cost of medication; 2) diminished treatment effectiveness with long-term use; 3) poor self-efficacy; 4) relief of symptoms after short-term controller medication use; 5) occurrence/fear of side effects; 6) difficulty obtaining medication; 7) not specifically stated by their doctor or other health care professional that inhaled therapy should be long-term use; and 8) other.

Statistical Analyses

Variables are presented as mean values with standard deviation or frequency and percentage. Potential associations were tested using partial correlation, the χ² test, Fisher’s exact test, or the Kruskal–Wallis test, as appropriate. Factors that were associated (p < 0.05) with non-adherence in the univariate analysis were included in the multivariate regression analysis with a stepwise procedure to identify risk factors that were independently associated with non-adherence. Results were considered statistically significant when p-values were below 0.05.

Results

Study Recruitment

A total of 296 participants had pneumoconiosis with COPD and were eligible for inclusion. All of them were male. During follow-up, 15 (5.07%) were dead, 56 (18.92%) were lost follow-up, and 12 (4.05%) refused to participate. Finally, 213 participants completed the 2-year follow-up of adherence since the baseline visit (Figure 1).

Figure 1 Study flow diagram.

Demographic and clinical characteristics of the 296 participants in baseline are shown in Table 1. Mean age was 58.82 ± 8.64 years, mean BMI was 23.33 ± 11.98 kg/m². The majority of patients had low educational level, 44.26% were middle school, 49.66% were primary school and below. Tobacco smoking was common in the subjects. Overall, 34.46% were current smokers, 47.97% were former smokers, and only 17.57% were never smokers. In 47.97% of all cases, mono-therapy (LAMA) was prescribed, 29.73% was prescript with triple-therapy (LAMA + LABA + ICS), and 22.3% were prescript with dual-therapy (ICS+LABA). According to CAT (≥10) and mMRC (≥2) tools, uncontrolled poor health status was found in 209 (70.61%) and 201 (67.91%) subjects, respectively. Number ≥2 and ≥1 AE in the past year were seen in 124 (41.89%) and 181 (61.15%) subjects, with GOLD group B (44.59%) being the largest followed by groups D (39.86%), A (13.51%), and C (2.03%).

Table 1 Demographic, Clinical, and Functional Characteristics of Pneumoconiosis with COPD

Correlation of Dust Exposure and Smoke Exposure to COPD-Related Characteristics

After adjusting for age, we found dust exposure duration was positively correlated with number of AE in the last year (r = 0.181, p = 0.002) for pneumoconiosis with COPD. CAT score (r = −0.355, p < 0.001), mMRC grade (r = −0.333, p = 0.002), and number of AE in the last year (r = −0.270, p < 0.001) were negatively correlated with pre-FEV₁. Meanwhile, there is strong association among CAT score and mMRC grade (r = 0.504, p < 0.001), CAT score and number of AE (r = 0.378, p < 0.001), and mMRC grade and number of AE (r = 0.378, p < 0.001). There is no association between smoking index to any of these COPD-related characteristics (p > 0.05) (Table 2).

Table 2 Correlations Between Symptoms (CAT and mMRC Grade), Lung Function, Exacerbation Frequency in the Last Year, and Dust Exposure Duration in Baseline (n = 296)

Adherence to COPD Treatment

Among the participants, 122 (57.28%) were non-adherent to the inhaled therapy in 2-year follow-up. Characteristics of adherent and non-adherent are presented in Table 3. There was no significant difference observed in age, smoking index, dust exposing duration, dust exposure type, education level, marital status, categories of inhaled therapy, and smoking status between adherence classes. Compared to adherent, non-adherent had higher FEV₁ value, lower mMRC grade, lower CAT scores, and less severe disease (GOLD group). They also experienced less number of AE in the past year in baseline (p < 0.001). A higher proportion of non-adherent had a BMI ≥ 25 kg/m² (p < 0.05).

