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Mucolytic Agents and Statins Use is Associated with a Lower Risk of Acute Exacerbations in Patients with Bronchiectasis-Chronic Obstructive Pulmonary Disease Overlap

Background: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap (BCO) is a neglected area of trials, and it is not covered by guidelines for clinical practice. Methods: Using the National Health Insurance Research Database of Taiwan, COPD patients with or without bronchiectasis from 2000 to 2009 were enrolled as the BCO and COPD alone cohorts, respectively. Patients followed for <28 days, diagnosed with COPD who were not prescribed with COPD medications, and those diagnosed with bronchiectasis who did not receive a chest X-ray or computed tomography were excluded. The primary endpoints were acute exacerbations and mortality. Results: There were 831 patients in the BCO cohort and 3321 patients in the COPD alone cohort, covering 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. The BCO cohort had higher risk for exacerbations (adjusted hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.94–2.63) and mortality (HR 1.46, 95% CI 1.24–1.73) than the COPD alone cohort. In the patients overall, the use of statins, macrolides, and mucolytic agents was associated with significantly lower risks of acute exacerbations (statins, HR 0.37, 95% CI 0.29–0.46; macrolides, HR 0.65, 95% CI 0.45–0.93; mucolytic agents, HR 0.68, 95% CI 0.59–0.78). Statins were associated with a significantly lower risk of mortality (HR 0.32, 95% CI 0.25–0.41). In the BCO group, statins and mucolytic agents use was associated with significantly lower risks of acute exacerbations (statins, HR 0.44, 95% CI 0.29–0.65; mucolytic agents, HR 0.58, 95% CI 0.45–0.75). Conclusion: Statins and mucolytic agents use may lower risk of acute exacerbation in patients with BCO.


Introduction
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease which results in high morbidity and mortality [1]. COPD is an important public health problem, and experts have reported that it remains a growing, but neglected global epidemic. COPD is currently the third leading cause of death worldwide in 2016 according to the World Health Organization [2]. COPD and bronchiectasis are different diseases but share many characteristics, including physiopathological and clinical presentations [3]. COPD and bronchiectasis can overlap in some patients, the so called "bronchiectasis-COPD overlap" (BCO) [3]. Based on current guidelines for COPD [1], BCO is diagnosed by radiological and clinical features. The importance of BCO has been emphasized in COPD [1] and bronchiectasis [4] guidelines. Importantly, patients with BCO have a higher risk of acute exacerbations [5] and mortality [6,7] than those with COPD alone. The aim of the present study was to evaluate medications effect on acute exacerbations in patients with BCO. A nationwide population-based study was conducted to analyze the effects of mucolytic agents, macrolides, and statins on acute exacerbations in patients with BCO.

Data Source
The Taiwan National Health Research Institute (NHRI) managed and released the National Health Insurance Research Database (NHIRD) for research purposes. The National Health Insurance (NHI) program of Taiwan has been operational in Taiwan since 1995 to provide comprehensive medical services for all Taiwanese citizens [8]. In 2010, the NHIRD contains the claims data of 23 million individuals, which provides coverage to >99% of the entire population of Taiwan. The NHI medical claims databases contain information on demographic characteristics, diseases diagnosis, treatment and related medical expenditures, and orders of ambulatory and inpatient care. From NHIRD, all patients diagnosed with COPD and bronchiectasis were selected. This study used claims data from the Longitudinal Health Insurance Database 2000 (LHID2000) and LHID2005, which contains all the original claims data of 1 million beneficiaries randomly sampled from the NHIRD from 1995 to 2011. The released database has been validated by the NHRI to be representative of the total population in Taiwan. The accuracy of diagnoses recorded in the NHIRD, such as sleep apnea [8], pneumonia [8], asthma [9], COPD [9], tuberculosis [10], and tuberculosis contact [11] has been validated. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (2017-09-002AC).

Study Design and Population
In this retrospective cohort study, we analyzed the effects of medications on acute exacerbations in patients with BCO. We enrolled adult patients (≥40 years old) who were newly diagnosed with COPD from 2000 to 2009. The inclusion criteria were patients with a diagnosis of COPD with at least two recorded outpatient visits or two emergency room visits or one hospitalization for COPD. Patients with COPD were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 491, 492, 496. Patients with a diagnosis of COPD who were not prescribed with COPD medications within 1 year were excluded. Patients with bronchiectasis were identified by the ICD-9-CM code 494. Patients with a diagnosis of bronchiectasis who did not receive a chest X-ray or computed tomography within 180 days prior to the diagnosis were excluded. The overall cohort of patients with newly-diagnosed COPD was then divided into two cohorts: those with COPD without bronchiectasis (COPD alone group), and those with COPD with concurrent bronchiectasis (BCO group). The index date was defined as the first date on which bronchiectasis was initially diagnosed. Four age-, gender-, and year of enrollment-matched groups of patients with COPD without bronchiectasis were randomly selected from the same datasets. Participants were followed until death, withdrawal from the NHI program, or 31 December 2011, whichever occurred first. Data on the use of mucolytic agents, macrolides, and statins were extracted. The occurrence of acute exacerbations of COPD and bronchiectasis, regardless of which occurred first, was analyzed. We also excluded patients with a follow-up period <28 days, and who had received a diagnosis of bronchiectasis before the study period.

