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Statin Use and Risk of COPD Exacerbation Requiring Hospitalization

      Abstract

      Background

      Despite recent studies that suggested statins' beneficial effects on chronic obstructive pulmonary disease (COPD) outcomes, the impact, if any, of statins on COPD exacerbations remains unclear. This study aimed to examine the association between statin use and risk of hospitalized COPD exacerbation, and to assess whether the association varied by statin initiation, dose, or duration of use.

      Methods

      A retrospective nested case-control study among patients with COPD was conducted analyzing a nationwide health insurance claims database in Taiwan. Cases were subjects hospitalized for COPD exacerbations; each case was matched to 4 randomly selected controls on age, sex, cohort entry, and number of COPD-related outpatient visits by an incident-density sampling approach. Conditional logistic regressions were employed to quantify the COPD exacerbation risk associated with statin use.

      Results

      The study cohort comprised 14,316 COPD patients, from which 1584 cases with COPD exacerbations and 5950 matched controls were identified. Any use of statins was associated with a 30% decreased risk of COPD exacerbation (95% confidence interval [CI], 0.56-0.88), and current use of statins was related to a greater reduced risk (adjusted odds ratio [OR] 0.60; 95% CI, 0.44-0.81). A dose-dependent reduced risk of COPD exacerbation by statins was observed (medium average daily dose: adjusted OR 0.60; 95% CI, 0.41-0.89; high daily dose: adjusted OR 0.33; 95% CI, 0.14-0.73). The reduced risk remained significant for either short or long duration of statin use.

      Conclusions

      Statin use was associated with a reduced risk of COPD exacerbation, with a further risk reduction for statins prescribed more recently or at high doses.

      Keywords

      Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease currently affecting an estimated 64 million people worldwide.

      World Health Organization. Chronic Obstructive Pulmonary Disease (COPD): burden of COPD. Available at http://www.who.int/mediacentre/factsheets/fs315/en/. Accessed November 27, 2012.

      Acute exacerbations of COPD are a major cause of morbidity and mortality,
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      which accounts for 39 million disability-adjusted life years
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      Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.
      Additionally, COPD exacerbations lead to a major cause of hospitalizations, with estimated rates of 26.9 to 87.1 per 10,000 population in the Asia Pacific region,
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      Trends in COPD mortality and hospitalizations in countries and regions of Asia-Pacific.
      and 23.6 per 10,000 population in the US.
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      Trends in hospitalization with chronic obstructive pulmonary disease-United States, 1990-2005.
      However, current pharmaceutical therapies for COPD do not entirely prevent patients from attacks of acute exacerbations, and have a minimal effect on attenuating the disease progression.
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      • Any use of statins in chronic obstructive pulmonary disease (COPD) is associated with a substantial reduction in the risk of COPD exacerbation, compared with nonuse.
      • The observed protective effect on COPD exacerbation is further increased for statins initiated more currently, prescribed at higher average daily doses, or used in patients with coronary heart diseases.
      • The role of statin use as an adjunctive treatment for COPD should be clarified in a randomized controlled trial.
      Statins, a class of potent lipid-lowering agents, were observed to exert anti-inflammatory
      • Young R.P.
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      and immunomodulatory
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      • Morimoto K.
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      Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease.
      effects on COPD. Evidence from animal
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      Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice.
      and human
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      Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis.
      studies has suggested that statins inhibit both pulmonary and systemic inflammation as well as improve exercise tolerance in COPD patients.
      • Lee T.M.
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      • Chang N.C.
      Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin.
      Additionally, recent observational studies reported a 28%-40% reduced risk of COPD hospitalizations
      • Mancini G.B.
      • Etminan M.
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      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      • Huang C.C.
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      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Bartziokas K.
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      • Minas M.
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      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      and 10-fold decrease in the risk for intubation,
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      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      as well as 54%-71% decreased mortality risk associated with statin use in COPD patients.
      • Mortensen E.M.
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      • Pugh M.J.
      • et al.
      Impact of statins and ACE inhibitors on mortality after COPD exacerbations.
      • Frost F.J.
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      • Soyseth V.
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      Statin use is associated with reduced mortality in COPD.
      However, these studies were hampered by either small sample size,
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      • Frost F.J.
      • Petersen H.
      • Tollestrup K.
      • Skipper B.
      Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.
      incomprehensive statin measurement,
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Mortensen E.M.
      • Copeland L.A.
      • Pugh M.J.
      • et al.
      Impact of statins and ACE inhibitors on mortality after COPD exacerbations.
      inadequate adjustment for confounding,
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      immeasurable bias,
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      • Suissa S.
      Co-morbidity in COPD: the effects of cardiovascular drug therapies.
      or immortal time bias.
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Frost F.J.
      • Petersen H.
      • Tollestrup K.
      • Skipper B.
      Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.
      • Soyseth V.
      • Brekke P.H.
      • Smith P.
      • Omland T.
      Statin use is associated with reduced mortality in COPD.
      • Suissa S.
      Co-morbidity in COPD: the effects of cardiovascular drug therapies.
      Consequently, whether use of statins exerts a beneficial effect on COPD exacerbations remains unclear.
      This study aimed to evaluate whether statin use is associated with a reduced risk of COPD exacerbation requiring hospitalization by analyzing a nationwide health care database of pharmacy and medical encounters, and to assess whether the effect varied by recent initiation of statin therapy, dose, or duration of statin use.