Table 3 Socio-Demographic and Clinical Characteristics of Adherent and Non-Adherent

Reasons for Non-Adherence

A number of factors were identified as the reason for non-adherence of the patients towards their inhaled therapy. “Relief of symptoms after short-term controller medication use” was the major reason for patient non-adherence, 53.28%, followed by “High cost of medication”, 9.84%, and “Diminished treatment effectiveness with long-term use”, 9.02%, and “Not specifically stated by their doctor or other health care professional that inhaled therapy should be long-term use” accounts for 9.02%. 1.64% discontinued their inhaled therapy because of the occurrence of side effect, difficulty obtaining medication and poor self-efficacy, 13.93% gave no reasons for non-adherence. We found that different levels of adherence and poor-adherence behaviors were mainly intentional.

Predictors of Non-Adherence

In the multivariable model, low mMRC scores (OR = 0.406, CI = 0.214–0.771) and high pre-FEV₁ value (OR = 1.04, CI = 1.018–1.064) were risk factors found for non-adherent of inhaled therapy (Table 4). The patients’ age, smoking index, dust exposing duration, dust exposure type, education level, marital status, categories of inhaled therapy, and smoking status did not influence adherence.

Table 4 Multivariable Regression Analysis for Non-Adherent of Inhaled Therapy in Pneumoconiosis with COPD

Discussion

To the best of our knowledge, this is the first study to describe the current status of adherence to inhaled therapy in pneumoconiosis complicated with COPD. These findings help to define potential targets for intervention.

In our retrospective analysis, cumulative dust exposure duration but not smoking index was positively correlated with number of AE in the last year. Although it was statistically significant, the correlation between dust exposure and number of AE in the last year was weak. This may be explained by the definition of dust exposure duration in our study, since we use both hour and year to quantify this indicator. Objective indicators such as cumulative dust exposure dose are believed as more appropriate measurements if available. Exacerbations of COPD indicate progression of the disease and are associated with reduced health status,²⁸ our findings link the impact of dust exposure in clinical outcomes in occupational COPD. We also found there were close correlations between pre-FEV₁ and scores for CAT, mMRC, and number of AE. The association between lung function parameters and health status measures is known from results of previous cross-sectional studies.²⁹

In the follow-up, patient-reported non-adherence to prescript inhaler therapy was as high as 57.28% in pneumoconiosis with COPD. Medication adherence among patients with COPD is always a matter of concern worldwide.³⁰ In the real world, adherence for maintenance medications of COPD is bad. By using a large administrative claims database, Dhamane et al observed that 79.2% of patients were non-adherent to maintenance COPD medications.³¹ A large prospective cohort study conducted in China also showed COPD patients had adherence rates of 74.65%, 49.63%, and 33.61% at 4-, 12-, and 24-week telephone follow-ups.³² Another retrospective cohort study reported that approximately two-thirds of patients with COPD failed to continue treatment after 12 months.³³ Our study was based on a 2-year follow-up on a relative severe stage of COPD and reports patients with pneumoconiosis and COPD had a significantly high discontinuation rate overall.

The factors that contribute to sub-optimal adherence in COPD can grouped into 3 major categories.²⁷ They are medication (complex regimen, multiple inhalers, inhaler technique, efficacy to onset, side effect, cost), unintentional (age-related factors, forgetfulness, misunderstood directions, comorbidities, health literacy), and intentional (perception of treatment, denial about disease, inappropriate expectations, dissatisfaction with health care providers, cultural issues). In this study, “Relief of symptoms after short-term controller medication use” and “Diminished treatment effectiveness with long-term use” are the main intentional reason patients give for non-adherence. This finding is consistent with other studies.^16,32 To address these patient related factors, there is need for more regular follow-up visits, comprehensive self-management programs involving patient education activities,³⁴ and counseling sessions. “High cost of medication” accounts for the main medication reason for non-adherence. Inequity in health service utilization is a major health policy challenge in China,³⁵ however, rare insurance covers the maintenance medications of COPD. And in reality, the social and economic factors may be interacting and affecting patient related factors, so economic reason needs more attention and effort.¹⁰ Surprisingly, we found some patients indicate that they were not specifically stated by their doctor or other health care professional that inhaled therapy should be long-term use since baseline. This points to us that ineffective doctor–patient communication is a potential hazard for these patients.³⁶ Improved patient–provider communication may help solve this problem and promote inhaled therapy adherence.³⁷