Potential Confounders and Classification of Severity
To investigate the effects of medications on reducing acute exacerbations, we collected and analyzed age, sex, comorbidities, and severity of COPD. In addition, we assessed diabetes mellitus, cardiovascular disease, stroke, chronic kidney disease, antecedent pneumonia, and malignancy as comorbidities.
Based on the international guideline for COPD [1], the frequency of past exacerbations has been recommended as an important factor in classifying the severity of COPD. The severity of COPD was estimated by the annual frequency of hospitalizations (0 and ≥1) and emergency department visits (0 and ≥1) for acute exacerbations and COPD medications (0-2 and ≥3) in the year before the index date. COPD medications included long-acting β2-agonists, long-acting muscarinic antagonists, short-acting β2-agonists, short-acting muscarinic antagonists, inhaled corticosteroids, and xanthine.

Effect of Exposure to Co-Medications
Information on the prescriptions of co-medications during the follow-up period was extracted to analyze the effects on the development of acute exacerbations in the COPD and BCO cohorts. The patients who were prescribed with co-medications for ≥28 days were assigned to the respective co-medication groups. The three groups of COPD co-medications were macrolides (azithromycin, clarithromycin, erythromycin, josamycin, midecamycin, oleandomycin, roxithromycin, spiramycin, telithromycin, and troleandomycin); mucolytic agents (acetylcysteine, carbocysteine, ambroxol, iodinated glycerol, bromhexine, mesna, and eprazinone); and statins (simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin).

Statistical Analysis
All analyses were conducted using the SAS software (Version 9.4; SAS Institute, Cary, NC, USA). The differences in baseline characteristics and comorbidities between the two groups were examined using the independent Student's t-test (for continuous variables) or Pearson's χ 2 test (for categorical variables), as appropriate. The Kaplan-Meier method was used to estimate the outcomes. The differences between the curves were assessed by the log-rank test. Cox proportional-hazards regression models were used to determine the effect of the use of COPD co-medications on reducing acute exacerbations. The proportional hazards assumption was fulfilled in this study. Variables with a p value less than 0.1 in the univariate analyses were entered into the multivariate analysis. All data are expressed as means ± standard deviation or numbers and percentages unless otherwise stated. Two-tailed p values < 0.05 were considered to be significant. All analyses were conducted using SAS statistical software, version 9.4.

Clinical Characteristics of the Study Population
A total of 71,185 patients with newly diagnosed COPD between 1 January 2000 and 31 December 2009 were identified. Of these patients, 2906 who received a diagnosis of bronchiectasis before COPD and those with a follow-up period <28 days (n = 4826) were excluded. After excluding those with bronchiectasis who did not undergo chest computed tomography or an X-ray within 180 days (n = 2848), the BCO cohort consisted of 831 subjects. Another 3321 age-, gender-and index year -matched COPD patients without bronchiectasis were randomly enrolled in the COPD alone cohort. Data for the BCO (COPD + bronchiectasis) and COPD alone cohorts covered 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. Supplemental Figure S1 shows a flow chart of the study population selection.

