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The effects of medications for treating COPD and allied conditions on stroke: a population-based cohort study

The effects of medications for treating COPD and allied conditions on stroke: a population-based... www.nature.com/npjpcrm ARTICLE OPEN The effects of medications for treating COPD and allied conditions on stroke: a population-based cohort study 1 1 2,3 4,5 6 7,8✉ Ai-Ling Shen , Hsiu-Li Lin , Hsiu-Chen Lin , Jane Chen-Jui Chao , Chien-Yeh Hsu and Chung-Yu Chen Patients with chronic obstructive pulmonary disease (COPD) are at higher risk of stroke. This study aimed to investigate the clinical factors of stroke risk in COPD and allied conditions patients and associations between medications for treating COPD and allied conditions. The population-based study cohort comprised 24,173 patients diagnosed with COPD and allied conditions between 2000 and 2013, and 24,170 selected matched patients without COPD comprised the comparison cohort from a nationwide database. Cox-proportional hazard regression was performed to determine the impact of medical therapies, comorbidities, and other clinical factors on stroke risk. Of the 48,343 included patients, 1394 (2.9%) experienced stroke during follow-up, with a significant difference between COPD and allied conditions cohort (1003/4.2%) and comparison cohort (391/1.6%) (adjusted hazard ratio [aHR]: 2.72, p < 0.001). Cox-regression analysis revealed that COPD and allied conditions patients who were older (>65 years) (HR: 1.06); male (HR: 1.39); with hypertension (HR: 1.46), diabetes mellitus (HR: 1.33) and atrial fibrillation (HR: 1.63) had increased stroke risk. Mucolytics (HR: 0.44) and combination therapy with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) (HR: 0.75) were associated with decreased stroke risk in COPD and allied conditions patients. Among COPD and allied conditions patients, major comorbidities increase risk of stroke. Therapy with mucolytic agents and combination ICS/LABA is associated with risk reduction. npj Primary Care Respiratory Medicine (2022) 32:4 ; https://doi.org/10.1038/s41533-021-00267-3 18–24 INTRODUCTION cardiovascular events . Therefore, the safety of COPD medicationsisstill beingdebated. Chronic Obstructive Pulmonary Disease (COPD) is the third leading The present study sought to further investigate the relationship cause of death worldwide . COPD is a complex respiratory between COPD and incident stroke in COPD patients compared to disorder characterized by chronic air flow limitations and the general population in Taiwan. The primary aim of this study increased inflammatory response in the airways. The prevalence was to clarify whether COPD and allied conditions patients are at of comorbidities is also reported to be higher in patients with increased incidence of stroke over time. Secondary aims were to COPD than in non-COPD patients and have a significant impact on 1,2 identify the risk factors for stroke among COPD and allied prognosis . The most prevalent comorbidities include cardiovas- conditions patients and associations between medications for cular disease (hypertension, ischaemic heart disease, heart failure), treating COPD and allied conditions and stroke. metabolic syndrome (including obesity, diabetes mellitus, hyperli- 1–3 pidemia), and chronic kidney disease (CKD) . COPD in the presence of these comorbidities is considered a risk factor 4,5 METHODS associated with stroke . Many population-based studies have 6–12 found associations between COPD and stroke and increased Data source evidence from recent systematic reviews and meta-analyses have This study extracted patient data from the Longitudinal Health indicated that stroke risk is higher among COPD patients than in Insurance Database (LHID), which is a random subset of the 13–15 non-COPD patients . Potential mechanisms by which COPD Taiwan National Health Insurance Research Database (NHIRD) and and stroke may be linked include systemic inflammation, hypoxia, contains all medical claims data from one million patients insured 16,17 hypercapnia, and oxidative stress . during 2000 through 2013. The NHIRD was established in 1996 Inhaled bronchodilators, including long-acting β2-agonists and encompasses all claims data of medical services used by (LABA) and long-acting muscarinic antagonists (LAMA), and nearly 99% of 23 million Taiwanese. No significant differences are inhaled corticosteroids (ICS) are cornerstone therapies for COPD shown in the distribution of age and sex between the LHID subset patients . The clinical efficacy of inhaled bronchodilators has and the original NHIRD. All data related to personal identification been demonstrated in clinical trials , including improvements were encrypted by the National Health Insurance Administration in overall quality of life, prevention of deteriorating lung (NHIA) before being published. The confidentiality of patients in function, and reducing the frequency of acute exacerbations the dataset is protected by NHIA data regulations. leading to hospitalization. However, several studies have raised All the information related to personal identification had been concerns that inhaled bronchodilators increase the risk of encrypted by the Bureau of National Health Insurance of Taiwan 1 2 Department of Neurology, Sijhih Cathay General Hospital, New Taipei City, Taiwan. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical 3 4 University, Taipei, Taiwan. Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan. School of Nutrition and Health Sciences, College of Nutrition, 5 6 Taipei Medical University, Taipei, Taiwan. Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Department of Information Management, National Taipei 7 8 University of Nursing and Health Sciences, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. email: c8101147@ms16.hinet.net Published in partnership with Primary Care Respiratory Society UK 1234567890():,; A.-L. Shen et al. Fig. 1 Flow chart of the study population. LHID Longitudinal Health Insurance Database, COPD Chronic obstructive pulmonary disease, NHIRD National Health Insurance Research Database. before the dataset was published. The confidentiality of patients (code 413), tuberculosis (code 010.90), or lung cancer (code 162) in the dataset was protected. Therefore, this study was exempt before the first COPD diagnosis (n = 8506). Patients who had no from full review by the Institutional Review Board of Sijhih Cathay further follow-up in their medical records after admission for General Hospital. All study procedures have been performed in COPD and allied conditions, which may be suggestive of death, accordance with the ethical standards laid down in the 1964 were also excluded (n = 221). After all exclusions, 24,173 patients Declaration of Helsinki and its later amendments. were included as the analytic sample (Fig. 1). To construct the control group, for each included patient, one non-COPD and allied conditions patient was randomly selected Study sample from the database by matching age, sex, and year of enrolment. We identified all LHID patients who were diagnosed with COPD The same exclusion criteria for the COPD and allied conditions and allied conditions (ICD-9 code 490–493 [490 Bronchitis], not group were