      Methods

      Data Source

      This study employed a population-based nested case-control study design using data from the Longitudinal Health Insurance Database (LHID) from January 1, 2000 to December 31, 2008. The LHID is constructed from all claims for payment in the Taiwan National Health Insurance (NHI) program, in which up to 99% of the 23 million inhabitants of Taiwan are enrolled.
      • Wu T.Y.
      • Majeed A.
      • Kuo K.N.
      An overview of the healthcare system in Taiwan.
      The LHID contains all transactions of de-identified and encrypted medical and pharmacy claims from any inpatient, outpatient, and emergency service of one million NHI beneficiaries who were randomly selected from the entire NHI beneficiaries population. Subjects retrieved in the LHID are representative of the entire NHI enrollment.

      Taiwan National Health Insurance Research Database. Introduction to the National Health Insurance Research Database. Available at http://w3.nhri.org.tw/nhird/date_01.html. Accessed November 27, 2012.

      The database has been employed to study beneficial and adverse effects of drug use.
      • Chiu H.F.
      • Ho S.C.
      • Chang C.C.
      • et al.
      Statins are associated with a reduced risk of gastric cancer: a population-based case-control study.
      • Wang M.T.
      • Tsai C.L.
      • Lo Y.W.
      • et al.
      Risk of stroke associated with inhaled ipratropium bromide in chronic obstructive pulmonary disease: a population-based nested case-control study.
      The access to and use of the LHID for this study was approved by the National Health Research Institutes, which manages and constructs the database.

      Cohort Selection

      The study cohort consisted of all patients with 2 or more COPD-related outpatient visits involving at least 2 COPD-related medications within a year, and aged >45 years old at the second COPD outpatient visit from January 1, 2001 to December 31, 2007. Specifically, the diagnosis of COPD was identified based on the International Classification of Diseases, 9th Revision, Clinical Modification codes (ICD-9-CM codes 491, 492, 496), and the COPD-related medications comprised short-acting β2-agonists, inhaled long-acting β2-agonists, inhaled corticosteroids, inhaled anticholinergics, and theophyllines. Cohort entry was marked by the date of the second outpatient visit for COPD.
      Patients were excluded if they discontinued the NHI program, were admitted for COPD exacerbation, ever had an asthma diagnosis (ICD-9-CM code 493) in the year before cohort entry, or received any diagnosis of lung cancer (ICD-9-CM codes 162-164) during follow-up.
      The study cohort was followed from the entry date to the occurrence of hospitalization for COPD exacerbations, discontinuation of enrollment in the NHI program, or the end of the study period (December 31, 2008), whichever came first.

      Case Identification and Control Selection

      We identified cases and selected controls from the study cohort. Specifically, cases with hospitalization for COPD exacerbation were defined as patients admitted with a primary diagnosis of COPD (ICD-9-CM codes 491, 492, 496)
      • Vaz Fragoso C.A.
      • Concato J.
      • McAvay G.
      • et al.
      Respiratory impairment and COPD hospitalisation in older persons: a competing risk analysis.
      or those with a primary diagnosis of pneumonia (ICD-9-CM codes 480-486)
      • Gil A.
      • Gil R.
      • Oyaguez I.
      • et al.
      Hospitalization by pneumonia and influenza in the 50-64 year old population in Spain (1999-2002).
      concurrently accompanied by a secondary diagnosis of COPD.
      • Soyseth V.
      • Brekke P.H.
      • Smith P.
      • Omland T.
      Statin use is associated with reduced mortality in COPD.
      We included the pneumonia events due to their frequent coexistence with COPD exacerbations.
      • Lieberman D.
      • Gelfer Y.
      • Varshavsky R.
      • et al.
      Pneumonic vs nonpneumonic acute exacerbations of COPD.
      The date of the first admission for COPD exacerbations was defined as the index date. Each case was matched with up to 4 controls randomly selected from all patients who were at risk of COPD exacerbation at the time of each case's occurrence by age (±5 years), sex, cohort entry date (±180 days), and number of COPD-related outpatient visits (0, 1-3, ≥4 visits) measured in the 6 months before the index date. Control patients were assigned the same index date as their corresponding cases.