Factors associated with non-adherence in patients with COPD have also been largely explored in several previous studies. Socioeconomic factors, including unemployment, low income status, immigration status, and living alone, social/familial support, health literacy, specific comorbidities,¹⁷ inhaled therapy type,¹⁸ and smoking status¹⁶ have been shown to influence adherence in COPD. However, level of education, marital status, dust exposure type, categories of inhaled therapy, and smoking status was found not to be associated with adherence in our study. This difference could be attributed to variations in the socio-economic status, cultural backgrounds, and health care services across the study settings. Importantly we found risk factors associated with non-adherence in pneumoconiosis with COPD were fewer dyspnea burden and more mild airflow limitation. This is in accordance with previous studies, where adherence was better in patients with more severe COPD.^16,21,38,39 Owing to the fact that inhaled medications in some COPD patients have symptomatic effect, relief of clinical symptoms can be misinterpreted and can lead to treatment interruption and cessation.⁴⁰ More severe patients are more adherent probably because they are more symptomatic or experience more relief of symptoms, while patients with milder disease may not see the need to regularly take their prescribed medication as they may believe that their symptoms are not serious or their condition is controlled.⁴¹ As observed in our study, more than half (53.28%) of the non-adherent did not use drug because of symptom relief after short-term use. COPD patients suffered from occupational exposure developed more severe dyspnea than those exposed to tobacco alone.⁶ However, non-adherence to therapy can be surprising high in our study, that in very symptomatic patients (mMRC grade ≥ 2) and less symptomatic patients (mMRC grade < 2), the future non-adherence rate was as high as 48.61% (70/144) and 75.36% (52/69), respectively. Disease heterogeneity for pneumoconiosis with COPD and subjective cognition on COPD may play a role in individual adherence behavior.^15,42

This study was based in a “real life” setting and adherence is measured by self-report. Self-reports may have introduced some recall, social desirability, and/or interviewer bias, leading to an over-estimate of the patient’s actual medication adherence. However, the researchers pose such questions in a non-judgmental fashion and that the question be prefaced by a normalizing statement, allowing the patient to feel more comfortable about telling the truth. Self-reported medication adherence measures are ease and cost-effectiveness of implementation in a clinical setting and they may also have the benefit of demonstrating high specificity in capturing people who are truly non-adherent. Referring to non-adherence, the present study shows that a substantial number of patients (42.72%) purposely chose not to take their inhaled medication, which was deliberate non-adherence. Moreover, the methods used in our study measure adherence in long-term periods instead of adherence in recent weeks.

This study had some limitations. First, no control group such as tobacco smokers with COPD was used. However, a recent large sample study in our center showed 33.2% of COPD had poor inhaled drug adherence after 6 months of follow-up.⁴³ Referred to these data, pneumoconiosis with COPD have worse inhaled drug adherence despite similar baseline status. Second, assessment of medication adherence was based on self-reports which could introduce recall bias and inaccuracy in the data collected, when compared to other objective methods. We see the following strengths of our study. First, it was possible for us to reach a relative large population of pneumoconiosis with COPD. Second, our pneumoconiosis patients complicated with COPD were evaluated and treated in an described outpatient structure based on existing guidelines for patients with COPD.

Conclusions

Overall, 57.28% of the pneumoconiosis with COPD were non-adherent to the inhaled therapy in 2-year follow-up. Mild airflow limitation and low dyspnea burden were risk factors for non-adherence in pneumoconiosis with COPD. Interventions to improve adherence to inhaled therapy should include aggressive counseling and health education with a focus on patients with low dyspnea burden and mild airway limitation. A better understanding of the clinical factors influencing patient adherence, and strategies to improve adherence, could lead to beneficial interventions in pneumoconiosis with COPD.