applied to selection of controls. Three patients had no specified as acute or chronic; 491 Chronic bronchitis; 492 matched control, therefore, the control group included only Emphysema; 493 Asthma) by pulmonary specialists in outpatient 24,170 subjects. services and hospital admission records between January 1, 2000, In the process of selecting control group, we firstly excluded and December 31, 2013 (n = 52,612). Because this study aimed to patients with diagnosis of COPD and allied conditions (n = 52,612) assess the risk of stroke in the newly-diagnosed COPD and allied from the one million patients of original Longitudinal Health conditions population, patients with any record of having COPD Insurance Database. We extracted all the out-patient visit records and allied conditions before 2002 (n = 9432) were excluded. We between 2002 and 2013 of every candidate for control group. We excluded code 494–496 patients with lung disease accompanied divided these records into 24 groups based on the year of visit by COPD (494 Bronchiectasis; 495 Extrinsic allergic alveolitis; 496 date and sex of patient. Because one patient may have multiple Chronic airway obstruction, not elsewhere classified) (n = 2080). visit records during a year, we randomly select one index record We also excluded those who were younger than 45 years (n = for each candidate in each year. Next, we divided COPD and allied 8200) and those who had stroke (ICD-9 code 430–434, 436, 438), conditions patients into 24 groups based on the year of the myocardial infarct (code 410), heart failure (code 428), angina earliest date of COPD and allied conditions diagnosis and sex of npj Primary Care Respiratory Medicine (2022) 4 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; A.-L. Shen et al. patient. For each COPD and allied conditions patient, we randomly Fisher’s exact test if case numbers were < 5 in either cell of selected one age-matched patient in the corresponding sex and cross-table. Continuous variables were tested by non-parametric year group, and excluded this control patient from the following Kruskal–Wallis test. The stepwise Cox proportional hazards matching process to assure no duplicate selection. regression was performed to test the effects of all variables on stroke and was applied in the time to event model. The Kaplan- Meier method was used to estimate the risk of stroke as a Study design function of time. All comparisons were two-sided, and p <0.05 For the studied cases, the index date was defined as the earliest was considered statistically significant. date of COPD and allied conditions diagnosis. For the control group without COPD and allied conditions, the first outpatient department visit date in the comparison year was assigned as the RESULTS index date. Each patient in both groups was tracked to the earliest Stroke incidence increased in patients with COPD and allied date admitted to hospital with a principal diagnosis of stroke (ICD- conditions 9 code 430–434, [430 Subarachnoid haemorrhage, 431 Intracer- ebral haemorrhage, 432 Other and unspecified intracranial The study cohort comprised 24,173 patients with newly- haemorrhage, 433 Occlusion and stenosis of precerebral arteries, diagnosed COPD and allied conditions. The median age was 64 434 Occlusion of cerebral arteries], and 436 Acute, but ill-defined, years (interquartile range [IQR] = 54–73 years) and 9883 (40.9%) cerebrovascular disease) or to the last outpatient record date in were female. Table 1 shows the comparisons of baseline the database if no stroke was diagnosed. The period between the characteristics and comorbidities between COPD and control index date and the end tracking date was recorded for additional groups. In the COPD group, 1003 (4.2%) were admitted to hospital survival analyses. The demographic data, including date of birth for stroke during a median observation time of 5.3 years (IQR = and sex, were extracted from the claims data. 2.4–8.4 years), compared to 391 (1.6%) strokes in matched control Four related comorbidities were retrieved: hypertension (ICD-9 patients during a median observation time of 5.5 years (IQR = code 401–405), diabetes mellitus (DM, code 250), dyslipidemia 2.7–8.5 years). Patients with newly-diagnosed COPD and allied (code 272), and atrial fibrillation (AF, code 427.31) to evaluate the conditions had a significantly higher incidence of stroke (adjusted influence of these comorbidities on stroke incidence during the HR 2.72 with 95% CI, 2.42–3.05, p < 0.001) compared to the non- study period. COPD controls (Table 2). Figure 2 illustrates the results of the Kaplan–Meier curve Main measures analysis for the COPD and control groups. Stroke incidence in The hazard ratios (HRs) for the time-to-event model for stroke was COPD group increased significantly with time compared to that of compared between patients with COPD and allied conditions the non-COPD control group (log rank test, p < 0.001). After (COPD group) and without COPD and allied conditions (non-COPD adjustments made for the common stroke risk factor, including control group). To evaluate risk factors for stroke among COPD age, sex, diabetes mellitus, hypertension, dyslipidemia, and atrial and allied conditions patients, prescription days were summed for fibrillation, patients with newly-diagnosed COPD and allied each class of COPD and allied conditions medications received conditions still had a significantly higher incidence of stroke. during the entire observation period according to the Anatomical Therapeutic Chemical Classification System with Defined Daily 25 Risk factors of stroke analyses in COPD and allied conditions Doses (ATC/DDD) . The classes of interest drugs approved in In the COPD group, 1003 patients (4.2%) had stroke and 23,170 Taiwan include short-acting inhaled beta-agonists (SABA, ATC code R03AC02), long-acting inhaled beta-agonists (LABA, patients (95.8%) had no stroke. Table 3 shows the demographic R03AC12, 13, 18, 19), short-acting muscarinic antagonists (SAMA, and clinical characteristics, comorbidities, and total prescription R03BB01), long-acting muscarinic antagonists (LAMA, R03BB04, 06, days of each class of COPD and allied conditions treatment 07), LAMA combined with LABA (R03AL03, 06), methylxanthines medications. The patients with stroke were significantly older and (R03DA04), mucolytics (R05CB01), inhaled glucocorticosteroids more likely to be male than those without stroke; they also (ICS, R03BA01, 02, 05, 08), and ICS combined with LABA (R03AK06, 07, 10). “Total prescription days” were defined as more than Table 1. Comparison of population with COPD and control group 60 days for users of the specific medication class. HRs was with respect to characteristics in demographics and comorbidities calculated for each demographic factor, comorbidities, and drug (n = 48,343). classes for stroke among COPD and allied conditions patients. The recurrence of stroke (re-stroke) was defined as another hospital Variable COPD Control P value admission with the principle diagnosis of stroke three months (n = 24,173) (n = 24,170) later after the index stroke to reduce the impact of stroke n % n % progression or complication. Furthermore, the risk of recurrent stroke is highest during the first 90 days after an index stroke; Median age (IQR) 