      Exposure Measurement

      Use of statins was measured with several approaches. First, any use of statins from cohort entry to the index date was evaluated. Second, use of statins was further categorized as current use (≤180 days), recent use (181-365 days), or past use (>365 days) according to the end of the most recent prescription before index date. Additionally, average daily dose and duration of statin use were estimated among the current users. The average daily dose of all statins prescribed in the current use period was evaluated according to the international standard of defined daily dose (DDD),
      World Health OrganizationCollaborating Centre for Drug Statistics Methodology
      ATC Index with DDDs and Guidelines for ATC Classification and DDD Assignment.
      and classified as <0.5, 0.5-1.0, and >1.0 DDD. Furthermore, continuous use of statins was assessed using a 7-day interval between 2 successive prescriptions and categorized as ≤30, 31-90, and >90 days. Subjects without any statin prescribed from cohort entry to index date constituted the reference group throughout the analyses.

      Statistical Analyses

      Conditional logistic regression models were employed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to quantify the risk of COPD exacerbation associated with statin use. The variables listed in Table 1 were considered as potential covariates and included in the multivariate analyses if they were statistically significant in the univariate analyses (P <.05). In particular, the comorbid diseases, concomitant medications, COPD medications were measured between cohort entry and index date, in the year before index date, and in the 6 months preceding index date, respectively. Comorbidities are detailed in Supplementary Table 1 (online). Additionally, due to the unavailability of pulmonary test data, proxy indicators of COPD severity, including the number of COPD-related outpatient visits (0, 1-3, ≥4 visits) and number of individual types of COPD medications (0-2, ≥3 types) prescribed, also were measured during the 6 months before index date. Data cleaning and analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC) and STATA version 10.1 (STATA, College Station, Tex), respectively.
      Table 1Baseline Characteristics between Cases and Controls
      VariablesCases (n = 1584)Controls (n = 5950)Crude OR (95% CI)
      Age
      Matching variables.
      , mean (IQR)
      74.6 (70.0-80.6)74.1 (69.9-80.0)1.09 (1.07-1.12)
      Male
      Matching variables.
      , n (%)
      1261 (79.6)4768 (80.1)NA
      Comorbidities
      Comorbidities were measured from cohort entry to index date.
      , n (%)
       Coronary heart disease
      AMI15 (1.0)30 (0.5)1.92 (1.03-3.58)
      Stroke393 (24.8)971 (16.3)1.73 (1.51-1.99)
      Ischemic heart disease356 (22.5)1245 (20.9)1.09 (0.95-1.25)
      Angina67 (4.2)261 (4.4)0.96 (0.73-1.26)
      Peripheral vascular disease45 (2.8)186 (3.1)0.89 (0.64-1.24)
       CHF192 (12.1)458 (7.7)1.65 (1.38-1.98)
       Hypertension753 (47.5)2987 (50.2)0.88 (0.79-0.99)
       Diabetes mellitus264 (16.7)964 (16.2)1.03 (0.89-1.20)
       Depression60 (3.8)194 (3.3)1.17 (0.87-1.58)
       Renal failure71 (4.5)211 (3.6)1.29 (0.98-1.70)
       Chronic liver disease102 (6.4)345 (5.8)1.12 (0.89-1.40)
       Dementia174 (11.0)326 (5.5)2.17 (1.77-2.67)
      Co-medications
      Co-medications were measured in the year before index date.
      , n (%)
       ACEIs324 (20.5)1206 (20.3)1.01 (0.88-1.16)
       ARBs288 (18.2)1081 (18.2)0.97 (0.83-1.12)
       CV-selective beta-blockers154 (9.7)832 (14.0)0.66 (0.55-0.80)
       Nonselective beta-blockers254 (16.0)883 (14.8)1.08 (0.92-1.26)
       NSAIDs1079 (68.1)4023 (67.6)1.02 (0.90-1.15)
       SCSs963 (60.8)2352 (39.5)2.37 (2.11-2.66)
       Immune mediators79 (5.0)231 (3.9)1.29 (0.99-1.68)
       CYP 3A4 inhibitors511 (32.3)1453 (24.4)1.46 (1.29-1.65)
       CYP 3A4 inducers240 (15.2)571 (9.6)1.70 (1.44-2.00)
       Antibiotics
      Only antibiotics and vaccines indicated for influenza and pneumonia were included.
      1182 (74.6)3654 (61.4)1.84 (1.62-2.09)
       Vaccines
      Only antibiotics and vaccines indicated for influenza and pneumonia were included.
      448 (28.3)1903 (32.0)0.78 (0.68-0.89)
       PPIs202 (12.8)530 (8.9)1.50 (1.26-1.78)
       H2-blockers472 (29.8)1488 (25.0)1.26 (1.11-1.43)
       Other lipid-lowering agents
      Included fibrates, resins, niacins, and probucols.
      37 (2.3)233 (3.9)0.58 (0.41-0.83)
      COPD medications
      Chronic obstructive pulmonary disease (COPD) medications and COPD severity proxy indicators were measured from the 6 months before index date.
      , n (%)
       SABA881 (55.6)1614 (27.1)3.75 (3.31-4.25)
       LABA166 (10.5)320 (5.4)2.02 (1.64-2.48)
       Theophyllines1196 (75.7)3435 (57.7)2.65 (2.30-3.06)
       ICS241 (15.2)556 (9.3)1.67 (1.42-1.98)
       Anticholinergics509 (32.1)658 (11.1)4.28 (3.69-4.97)
      COPD severity proxy indicators
      Chronic obstructive pulmonary disease (COPD) medications and COPD severity proxy indicators were measured from the 6 months before index date.
      , n (%)
       COPD-related outpatient visits
      Matching variables.
      0736 (46.5)2911 (48.9)NA
      1∼3501 (31.6)1914 (32.2)NA
      ≥4347 (21.9)1125 (18.9)NA
       COPD medications
      0∼21098 (69.3)5272 (88.6)1.00
      ≥3486 (30.7)678 (11.4)3.82 (3.29-4.44)
      ACEIs = angiotensin-converting enzyme inhibitors; AMI = acute myocardial infarction; ARBs = angiotensin receptor blockers; CHF = congestive heart failure; CI = confident interval; ICS = inhaled corticosteroids; IQR = interquartile range; LABA = long-acting β2-agonists; NA = not applicable; NSAIDs = nonsteroidal anti-inflammatory agents; OR = odds ratio; PPIs = proton pump inhibitors; SABA = short-acting β2-agonists; SCSs = systemic corticosteroids.
      Matching variables.
      Comorbidities were measured from cohort entry to index date.
      Co-medications were measured in the year before index date.
      § Only antibiotics and vaccines indicated for influenza and pneumonia were included.
      || Included fibrates, resins, niacins, and probucols.
      Chronic obstructive pulmonary disease (COPD) medications and COPD severity proxy indicators were measured from the 6 months before index date.