Discussion
In this study, we found health care services were markedly increased in the BCO cohort compared to the COPD alone cohort. Our study showed that the use of statins and mucolytic agents was associated with a decreased risk of acute exacerbation in the patients with BCO. Until now, this is the largest cohort study to investigate the effect of co-medications on the risk of acute exacerbations among patients with BCO.
Because the patients were collected from a national health registry, the selection bias could be minimized. The NHI program provides coverage to almost all residents of Taiwan, thereby minimizing referral bias. The diagnosis of COPD required a prescription with at least one COPD medication, and the diagnosis of bronchiectasis required chest X-ray or computed tomography confirmation. In compliance with the international guideline [1], COPD disease severity could be classified according to the average number of acute exacerbations per year. We used sensitivity analysis to explore the effect of co-medications on acute exacerbations in both cohorts.
Previous epidemiological studies [5,6,[12][13][14] have shown that BCO was associated with more respiratory symptoms and acute exacerbations compared to patients with COPD alone. In this study, the BCO cohort had more medications and acute exacerbations than the COPD alone cohort, which is consistent with previous studies. Two cohort studies [6,12] conducted by Martinez-Garcia et al. in Spain enrolled 92 patients and 201 patients with COPD, respectively, and showed that bronchiectasis was associated with a higher risk of hospitalization due to exacerbations of COPD in the previous year (odds ratio, 3.07; 95% CI, 1.07-8.77) and an independently increased risk of all-cause mortality (HR, 2.54; 95% CI, 1. 16-5.56) in patients with COPD. In this study, the BCO group had more total exacerbations (RR, 3.42), outpatient department visits (RR, 3.59), emergency department visits (RR, 2.79), hospital admissions (RR, 3.14), intensive care unit admissions (RR, 4.34), and medications for exacerbations than the COPD alone cohort. After adjustments, bronchiectasis was associated with higher risks of acute exacerbations (HR, 2.26) and mortality (HR, 1.46).
Mucolytic agents can be a safe, effective, and inexpensive option for the management of COPD and bronchiectasis. However, mucolytic agents do not improve lung function or the risk for death. A previous meta-analysis reported that mucolytic agents were significantly effective in reducing acute COPD exacerbations [15]. However, very high heterogeneity was noted in the meta-analysis, and so the results need to be interpreted with caution. Importantly, mucolytic agents did not show any survival benefits in that meta-analysis. In a more recent systematic review [16], high doses of mucolytic agents had significantly more effect against exacerbations than low doses of mucolytic agents in COPD. Mucus clearance is important in the management of bronchiectasis [17]. Hence, the benefits of mucolytic agents in bronchiectasis remain unclear [18]. High doses of mucolytic agents combined with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. One 15-day trial [19] with 88 patients with bronchiectasis showed that high doses of bromhexine eased difficulty in expectoration and reduced sputum production. In this study, we found that mucolytic agents use was associated with a dose-dependent lower risk of acute exacerbations in both the BCO and COPD alone cohorts.
Macrolides have been shown to have immunomodulatory effects and indirect activity against bacterial pathogens through suppression of virulence factors, and this could contribute to the reduction in acute exacerbations of COPD [20,21]. Patients with bronchiectasis have excessive neutrophilic inflammation and a high microbial load in their airways [22]. The ideal treatment for bronchiectasis would break the vicious cycle of mucus stasis, bacterial infection, neutrophilic inflammation, and airway remodeling [23]. Long-term antibiotic therapy might be beneficial for patients with bronchiectasis by reducing bacterial loads. It is not surprising that the duration of antibiotic therapy was significantly longer in the BCO cohort than the COPD alone cohort in this study. In this study, macrolides use was associated with a decreased risk of acute exacerbations in the patients with COPD and a non-significantly decreased risk of acute exacerbations in the patients with BCO. However, only 8.42% of the patients with BCO used macrolides, and the detection power was very low in the BCO cohort.
Statins have been proven to have anti-inflammatory and immunomodulatory effects [24], including reducing proinflammatory cytokines and neutrophil migration [25]. Recently, statins have emerged as a possible therapy for COPD by modifying inflammation. A recent systematic review [26] reported that statins may reduce acute exacerbations and mortality in patients with COPD. In addition, a randomized controlled trial [27] in the UK enrolled 60 patients with bronchiectasis, 30 of whom received high-dose atorvastatin (80 mg) therapy and 30 a placebo. The results showed that six months of statins therapy improved coughing on a quality-of-life scale in patients with bronchiectasis. Post-hoc analysis of that trial showed that the patients treated with statins had fewer exacerbations during treatment. In the current study, statins use was associated with a lower risk of acute exacerbations and mortality in both the BCO and COPD alone groups, which is consistent with previous studies.
The results of our study suggest that mucolytic agents, macrolides and statins use may effectively reduce acute exacerbations in patients with COPD. Our findings also strengthen the evidence for the benefits of treatment with mucolytic agents, macrolides, and statins in patients with BCO, which could improve the current under-prescription of these drugs in clinical practice. As far as we know, this study is the first to investigate the effect of statins on acute exacerbations in BCO.
There are several limitations to this study. First, some personal information, smoking status, family history, images, and results of pulmonary function tests were not available in the claim database. Second, diagnoses of COPD and bronchiectasis that were recorded by clinicians in the real-world setting may be less accurate than those made in a prospective study design. In our previous work [9], the definition of COPD has been validated. The validation study confirmed the accuracy of definitions of COPD (86.2% sensitivity). Third, we could not assess drug adherence directly. Non-adherence to COPD medications can result in underestimation of the actual effects of medications. Finally, the information of symptom scales of COPD is not available in this study. Functional status is highlighted from the guideline as important for exacerbation rate.

Conclusions
This study demonstrated a higher risk of acute exacerbations and mortality in patients with BCO than among those with COPD alone. Mucolytic agents and statins use is associated with a lower risk of future acute exacerbations in the patients with BCO. Further clinical trials are necessary to assess the effects of medications in patients with BCO.
Supplementary Materials: The following are available online at http://www.mdpi.com/2077-0383/7/12/517/s1, Figure S1: Flow diagram summarizing the process of enrollment, Table S1: Analysis of risk factors for acute exacerbations in both BCO and COPD alone groups by Cox proportional hazards regression analysis, Table S2: Analysis of risk factors for mortality in both the BCO and COPD alone groups by Cox proportional hazards regression analysis, Table S3: Characteristics of the BCO and COPD alone cohorts.