64 (54–73) 64 (54–73) 1 longitudinal studies indicate that approximately 1 out of every 2 Female 9883 40.9 9882 40.9 1 recurrences occurring in the first year occurs within the first Stroke 1003 4.2 391 1.6 <0.001 90 days . Since patients with acute stroke may be admitted repeatedly for rehabilitation within 3 months after the first stroke. Re_stroke 126 0.5 13 0.1 <0.001 Factors associated with re-stroke in 1,703 patients with stroke Comorbidity were analyzed, including demographic characteristics, index Diabetes mellitus 5670 23.5 7221 29.9 <0.001 stroke type (i.e., ischaemic or haemorrhagic), comorbidities, and Hypertension 13,291 55.0 14,881 61.6 <0.001 COPD and allied conditions medications. Dyslipidemia 8152 33.7 9410 39.0 <0.001 Atrial fibrillation 621 2.6 626 2.6 0.88 Statistical analysis Mean observation years 5.5 ± 3.5 5.6 ± 3.4 All statistical analyses were performed using the SAS statistical package, version 9.4 (SAS,Inc.; Cary,NC, USA).Comparisons of IQR interquartile range, COPD chronic obstructive pulmonary disease. categorical variables were performed using the χ2test, or Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 4 A.-L. Shen et al. exhibited a significantly higher rate of DM, hypertension, and AF than patients without COPD and allied conditions. Major but had lower incidence of dyslipidemia. comorbidities were shown to increase risk of stroke, while the Univariate analysis revealed that SABA, LAMA, mucolytics, and use of mucolytic agents and combination ICS-LABA treatment agents of ICA combined with LABA were prescribed significantly were associated with risk reduction. Advanced age and male less often in stroke patients than in those without stroke but more gender were also associated with increased stroke risk in COPD methylxanthine was prescribed in stroke patients compared to and allied conditions patients. This is the first study to raise the those without stroke. Table 4 shows the comparison of character- possibility that medications used for treating COPD and allied istics in demographics, comorbidities, medications between groups conditions patients may decrease stroke risk. The study only with or without re-stroke of patients with COPD and stroke (n= suggests potential correlation, and that needs to be further 1003). Figure 3 demonstrates the adjusted HR and range of 95% CI confirmed by higher-quality prospective cohort studies. of the stroke risk factors and protective factors. It also shows the COPD and stroke are both leading causes of morbidity and results of multivariate analysis, including that age (HR= 1.06, 95% 27,28 mortality worldwide . Advanced age, smoking, systemic CI: 1.06–1.07, p < 0.001), male sex (HR= 1.39, 95% CI: 1.22–1.59, p < inflammation, and oxidative stress appear to play major roles in 6,13,15,16,29 0.001), hypertension (HR= 1.46, 95% CI: 1.27–1.68, p <0.001), DM the pathophysiological links between COPD and stroke . (HR= 1.46, 95% CI: 1.16–1.53, p <0.001), and AF (HR= 1.46, 95% CI: Recent studies have demonstrated that underlying comorbidities 1.27–2.08, p < 0.001) was associated with significantly increased risk such as cardiovascular disease (CVD) and chronic kidney disease of stroke among patients with COPD. However, dyslipidemia (HR= (CKD) are independent risk factors for cardiovascular events in 0.62, 95% CI: 0.54–0.72, p < 0.001), mucolytics (HR= 0.44, 95% CI: 30–32 COPD patients . In COPD patients with both CKD and CVD, this 0.36–0.53, p < 0.001), agents with ICS-LABA combination (HR= 0.75, risk for stroke is intensified to 6.32-fold over that of those with 95% CI: 0.60–0.95, p= 0.02) were associated with significant neither of these comorbidities . Results of the present study reduction in stroke risk. showed that COPD and allied conditions patients who were older adults, male, with hypertension, DM and atrial fibrillation had significantly higher risk of stroke. Since comorbidities are frequent DISCUSSION in COPD and significantly affect patient’s quality of life, exacer- In this population-based cohort study, COPD and allied conditions 1,2 bation frequency, and survival , underlying comorbidities could patients were associated with a higher risk of stroke over time 33–35 be considered as major “treatable traits” of COPD . Many observational studies and meta-analyses have reported that increased cardiovascular risk in patients with COPD is Table 2. Crude and adjusted hazard ratios for stroke among patients 19,36–39 associated with their use of long-acting bronchodilators . with COPD compared to control. Nevertheless, randomized controlled trials have failed to show an 40–42 Total COPD Control increased cardiovascular risk . A recent study also observed n = 24,173 n = 24,170 that COPD patients with baseline CVD had higher risk of cardiovascular effects than those without, regardless of treatment Stroke 1394 (2.9%) 1003 (4.2%) 391 (1.6%) regimens for COPD . Results of the present study indicated that Crude HR (95% CI) 2.62 (2.33–2.95)*** 1.00 COPD and allied conditions patients treated with bronchodilators Adjusted HR (95% CI) 2.72 (2.42–3.05)*** 1.00 such as LABA and LAMA did not have increased risk of stroke, in COPD chronic obstructive pulmonary disease, HR hazard ratio, CI fact, COPD and allied conditions patients treated with mucolytics confidence interval. or ICS-LABA actually had reduced risk of stroke. Exacerbations of Adjustments were made for age, sex, diabetes mellitus, hypertension, COPD may also be reduced in patients treated with mucoly- dyslipidemia, and atrial fibrillation. 43,44 tics . In addition, those treated with inhaled ICS-LABA also have *** Indicates p < 0.001. 30,45 been shown to have reduced risk of stroke . ICS-LABA combined treatment is shown to modulate systemic inflammation Fig. 2 Kaplan–Meier curve plot of COPD and non-COPD control groups for stroke over time. Patients with newly-diagnosed COPD and allied conditions had a significantly higher adjusted hazard ratio (HR) of 2.75 (95% confidence interval [CI], 2.46–3.08, p < 0.001) for stroke with time, compared to the non-COPD control group (log rank test, p < 0.001). npj Primary Care Respiratory Medicine (2022) 4 Published in partnership with Primary Care Respiratory Society UK A.