      Sensitivity Analyses

      To test the robustness of the main finding, several additional analyses were conducted. First, we stratified patients by co-existing coronary heart diseases, excluded subjects with any diagnosis of asthma during the follow-up period, and evaluated the effect of nonstatin lipid-lowering agents including niacin, fibrates, or bile acid sequestrants. Additionally, COPD exacerbations were redefined as hospitalizations with a primary diagnosis of COPD, inpatient visits with a primary diagnosis of pneumonia concurrently accompanied by a secondary diagnosis of COPD, and those requiring intubations, respectively. Furthermore, statin users were classified as prevalent users and incident users, defined as those with and without any statin prescribed during the year before cohort entry, respectively. Current use of statins was further categorized based on the end date of the most recent prescription as ≤7, 8-30, and 31-180 days before index date. Moreover, we performed stratified analyses by concomitant use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, theophyllines, systematic corticosteroids (SCS), and number of individual types of COPD medications to evaluate the existence of an effect modification. In order to address healthy user bias,
      • Shrank W.H.
      • Patrick A.R.
      • Brookhart M.A.
      Healthy user and related biases in observational studies of preventive interventions: a primer for physicians.
      we measured and adjusted for use of statin-related preventive health services,
      • Brookhart M.A.
      • Patrick A.R.
      • Dormuth C.
      • et al.
      Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect.
      including prostate-specific antigen test and fecal occult blood test, as well as pneumonia/influenza vaccines in the 1 year before index date. Finally, a rule-out approach was adopted to estimate how strongly the unmeasured binary confounder of smoking needs to be associated with statin use and risk of COPD exacerbations to fully explain our findings. The prevalence of smoking in COPD was assumed to be 65%,
      • Liu S.F.
      • Lin K.C.
      • Chin C.H.
      • et al.
      Factors influencing short-term re-admission and one-year mortality in patients with chronic obstructive pulmonary disease.
      and 15% of the Taiwanese COPD population were estimated to be prescribed statins.