-L. Shen et al. Table 3. Comparison of characteristics in demographics, Table 4. Comparison of characteristics in demographics, comorbidities, and medications among patients with and without comorbidities, medications between groups with or without re-stroke stroke in study cohort with COPD (n = 24,173). of patients with COPD and stroke (n = 1003). Variable Stroke No stroke P value Variable Re-stroke No re-stroke P value (n = 1003) (n = 23,170) (n = 126, 12.6%) (n = 877, 87.4%) n % n % n % n % Median age (IQR)*** 72 (64–79) 63 (54–73) <0.001 Median age (IQR) 70 (62–77) 72 (64–79) 0.04* Female*** 326 32.5 9557 41.3 <0.001 Female 36 28.6 290 33.1 0.31 Spirometry 410 40.9 10,200 44.0 0.05 Stroke type, infarct 114 90.5 691 78.8 <0.01** Comorbidity Comorbidity Diabetes mellitus*** 298 29.7 5372 23.2 <0.001 Diabetes mellitus 39 31.0 259 29.5 0.74 Hypertension*** 724 72.2 12,567 54.2 <0.001 Hypertension 81 64.3 643 73.3 0.03* Dyslipidemia*** 281 28.0 7871 34.0 <0.001 Dyslipidemia 23 18.3 258 29.4 0.01* Atrial fibrillation*** 66 6.6 555 2.4 <0.001 Atrial fibrillation 11 8.7 55 6.3 0.30 Medication Medication SABA* 10 1.0 468 2.0 0.02 SABA 0 0 10 1.1 0.23 LABA 8 0.8 229 1.0 0.55 LABA 0 0 8 0.9 0.28 SAMA 34 3.4 596 2.6 0.11 SAMA 4 3.2 30 3.4 0.89 LAMA* 45 4.5 1,417 6.1 0.03 LAMA 4 3.2 41 4.7 0.45 Methylxanthine* 308 30.7 6378 27.5 0.03 Methylxanthine 34 27.0 274 31.2 0.33 Mucolytics*** 115 11.5 4154 18.0 <0.001 Mucolytics 15 11.9 100 11.4 0.87 ICS 24 2.4 746 3.2 0.14 ICS 3 2.4 21 2.4 1.00 ICS-LABA** 93 9.3 2869 12.4 0.003 ICS-LABA 7 5.6 86 9.8 0.14 Mean observation years*** 4.0 ± 2.9 5.6 ± 3.5 <0.001 IQR interquartile range. COPD chronic obstructive pulmonary disease, IQR interquartile range, SABA short-acting β2-agonists, LABA long-acting β2-agonists, SAMA short-acting muscarinic antagonist, LAMA long-acting muscarinic antagonist, ICS in exacerbations, mortality, functional capacity, quality of life, or inhaled corticosteroids. lung function . Results of the present study used the database *<0.05; **<0.01; ***<0.001. released by the National Health Insurance of Taiwan, in which statins are routinely prescribed when patients are diagnosed with hyperlipidemia. Therefore, we infer that the use of statins in COPD patients with hyperlipidemia is associated with decreased and mucolytics also may have antioxidant characteristics that risk of stroke. could possibly alter the risk of stroke in patients with COPD. The lower prevalence of DM, hypertension, and dyslipidemia in Our findings presented that the use of LAMA in COPD cohort COPD population compared to control group may result from (4.5 and 6.1%) was lower than the use of ICS-LABA (9.3 and 12.4%). nutritional depletion and racial difference. First, COPD increases The patients in the study were from a population-based data. nutritional requirements, alters metabolic processes, compromises There was the potential risk of patient misclassification, and not all nutritional intake, and results in nutritional depletion conse- the prescriptions of inhaled bronchodilators were regulated by quently . Patients with COPD for a long time may develop weight guidelines. Thus, the COPD treatment may not be standardized. In loss, sarcopenia, and pulmonary cachexia and therefore have a addition, a nationwide population-based study in Taiwan based lower risk of metabolic syndrome. As the relative old age of our on NHI claims data for 2009–2011 suggested that patients with study cohort (median: 63 years), chronic undernutrition may asthma and COPD overlap (ACO) experience a higher disease reduce the development of these 3 comorbidities. A previous burden than patients with asthma or COPD alone. Therefore, ICS- study on primary care data showed a similar reduction in DM LABA therapy contributed the most to the total medication use, prevalence in older COPD patients (OR for ≥75 years: 0.8 (0.7–0.9) followed by LAMA monotherapy in the ACO and COPD cohort for ex-smoker and 0.7 (0.7–0.8) for current smoker) . Second, (ACO, ICS-LABA v.s. LAMA: 35.0% v.s. 9.5%; COPD, ICS-LABA v.s. Japanese studies reported different characteristics of Japanese LAMA: 11.1% v.s. 6.9%, respectively) . COPD patients from those of Westerners, including older age, Results of the present study revealed that COPD and allied lower BMI (body mass index), more emphysema-dominant lung conditions patients with hyperlipidemia had a decreased risk of disease, lower prevalence of cardiovascular comorbidities, DM, stroke. Hyperlipidemia, that is, high levels of total cholesterol and 51,52 and metabolic syndrome . The authors attributed these low-density lipoprotein (LDL) cholesterol are both associated with findings to the difference in COPD pathophysiology between an increased risk of ischaemic stroke . Large-scale evidence from randomized trials shows that each 1 mmol/L reduction in LDL these two populations, including ethnic/genetic, environmental, lifestyle, and socioeconomic factors. Since our study populations cholesterol with statin therapy produces a proportional reduction are also Asians, our research results are closer to the aforemen- of about 25% during each year in the rate of major vascular tioned Japanese studies. events . Lowering LDL cholesterol by 2 mmol/L with an effective The present study has several limitations, including that a statin regimen for about 5 years in 10,000 patients would typically prevent major vascular events in about 1000 (10%) patients at secondary database was used and data were analyzed retro- high risk of heart attacks and strokes . At the same time, statins spectively, which limits the inference of causation. Smoking and were also found to reduce the level of inflammation in people BMI status are not available in the NHIRD. The influences of result with COPD, although this did not result in any clear improvement were not evaluated in this study. Also, although the present study Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 4 A.-L. Shen et al. Fig. 3 Cox proportional hazards regression in time-to-event model for stroke risk factors analysis in COPD and allied conditions patients. Multivariate analysis revealed that age (hazard ratio [HR] = 1.06, 95% confidence interval [CI]: 1.06–1.07, p < 0.001), male sex (HR = 1.39, 95% CI: 1.22–1.59, p < 0.001), hypertension (HR = 1.46, 95% CI: 1.27–1.68, p < 0.001), diabetes mellitus (DM) (HR = 1.46, 95% CI: 1.16–1.53, p < 0.001), and atrial fibrillation (AF) (HR = 1.46, 95% CI: 1.27–2.08, p < 0.001) significantly increased the risk of stroke among patients with COPD and allied conditions. (ICS: inhaled corticosteroid, LABA long-acting inhaled beta-agonists). demonstrated that COPD and allied conditions patients have Received: 12 June 2021; Accepted: 6 December 2021; higher risk of stroke incidence, the percentages of major comorbidities such as hypertension, DM and atrial fibrillation were lower in COPD group compared to the non-COPD control group, which may demonstrate selection bias. Further, even though the LHID used in this study shows no significant REFERENCES differences in the distribution of age and sex between the subset 1. WHO Global Health Estimates. The top 10 causes of death. https://www.who.int/ news-room/fact-sheets/detail/the-top-10-causes-of-death. and the original NHIRD, because this study aimed to assess the risk 2. Putcha, N., Puhan, M. A., Hansel, N. N., Drummond, M. B. & Boyd, C. M. 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Inhaled anticholinergics and risk of major Open Access This article is licensed under a Creative Commons adverse cardiovascular events in patients with chronic obstructive pulmonary Attribution 4.0 International License, which permits use, sharing, disease: a systematic review and meta-analysis. JAMA 300, 1439–1450. (2008). adaptation, distribution and reproduction in any medium or format, as long as you give 37. Singh, S., Loke, Y. K., Enright, P. L. & Furberg, C. D. Mortality associated with appropriate credit to the original author(s) and the source, provide a link to the Creative tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: Commons license, and indicate if changes were made. The images or other third party systematic review and meta-analysis of randomised controlled trials. BMJ 342, material in this article are included in the article’s Creative Commons license, unless d3215 (2011). indicated otherwise in a credit line to the material. If material is not included in the 38. Au, D. H., Curtis, J. R., Every, N. R., McDonell, M. B. & Fihn, S. D. Association article’s Creative Commons license and your intended use is not permitted by statutory between inhaled betaagonists and the risk of unstable angina and myocardial regulation or exceeds the permitted use, you will need to obtain permission directly infarction. Chest 121, 846–851. (2002). from the copyright holder. To view a copy of this license, visit http://creativecommons. 39. Dong, Y. H., Chang, C. H., Gagne, J. J., Hsu, C. L. & Lai, M. S. Comparative cardi- org/licenses/by/4.0/. ovascular and cerebrovascular safety of inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a population-based cohort © The Author(s) 2022 study. Pharmacotherapy 36,26–37 (2016). 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The effects of medications for treating COPD and allied conditions on stroke: a population-based cohort study

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www.nature.com/npjpcrm ARTICLE OPEN The effects of medications for treating COPD and allied conditions on stroke: a population-based cohort study 1 1 2,3 4,5 6 7,8✉ Ai-Ling Shen , Hsiu-Li Lin , Hsiu-Chen Lin , Jane Chen-Jui Chao , Chien-Yeh Hsu and Chung-Yu Chen Patients with chronic obstructive pulmonary disease (COPD) are at higher risk of stroke. This study aimed to investigate the clinical factors of stroke risk in COPD and allied conditions patients and associations between medications for treating COPD and allied conditions. The population-based study cohort comprised 24,173 patients diagnosed with COPD and allied conditions between 2000 and 2013, and 24,170 selected matched patients without COPD comprised the comparison cohort from a nationwide database. Cox-proportional hazard regression was performed to determine the impact of medical therapies, comorbidities, and other clinical factors on stroke risk. Of the 48,343 included patients, 1394 (2.9%) experienced stroke during follow-up, with a significant difference between COPD and allied conditions cohort (1003/4.2%) and comparison cohort (391/1.6%) (adjusted hazard ratio [aHR]: 2.72, p < 0.001). Cox-regression analysis revealed that COPD and allied conditions patients who were older (>65 years) (HR: 1.06); male (HR: 1.39); with hypertension (HR: 1.46), diabetes mellitus (HR: 1.33) and atrial fibrillation (HR: 1.63) had increased stroke risk. Mucolytics (HR: 0.44) and combination therapy with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) (HR: 0.75) were associated with decreased stroke risk in COPD and allied conditions patients. Among COPD and allied conditions patients, major comorbidities increase risk of stroke. Therapy with mucolytic agents and combination ICS/LABA is associated with risk reduction. npj Primary Care Respiratory Medicine (2022) 32:4 ; https://doi.org/10.1038/s41533-021-00267-3 18–24 INTRODUCTION cardiovascular events . Therefore, the safety of COPD medicationsisstill beingdebated. Chronic Obstructive Pulmonary Disease (COPD) is the third leading The present study sought to further investigate the relationship cause of death worldwide . COPD is a complex respiratory between COPD and incident stroke in COPD patients compared to disorder characterized by chronic air flow limitations and the general population in Taiwan. The primary aim of this study increased inflammatory response in the airways. The prevalence was to clarify whether COPD and allied conditions patients are at of comorbidities is also reported to be higher in patients with increased incidence of stroke over time. Secondary aims were to COPD than in non-COPD patients and have a significant impact on 1,2 identify the risk factors for stroke among COPD and allied prognosis . The most prevalent comorbidities include cardiovas- conditions patients and associations between medications for cular disease (hypertension, ischaemic heart disease, heart failure), treating COPD and allied conditions and stroke. metabolic syndrome (including obesity, diabetes mellitus, hyperli- 1–3 pidemia), and chronic kidney disease (CKD) . COPD in the presence of these comorbidities is considered a risk factor 4,5 METHODS associated with stroke . Many population-based studies have 6–12 found associations between COPD and stroke and increased Data source evidence from recent systematic reviews and meta-analyses have This study extracted patient data from the Longitudinal Health indicated that stroke risk is higher among COPD patients than in Insurance Database (LHID), which is a random subset of the 13–15 non-COPD patients . Potential mechanisms by which COPD Taiwan National Health Insurance Research Database (NHIRD) and and stroke may be linked include systemic inflammation, hypoxia, contains all medical claims data from one million patients insured 16,17 hypercapnia, and oxidative stress . during 2000 through 2013. The NHIRD was established in 1996 Inhaled bronchodilators, including long-acting β2-agonists and encompasses all claims data of medical services used by (LABA) and long-acting muscarinic antagonists (LAMA), and nearly 99% of 23 million Taiwanese. No significant differences are inhaled corticosteroids (ICS) are cornerstone therapies for COPD shown in the distribution of age and sex between the LHID subset patients . The clinical efficacy of inhaled bronchodilators has and the original NHIRD. All data related to personal identification been demonstrated in clinical trials , including improvements were encrypted by the National Health Insurance Administration in overall quality of life, prevention of deteriorating lung (NHIA) before being published. The confidentiality of patients in function, and reducing the frequency of acute exacerbations the dataset is protected by NHIA data regulations. leading to hospitalization. However, several studies have raised All the information related to personal identification had been concerns that inhaled bronchodilators increase the risk of encrypted by the Bureau of National Health Insurance of Taiwan 1 2 Department of Neurology, Sijhih Cathay General Hospital, New Taipei City, Taiwan. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical 3 4 University, Taipei, Taiwan. Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan. School of Nutrition and Health Sciences, College of Nutrition, 5 6 Taipei Medical University, Taipei, Taiwan. Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Department of Information Management, National Taipei 7 8 University of Nursing and Health Sciences, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. email: c8101147@ms16.hinet.net Published in partnership with Primary Care Respiratory Society UK 1234567890():,; A.