      Results

      The study cohort comprised 14,316 COPD patients over the 8-year study period (Figure 1); they were aged 67.7 years, on average, and were cumulatively followed for 63,657 patient-years. After exclusion of 41 cases without any corresponding matched control, a total of 1584 case patients and 5950 matched controls were retrieved and analyzed. The mean follow-up period, from cohort entry to the index date, was 2.3 years for cases and 2.5 years for controls. Additionally, among 9.0% of cases and 12.3% of controls, statins were prescribed, with atorvastatin being the most frequently prescribed drug (41.8% vs 40.7%), followed by simvastatin (24.4% vs 14.8%), lovastatin (12.9% vs 16.3%), and fluvastatin (12.3% vs 11.2%).
      Figure thumbnail gr1
      Figure 1Study flow diagram. COPD = chronic obstructive pulmonary disease.
      Table 1 displays the characteristics of cases and their matched controls. Generally, cases and controls were quite comparable in sex, number of outpatient visits for COPD, and the majority of comorbidities. However, cases were more likely than controls to have a diagnosis of congestive heart failure, acute myocardial infarction, stroke, and dementia. It also was more likely for cases to be prescribed with systemic corticosteroids, CYP-3A4 inhibitors, CYP-3A4 inducers, antibiotics for influenza and pneumonia, proton pump inhibitors, and H2-blockers, as well as to receive more classes of COPD medications.
      The multivariate analyses indicated that any use of statins was associated with a 30% (adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.56-0.88) decrease in the risk for COPD exacerbation in comparison with nonuse, and the reduced risk seemed to vary by recency of statin use (Table 2). Specifically, the most significantly reduced risk was present for current use of statins (adjusted OR, 0.60; 95% CI, 0.44-0.81), whereas there was no statistically significantly reduced risk for past use (adjusted OR, 0.60; 95% CI, 0.33-1.10) and remote use of statins (adjusted OR, 0.95; 95% CI, 0.67-1.35). The full multivariate model analyzing the COPD exacerbation risk related to any stain use is shown in Supplementary Table 2 (online), with adjusted ORs of the covariates resembling those during the recency analysis (data not shown).
      Table 2Risk of COPD Exacerbation Associated with Any Use of Statins and Recency of Statin Use
      Cases (n = 1584)Controls (n = 5950)Crude OR (95% CI)Adjusted OR
      Adjusted for age, CHF, AMI, stroke, hypertension, dementia, CV-selective beta-blockers, CYP3A4 inhibitors, CYP3A4 inducers, SCS, vaccines, antibiotics, PPIs, H2-blockers, other lipid-lowering agents, individual types of COPD medications, and number of COPD medications.
      (95% CI)
      Nonuse of statin, n (%)1442 (91.0)5221 (87.8)ReferenceReference
      Any use of statin, n (%)142 (9.0)729 (12.3)0.69 (0.57-0.84)
      P <.05.
      0.70 (0.56-0.88)
      P <.05.
      By recency, n (%)
       Current (0-180 days)68 (4.3)424 (7.1)0.57 (0.44-0.75)
      P <.05.
      0.60 (0.44-0.81)
      P <.05.
       Past (181-365 days)15 (1.0)96 (1.6)0.55 (0.32-0.96)
      P <.05.
      0.60 (0.33-1.10)
       Remote (>365 days)59 (3.7)209 (3.5)0.99 (0.73-1.34)0.95 (0.67-1.35)
      AMI = acute myocardial infarction; CHF = congestive heart failure; CI = confident interval; COPD = chronic obstructive pulmonary disease; OR = odds ratio; PPIs = proton pump inhibitors; SCS = systemic corticosteroid.
      Adjusted for age, CHF, AMI, stroke, hypertension, dementia, CV-selective beta-blockers, CYP3A4 inhibitors, CYP3A4 inducers, SCS, vaccines, antibiotics, PPIs, H2-blockers, other lipid-lowering agents, individual types of COPD medications, and number of COPD medications.
      P <.05.
      Table 3 indicates that current use of stains reduced the risk of COPD exacerbation in a dose-dependent rather than a duration-dependent manner. Specifically, the most profound protective effect was observed for statins prescribed at high average daily doses (>1 defined daily dose [DDD]; adjusted OR 0.33; 95% CI, 0.14-0.73), followed by medium daily doses (0.5-1 DDD; adjusted OR 0.60; 95% CI, 0.41-0.89), but absent for low average daily doses (<.5 DDD; adjusted OR 0.82; 95% CI, 0.48-1.38). Conversely, the risk of COPD exacerbation was not further decreased with increasing duration of statin use (≤30 days; adjusted OR 0.53; 95% CI, 0.30-0.95; >90 days; adjusted OR 0.53; 95% CI, 0.33-0.85).