-L. Shen et al. Fig. 1 Flow chart of the study population. LHID Longitudinal Health Insurance Database, COPD Chronic obstructive pulmonary disease, NHIRD National Health Insurance Research Database. before the dataset was published. The confidentiality of patients (code 413), tuberculosis (code 010.90), or lung cancer (code 162) in the dataset was protected. Therefore, this study was exempt before the first COPD diagnosis (n = 8506). Patients who had no from full review by the Institutional Review Board of Sijhih Cathay further follow-up in their medical records after admission for General Hospital. All study procedures have been performed in COPD and allied conditions, which may be suggestive of death, accordance with the ethical standards laid down in the 1964 were also excluded (n = 221). After all exclusions, 24,173 patients Declaration of Helsinki and its later amendments. were included as the analytic sample (Fig. 1). To construct the control group, for each included patient, one non-COPD and allied conditions patient was randomly selected Study sample from the database by matching age, sex, and year of enrolment. We identified all LHID patients who were diagnosed with COPD The same exclusion criteria for the COPD and allied conditions and allied conditions (ICD-9 code 490–493 [490 Bronchitis], not group were applied to selection of controls. Three patients had no specified as acute or chronic; 491 Chronic bronchitis; 492 matched control, therefore, the control group included only Emphysema; 493 Asthma) by pulmonary specialists in outpatient 24,170 subjects. services and hospital admission records between January 1, 2000, In the process of selecting control group, we firstly excluded and December 31, 2013 (n = 52,612). Because this study aimed to patients with diagnosis of COPD and allied conditions (n = 52,612) assess the risk of stroke in the newly-diagnosed COPD and allied from the one million patients of original Longitudinal Health conditions population, patients with any record of having COPD Insurance Database. We extracted all the out-patient visit records and allied conditions before 2002 (n = 9432) were excluded. We between 2002 and 2013 of every candidate for control group. We excluded code 494–496 patients with lung disease accompanied divided these records into 24 groups based on the year of visit by COPD (494 Bronchiectasis; 495 Extrinsic allergic alveolitis; 496 date and sex of patient. Because one patient may have multiple Chronic airway obstruction, not elsewhere classified) (n = 2080). visit records during a year, we randomly select one index record We also excluded those who were younger than 45 years (n = for each candidate in each year. Next, we divided COPD and allied 8200) and those who had stroke (ICD-9 code 430–434, 436, 438), conditions patients into 24 groups based on the year of the myocardial infarct (code 410), heart failure (code 428), angina earliest date of COPD and allied conditions diagnosis and sex of npj Primary Care Respiratory Medicine (2022) 4 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; A.-L. Shen et al. patient. For each COPD and allied conditions patient, we randomly Fisher’s exact test if case numbers were < 5 in either cell of selected one age-matched patient in the corresponding sex and cross-table. Continuous variables were tested by non-parametric year group, and excluded this control patient from the following Kruskal–Wallis test. The stepwise Cox proportional hazards matching process to assure no duplicate selection. regression was performed to test the effects of all variables on stroke and was applied in the time to event model. The Kaplan- Meier method was used to estimate the risk of stroke as a Study design function of time. All comparisons were two-sided, and p <0.05 For the studied cases, the index date was defined as the earliest was considered statistically significant. date of COPD and allied conditions diagnosis. For the control group without COPD and allied conditions, the first outpatient department visit date in the comparison year was assigned as the RESULTS index date. Each patient in both groups was tracked to the earliest Stroke incidence increased in patients with COPD and allied date admitted to hospital with a principal diagnosis of stroke (ICD- conditions 9 code 430–434, [430 Subarachnoid haemorrhage, 431 Intracer- ebral haemorrhage, 432 Other and unspecified intracranial The study cohort comprised 24,173 patients with newly- haemorrhage, 433 Occlusion and stenosis of precerebral arteries, diagnosed COPD and allied conditions. The median age was 64 434 Occlusion of cerebral arteries], and 436 Acute, but ill-defined, years (interquartile range [IQR] = 54–73 years) and 9883 (40.9%) cerebrovascular disease) or to the last outpatient record date in were female. Table 1 shows the comparisons of baseline the database if no stroke was diagnosed. The period between the characteristics and comorbidities between COPD and control index date and the end tracking date was recorded for additional groups. In the COPD group, 1003 (4.2%) were admitted to hospital survival analyses. The demographic data, including date of birth for stroke during a median observation time of 5.3 years (IQR = and sex, were extracted from the claims data. 2.4–8.4 years), compared to 391 (1.6%) strokes in matched control Four related comorbidities were retrieved: hypertension (ICD-9 patients during a median observation time of 5.5 years (IQR = code 401–405), diabetes mellitus (DM, code 250), dyslipidemia 2.7–8.5 years). Patients with newly-diagnosed COPD and allied (code 272), and atrial fibrillation (AF, code 427.31) to evaluate the conditions had a significantly higher incidence of stroke (adjusted influence of these comorbidities on stroke incidence during the HR 2.72 with 95% CI, 2.42–3.05, p < 0.001) compared to the non- study period. COPD controls (Table 2). Figure 2 illustrates the results of the Kaplan–Meier curve Main measures analysis for the COPD and control groups. Stroke incidence in The hazard ratios (HRs) for the time-to-event model for stroke was COPD group increased significantly with time compared to that of compared between patients with COPD and allied conditions the non-COPD control group (log rank test, p < 0.001). After (COPD group) and without COPD and allied conditions (non-COPD adjustments made for the common stroke risk factor, including control group). To evaluate risk factors for stroke among COPD age, sex, diabetes mellitus, hypertension, dyslipidemia, and atrial and allied conditions patients, prescription days were summed for fibrillation, patients with newly-diagnosed COPD and allied each class of COPD and allied conditions medications received conditions still had a significantly higher incidence of stroke. during the entire observation period according to the Anatomical Therapeutic Chemical Classification System with Defined Daily 25 Risk factors of stroke analyses in COPD and allied conditions Doses (ATC/DDD) . The classes of interest drugs approved in In the COPD group, 1003 patients (4.2%) had stroke and 23,170 Taiwan include short-acting inhaled beta-agonists (SABA, ATC code R03AC02), long-acting inhaled beta-agonists (LABA, patients (95.8%) had no stroke. Table 3 shows the demographic R03AC12, 13, 18, 19), short-acting muscarinic antagonists (SAMA, and clinical characteristics, comorbidities, and total prescription R03BB01), long-acting muscarinic antagonists (LAMA, R03BB04, 06, days of each class of COPD and allied conditions treatment 07), LAMA combined with LABA (R03AL03, 06), methylxanthines medications. The patients with stroke were significantly older and (R03DA04), mucolytics (R05CB01), inhaled glucocorticosteroids more likely to be male than those without stroke; they also (ICS, R03BA01, 02, 05, 08), and ICS combined with LABA (R03AK06, 07, 10). “Total prescription