      Table 3Risk of COPD Exacerbation Associated with Current Use of Statins by Dose and Duration
      The dose and duration were measured in the current statin users, defined as those had a statin prescription at index date or ≤180 days preceding index date.
      Cases (n = 1584)Controls (n = 5950)Crude OR (95% CI)Adjusted OR
      Adjusted for age, CHF, AMI, stroke, hypertension, dementia, CV-selective beta-blockers, CYP3A4 inhibitors, CYP3A4 inducers, SCS, vaccines, antibiotics, PPIs, H2-blockers, other lipid-lowering agents, individual types of COPD medications, and number of COPD medications.
      (95% CI)
      Nonuse of statin, n (%)1442 (91.0)5221 (87.8)ReferenceReference
      Current use of statin, n (%)
      By dose
       <0.5 DDD21 (1.3)102 (1.7)0.77 (0.48-1.23)0.82 (0.48-1.38)
       0.5-1.0 DDD38 (2.4)228 (3.8)0.60 (0.42-0.85)
      P <.05.
      0.60 (0.41-0.89)
      P <.05.
       >1.0 DDD9 (0.6)94 (1.6)0.32 (0.16-0.64)
      P <.05.
      0.33 (0.14-0.73)
      P <.05.
      By duration
       ≤30 days16 (1.0)110 (1.9)0.52 (0.31-0.89)
      P <.05.
      0.53 (0.30-0.95)
      P <.05.
       31-90 days25 (1.6)138 (2.3)0.62 (0.40-0.94)
      P <.05.
      0.76 (0.47-1.23)
       >90 days27 (1.7)176 (3.0)0.55 (0.37-0.83)
      P <.05.
      0.53 (0.33-0.85)
      P <.05.
      AMI = acute myocardial infarction; CHF = congestive heart failure; CI = confident interval; COPD = chronic obstructive pulmonary disease; DDD = defined daily dose; OR = odds ratio; PPIs = proton pump inhibitors; SCS = systemic corticosteroid.
      The dose and duration were measured in the current statin users, defined as those had a statin prescription at index date or ≤180 days preceding index date.
      Adjusted for age, CHF, AMI, stroke, hypertension, dementia, CV-selective beta-blockers, CYP3A4 inhibitors, CYP3A4 inducers, SCS, vaccines, antibiotics, PPIs, H2-blockers, other lipid-lowering agents, individual types of COPD medications, and number of COPD medications.
      P <.05.
      Our primary findings remained robust during the majority of sensitivity analyses (Figure 2). Notably, the beneficial effect of statins persisted regardless of the hospitalized COPD exacerbation redefined based on a principle diagnosis of COPD, or according to a primary diagnosis of pneumonia accompanied by a secondary diagnosis of COPD. Stratified analyses indicated that the observed beneficial effect of statins remained in patients without concomitant use of angiotensin-converting enzyme inhibitors (adjusted OR 0.75; 95% CI, 0.58-0.96), angiotensin receptor blockers (adjusted OR 0.66; 95% CI, 0.50-0.86), beta-blockers (adjusted OR 0.67; 95% CI, 0.51-0.88), or systemic corticosteroids (adjusted OR 0.69; 95% CI, 0.48-0.98), whereas there was no more reduced risk of COPD exacerbation by statins in those with concomitant use of the above-mentioned medications. Current statin users in general had more comorbidities and received more statin-related preventive health services than nonusers (see Supplementary Table 3, online), and further adjustment for use of these services led to similar results (adjusted OR 0.71; 95% CI, 0.57-0.89).
      Figure thumbnail gr2
      Figure 2Risk of hospitalization for chronic obstructive pulmonary disease (COPD) exacerbations in the sensitivity analyses. * P <.05. †The effect of nonstatin lipid-lowering agents on COPD exacerbations was estimated with nonuse of any lipid-lowering agent as the reference group. ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; CHD = coronary heart disease; CI = confidence interval; OR = odds ratio.
      Figure 3 indicates that an unmeasured confounder of smoking needs to be 3 times less prevalent in statin users than nonusers, and to have a 10-fold increased risk of COPD exacerbations to fully explain our main findings. However, these scenarios are highly unlikely to occur.
      Figure thumbnail gr3
      Figure 3Sensitivity analysis assessing the strengths of associations between an unmeasured confounder of smoking and statin use and risk of chronic obstructive pulmonary disease (COPD) exacerbations that would explain our observed protective effect of statin use on COPD exacerbation (Adjusted odds ratio [Adj OR] = 0.70) or its upper 95% confidence limit (Adj OR = 0.88). Any combination of RRCD and OREC values resulting in points lower than and to the left of the solid line would be able to explain our main finding. OREC = association between statin use and smoking; RRCD = association between smoking and risk of COPD exacerbations.

      Discussion

      In this population-based nested case-control study, any use of statins is found to be associated with a 30% reduction in the risk of hospitalization for COPD exacerbation. The protective effect of statins on COPD exacerbations is more profound for statins used within 6 months, or for statins prescribed at medium or high average daily dose. This observational study revealed that statin use might be beneficial in COPD patients.
      Previous studies examining statin use in relation to COPD exacerbations
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      might be biased.
      • Suissa S.
      Co-morbidity in COPD: the effects of cardiovascular drug therapies.
      One hospital-based retrospective cohort study observed that statin use reduced risk of COPD exacerbation for up to 67% compared with nonuse.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      A nested case-control study, analyzing Quebec Linked Databases, revealed statin users were up to 28% less likely to be hospitalized for COPD than nonusers,
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      another cohort study of 6252 newly diagnosed COPD patients found a similar protective effect.
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      A further prospective observational study observed a 34%-40% lower risk of subsequent COPD exacerbation by statin use versus nonuse.
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      However, these studies were subjected to categorization of statin use based on a single prescription,
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      lack of adjustment for COPD severity and other important confounders (eg, respiratory antibiotics),
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      potential for confounding by indication,
      • Bartziokas K.
      • Papaioannou A.I.
      • Minas M.
      • et al.
      Statins and outcome after hospitalization for COPD exacerbation: a prospective study.
      immortal time bias,
      • Huang C.C.
      • Chan W.L.
      • Chen Y.C.
      • et al.
      Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
      • Blamoun A.I.
      • Batty G.N.
      • DeBari V.A.
      • et al.
      Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study.
      and immeasurable time bias.
      • Mancini G.B.
      • Etminan M.
      • Zhang B.
      • et al.
      Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
      These limitations were addressed in our study.
      The diverse immune modulating
      • Young R.P.
      • Hopkins R.
      • Eaton T.E.
      Pharmacological actions of statins: potential utility in COPD.
      • Morimoto K.
      • Janssen W.J.
      • Fessler M.B.
      • et al.
      Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease.
      and anti-inflammatory actions
      • Young R.P.
      • Hopkins R.
      • Eaton T.E.
      Pharmacological actions of statins: potential utility in COPD.
      • Hurst J.R.
      • Hagan G.
      • Wedzicha J.A.
      Mechanism of statin-associated mortality reduction in COPD.
      of statins might be the plausible mechanism accounting for the observed risk reduction of COPD exacerbations. In addition to inhibition of endogenous cholesterol synthesis, statins have been reported to exert strong immunomodulating effects.
      • Morimoto K.
      • Janssen W.J.
      • Fessler M.B.
      • et al.
      Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease.
      • Arnaud C.
      • Veillard N.R.
      • Mach F.
      Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis.
      Ample evidence also suggests that statins not only inhibit pulmonary inflammation, but also exhibit systemic anti-inflammatory effects in COPD.
      • Young R.P.
      • Hopkins R.
      • Eaton T.E.
      Pharmacological actions of statins: potential utility in COPD.
      These anti-inflammatory effects might be the mediator of clinically improved COPD-related end points. Specifically, one randomized controlled trial found that a 54% increase in exercise tolerance by pravastatin was associated with a reduction in high-sensitivity C-reactive protein and interleukin-6.
      • Lee T.M.
      • Lin M.S.
      • Chang N.C.
      Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin.
      Given that COPD is characterized by pulmonary and systemic inflammation, the above-mentioned statins' anti-inflammatory effects might contribute to the observed beneficial outcome.
      To our knowledge, this is the first study to observe a dose-dependent reduced risk of hospitalization for COPD exacerbation by stain use. Frost et al
      • Frost F.J.
      • Petersen H.
      • Tollestrup K.
      • Skipper B.
      Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.
      also reported that an 81% reduction in COPD-specific mortality was related to statins prescribed at a high average daily dose (>4 mg/day), but not at a low dose (≤4 mg/day). A randomized controlled trial indicated that statins were potentially related to an anti-inflammatory effect in a dose-dependent manner,
      • Nohria A.
      • Prsic A.
      • Liu P.Y.
      • et al.
      Statins inhibit Rho kinase activity in patients with atherosclerosis.
      which might provide the mechanistic underpinning for the observed dose-response relationships.
      Temporal properties of immune modulatory effects of statins might account for the observed non-duration-dependent relationship, although evidence is scarce. One study observed that 30-day continuous use of atorvastatin or pravastatin reduced high-sensitivity C-reactive protein for up to 87%, but 4 months or 24 months of statin use did not result in further reductions.
      • Ridker P.M.
      • Cannon C.P.
      • Morrow D.
      • et al.
      C-reactive protein levels and outcomes after statin therapy.
      Nonetheless, whether statins exert a duration-dependent effect on COPD exacerbation could not be clearly delineated without examining a wider range of duration, which warrants further researches.
      Despite the reported COPD benefits associated with use of ACEIs,
      • Shrikrishna D.
      • Astin R.
      • Kemp P.R.
      • Hopkinson N.S.
      Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease.
      ARBs,
      • Shrikrishna D.
      • Astin R.
      • Kemp P.R.
      • Hopkinson N.S.
      Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease.
      or beta-blockers,
      • Rutten F.H.
      • Zuithoff N.P.
      • Hak E.
      • et al.
      Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease.
      the reduced COPD exacerbation risk by statins was observed only in patients who had never used these medications. It is, therefore, suspected that statins' anti-inflammatory effects may not confer tangible benefit to COPD patients already receiving medications that exert anti-inflammatory properties, such as ACEIs.
      • Shrikrishna D.
      • Astin R.
      • Kemp P.R.
      • Hopkinson N.S.
      Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease.
      We also observed that the statins' beneficial effect was probably confined to patients with less COPD severity, including those without use of SCSs or those with ≤2 types of individual COPD medications. Accordingly, our findings seemed to indicate that the beneficial effects of statins are more profound in patients with less COPD severity than in those with severer severity. Due to lack of pulmonary function tests in the databases, future studies are needed to confirm whether or not the reduced risk of COPD exacerbation by statins varies depending on COPD severity. Conversely, although theophylline use was reported as a risk factor for COPD exacerbation,
      • Niewoehner D.E.
      • Lokhnygina Y.
      • Rice K.
      • et al.
      Risk indexes for exacerbations and hospitalizations due to COPD.
      it is unclear why the reduced exacerbation by statins persisted in the stratum of patients with theophylline use. The characterized specific conditions that might affect the effects of statin use on COPD exacerbation in this study provide important information on how a randomized control trial should be designed to clarify the role of statins as an adjunctive treatment for COPD.
      This study has several unique attributes. The study cohort was representative of the entire Taiwanese COPD population. In addition, the immeasurable time bias and recall bias are minimized by analyzing the database with comprehensive information on medical records and prescribed medications.