days” were defined as more than Table 1. Comparison of population with COPD and control group 60 days for users of the specific medication class. HRs was with respect to characteristics in demographics and comorbidities calculated for each demographic factor, comorbidities, and drug (n = 48,343). classes for stroke among COPD and allied conditions patients. The recurrence of stroke (re-stroke) was defined as another hospital Variable COPD Control P value admission with the principle diagnosis of stroke three months (n = 24,173) (n = 24,170) later after the index stroke to reduce the impact of stroke n % n % progression or complication. Furthermore, the risk of recurrent stroke is highest during the first 90 days after an index stroke; Median age (IQR) 64 (54–73) 64 (54–73) 1 longitudinal studies indicate that approximately 1 out of every 2 Female 9883 40.9 9882 40.9 1 recurrences occurring in the first year occurs within the first Stroke 1003 4.2 391 1.6 <0.001 90 days . Since patients with acute stroke may be admitted repeatedly for rehabilitation within 3 months after the first stroke. Re_stroke 126 0.5 13 0.1 <0.001 Factors associated with re-stroke in 1,703 patients with stroke Comorbidity were analyzed, including demographic characteristics, index Diabetes mellitus 5670 23.5 7221 29.9 <0.001 stroke type (i.e., ischaemic or haemorrhagic), comorbidities, and Hypertension 13,291 55.0 14,881 61.6 <0.001 COPD and allied conditions medications. Dyslipidemia 8152 33.7 9410 39.0 <0.001 Atrial fibrillation 621 2.6 626 2.6 0.88 Statistical analysis Mean observation years 5.5 ± 3.5 5.6 ± 3.4 All statistical analyses were performed using the SAS statistical package, version 9.4 (SAS,Inc.; Cary,NC, USA).Comparisons of IQR interquartile range, COPD chronic obstructive pulmonary disease. categorical variables were performed using the χ2test, or Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 4 A.-L. Shen et al. exhibited a significantly higher rate of DM, hypertension, and AF than patients without COPD and allied conditions. Major but had lower incidence of dyslipidemia. comorbidities were shown to increase risk of stroke, while the Univariate analysis revealed that SABA, LAMA, mucolytics, and use of mucolytic agents and combination ICS-LABA treatment agents of ICA combined with LABA were prescribed significantly were associated with risk reduction. Advanced age and male less often in stroke patients than in those without stroke but more gender were also associated with increased stroke risk in COPD methylxanthine was prescribed in stroke patients compared to and allied conditions patients. This is the first study to raise the those without stroke. Table 4 shows the comparison of character- possibility that medications used for treating COPD and allied istics in demographics, comorbidities, medications between groups conditions patients may decrease stroke risk. The study only with or without re-stroke of patients with COPD and stroke (n= suggests potential correlation, and that needs to be further 1003). Figure 3 demonstrates the adjusted HR and range of 95% CI confirmed by higher-quality prospective cohort studies. of the stroke risk factors and protective factors. It also shows the COPD and stroke are both leading causes of morbidity and results of multivariate analysis, including that age (HR= 1.06, 95% 27,28 mortality worldwide . Advanced age, smoking, systemic CI: 1.06–1.07, p < 0.001), male sex (HR= 1.39, 95% CI: 1.22–1.59, p < inflammation, and oxidative stress appear to play major roles in 6,13,15,16,29 0.001), hypertension (HR= 1.46, 95% CI: 1.27–1.68, p <0.001), DM the pathophysiological links between COPD and stroke . (HR= 1.46, 95% CI: 1.16–1.53, p <0.001), and AF (HR= 1.46, 95% CI: Recent studies have demonstrated that underlying comorbidities 1.27–2.08, p < 0.001) was associated with significantly increased risk such as cardiovascular disease (CVD) and chronic kidney disease of stroke among patients with COPD. However, dyslipidemia (HR= (CKD) are independent risk factors for cardiovascular events in 0.62, 95% CI: 0.54–0.72, p < 0.001), mucolytics (HR= 0.44, 95% CI: 30–32 COPD patients . In COPD patients with both CKD and CVD, this 0.36–0.53, p < 0.001), agents with ICS-LABA combination (HR= 0.75, risk for stroke is intensified to 6.32-fold over that of those with 95% CI: 0.60–0.95, p= 0.02) were associated with significant neither of these comorbidities . Results of the present study reduction in stroke risk. showed that COPD and allied conditions patients who were older adults, male, with hypertension, DM and atrial fibrillation had significantly higher risk of stroke. Since comorbidities are frequent DISCUSSION in COPD and significantly affect patient’s quality of life, exacer- In this population-based cohort study, COPD and allied conditions 1,2 bation frequency, and survival , underlying comorbidities could patients were associated with a higher risk of stroke over time 33–35 be considered as major “treatable traits” of COPD . Many observational studies and meta-analyses have reported that increased cardiovascular risk in patients with COPD is Table 2. Crude and adjusted hazard ratios for stroke among patients 19,36–39 associated with their use of long-acting bronchodilators . with COPD compared to control. Nevertheless, randomized controlled trials have failed to show an 40–42 Total COPD Control increased cardiovascular risk . A recent study also observed n = 24,173 n = 24,170 that COPD patients with baseline CVD had higher risk of cardiovascular effects than those without, regardless of treatment Stroke 1394 (2.9%) 1003 (4.2%) 391 (1.6%) regimens for COPD . Results of the present study indicated that Crude HR (95% CI) 2.62 (2.33–2.95)*** 1.00 COPD and allied conditions patients treated with bronchodilators Adjusted HR (95% CI) 2.72 (2.42–3.05)*** 1.00 such as LABA and LAMA did not have increased risk of stroke, in COPD chronic obstructive pulmonary disease, HR hazard ratio, CI fact, COPD and allied conditions patients treated with mucolytics confidence interval. or ICS-LABA actually had reduced risk of stroke. Exacerbations of Adjustments were made for age, sex, diabetes mellitus, hypertension, COPD may also be reduced in patients treated with mucoly- dyslipidemia, and atrial fibrillation. 43,44 tics . In addition, those treated with inhaled ICS-LABA also have *** Indicates p < 0.001. 30,45 been shown to have reduced risk of stroke . ICS-LABA combined treatment is shown to modulate systemic inflammation Fig. 2 Kaplan–Meier curve plot of COPD and non-COPD control groups for stroke over time. Patients with newly-diagnosed COPD and allied conditions had a significantly higher adjusted hazard ratio (HR) of 2.75 (95% confidence interval [CI], 2.46–3.08, p < 0.001) for stroke with time, compared to the non-COPD control group (log rank test, p < 0.001). npj Primary Care Respiratory Medicine (2022) 4 Published in partnership with Primary Care Respiratory Society UK A.-L. Shen et al. Table 3. Comparison of characteristics in demographics, Table 4. Comparison of characteristics in demographics, comorbidities, and medications among patients with and without comorbidities, medications between groups with or without re-stroke stroke in study cohort with COPD (n = 24,173). of patients with COPD and stroke (n = 1003). Variable Stroke No stroke P value Variable Re-stroke No re-stroke P value (n = 1003) (n = 23,170) (n = 126, 12.6%) (n = 877, 87.4%) n % n % n % n % Median age (IQR)*** 72 (64–79) 63 (54–73) <0.001 Median age (IQR) 70 (62–77) 72 (64–79) 0.04* Female*** 326 32.5 9557 41.3 <0.001 Female 36 28.6 290 33.1 0.31 Spirometry 410 40.9 10,200 44.0 0.05 Stroke type, infarct 114 90.5 691 78.8 <0.01** Comorbidity Comorbidity Diabetes mellitus*** 298 29.7 5372 23.2 <0.001 Diabetes mellitus 39 31.0 259 29.5 0.74 Hypertension*** 724 72.2 12,567 54.2 <0.001 Hypertension 81 64.3 643 73.3 0.03* Dyslipidemia*** 281 28.0 7871 34.0 <0.001 Dyslipidemia 23 18.3 258 29.4 0.01* Atrial fibrillation*** 66 6.6 555 2.4 <0.001 Atrial fibrillation 11 8.7 55 6.3 0.30 Medication Medication SABA* 10 1.0 468 2.0 0.02 SABA 0 0 10 1.1 0.23 LABA 8 0.8 229 1.0 0.55 LABA 0 0 8 0.9 0.28 SAMA 34 3.4 596 2.6 0.11 SAMA 4 3.2 30 3.4 0.89 LAMA* 45 4.5 1,417 6.1 0.03 LAMA 4 3.2 41 4.7 0.45 Methylxanthine* 308 30.7 6378 27.5 0.03 Methylxanthine 34 27.0 274 31.2 0.33 Mucolytics*** 115 11.5 4154 18.0 <0.001 Mucolytics 15 11.9 100 11.4 0.87 ICS 24 2.4 746 3.2 0.14 ICS 3 2.4 21 2.4 1.00 ICS-LABA** 93 9.3 2869 12.4 0.003 ICS-LABA 7 5.6 86 9.8 0.14 Mean observation years*** 4.0 ± 2.9 5.6 ± 3.5 <0.001 IQR interquartile range. COPD chronic obstructive pulmonary disease, IQR interquartile range, SABA short-acting β2-agonists, LABA long-acting β2-agonists, SAMA short-acting muscarinic antagonist, LAMA long-acting muscarinic antagonist, ICS in exacerbations, mortality, functional capacity, quality of life, or inhaled corticosteroids. lung function . Results of the present study used the database *<0.05; **<0.01; ***<0.001. released by the National Health Insurance of Taiwan, in which statins are routinely prescribed when patients are diagnosed with hyperlipidemia. Therefore, we infer that the use of statins in COPD patients with hyperlipidemia is associated with decreased and mucolytics also may have antioxidant characteristics that risk of stroke. could possibly alter the risk of stroke in patients with COPD. The lower prevalence of DM, hypertension, and dyslipidemia in Our findings presented that the use of LAMA in COPD cohort COPD population compared to control group may result from (4.5 and 6.1%) was lower than the use of ICS-LABA (9.3 and 12.4%). nutritional depletion and racial difference. First, COPD increases The patients in the study were from a population-based data. nutritional requirements, alters metabolic processes, compromises There was the potential risk of patient misclassification, and not all nutritional intake, and results in nutritional depletion conse- the prescriptions of inhaled bronchodilators were regulated by quently . Patients with COPD for a long time may develop weight guidelines. Thus, the COPD treatment may not be standardized. In loss, sarcopenia, and pulmonary cachexia and therefore have a addition, a nationwide population-based study in Taiwan based lower risk of metabolic syndrome. As the relative old age of our on NHI claims data for 2009–2011 suggested that patients with study cohort (median: 63 years), chronic undernutrition may asthma and COPD overlap (ACO) experience a higher disease reduce the development of these 3 comorbidities. A previous burden than patients with asthma or COPD alone. Therefore, ICS- study on primary care data showed a similar reduction in DM LABA therapy contributed the most to the total medication use, prevalence in older COPD patients (OR for ≥75 years: 0.8 (0.7–0.9) followed by LAMA monotherapy in the ACO and COPD cohort for ex-smoker and 0.7 (0.7–0.8) for current smoker) . Second, (ACO, ICS-LABA v.s. LAMA: 35.0% v.s. 9.5%; COPD, ICS-LABA v.s. Japanese studies reported different characteristics of Japanese LAMA: 11.1% v.s. 6.9%, respectively) . COPD patients from those of Westerners, including older age, Results of the present study revealed that COPD and allied lower BMI (body mass index), more emphysema-dominant lung conditions patients with hyperlipidemia had a decreased risk of disease, lower prevalence of cardiovascular comorbidities, DM, stroke. Hyperlipidemia, that is, high levels of total cholesterol and 51,52 and metabolic syndrome . The authors attributed these low-density lipoprotein (LDL) cholesterol are both associated with findings to the difference in COPD pathophysiology between an increased risk of ischaemic stroke . Large-scale evidence from randomized trials shows that each 1 mmol/L reduction in LDL these two populations, including ethnic/genetic, environmental, lifestyle, and socioeconomic factors. Since our study populations cholesterol with statin therapy produces a proportional reduction are also Asians, our research results are closer to the aforemen- of about 25% during each year in the rate of major vascular tioned Japanese studies. events . Lowering LDL cholesterol by 2 mmol/L with an effective The present study has several limitations, including that a statin regimen for about 5 years in 10,000 patients would typically prevent major vascular events in about 1000 (10%) patients at secondary database was used and data were analyzed retro- high risk of heart attacks and strokes . At the same time, statins spectively, which limits the inference of causation. Smoking and were also found to reduce the level of inflammation in people BMI status are not available in the NHIRD. The influences of result with COPD, although this did not result in any clear improvement were not evaluated in this study. Also, although the present study Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 4 A.-L. Shen et al. Fig. 3 Cox proportional hazards regression in time-to-event model for stroke risk factors analysis in COPD and allied conditions patients. Multivariate analysis revealed that age (hazard ratio [HR] = 1.06, 95% confidence interval [CI]: 1.06–1.07, p < 0.001), male sex (HR = 1.39, 95% CI: 1.22–1.59, p < 0.001), hypertension (HR = 1.46, 95% CI: 1.27–1.68, p < 0.001), diabetes mellitus (DM) (HR = 1.46, 95% CI: 1.16–1.53, p < 0.001), and atrial fibrillation (AF) (HR = 1.46, 95% CI: 1.27–2.08, p < 0.001) significantly increased the risk of stroke among patients with COPD and allied conditions. 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Inhaled anticholinergics and risk of major Open Access This article is licensed under a Creative Commons adverse cardiovascular events in patients with chronic obstructive pulmonary Attribution 4.0 International License, which permits use, sharing, disease: a systematic review and meta-analysis. JAMA 300, 1439–1450. (2008). adaptation, distribution and reproduction in any medium or format, as long as you give 37. Singh, S., Loke, Y. K., Enright, P. L. & Furberg, C. D. Mortality associated with appropriate credit to the original author(s) and the source, provide a link to the Creative tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: Commons license, and indicate if changes were made. The images or other third party systematic review and meta-analysis of randomised controlled trials. BMJ 342, material in this article are included in the article’s Creative Commons license, unless d3215 (2011). indicated otherwise in a credit line to the material. 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