      Taiwan National Health Insurance Research Database. Introduction to the National Health Insurance Research Database. Available at http://w3.nhri.org.tw/nhird/date_01.html. Accessed November 27, 2012.

      Furthermore, selection bias is potentially precluded due to the identification of cases and the matched controls from the same well-defined COPD cohort. Moreover, to our knowledge, this is the first study to evaluate the recency and duration effect of statin use on the risk of COPD exacerbations. Lastly, the observed dose-response relationship further strengthens the causality.
      Several limitations of this study merit discussion. First, the ICD-9 codes used for COPD exacerbations have been extensively employed in other studies,
      • Wang M.T.
      • Tsai C.L.
      • Lo Y.W.
      • et al.
      Risk of stroke associated with inhaled ipratropium bromide in chronic obstructive pulmonary disease: a population-based nested case-control study.
      • Vaz Fragoso C.A.
      • Concato J.
      • McAvay G.
      • et al.
      Respiratory impairment and COPD hospitalisation in older persons: a competing risk analysis.
      • Gil A.
      • Gil R.
      • Oyaguez I.
      • et al.
      Hospitalization by pneumonia and influenza in the 50-64 year old population in Spain (1999-2002).
      but haven't been clinically validated in the LHID. However, the internal findings seemed to support the coding validity in that the proxy indicators of COPD severity and medications for COPD exacerbations were more prevalent in cases than controls (Table 1). Second, only hospitalization for COPD exacerbation was investigated as the study outcome. However, COPD exacerbation requiring hospitalization represents the acute deterioration of disease and relates to an escalating mortality rate in subsequent years.
      • Garcia-Aymerich J.
      • Serra Pons I.
      • Mannino D.M.
      • et al.
      Lung function impairment, COPD hospitalisations and subsequent mortality.
      Third, this study analyzed the administrative claims database, and important clinical characteristics could not be described and taken into consideration, such as laboratory data indicating COPD severity. Nevertheless, the proxy indicators for COPD severity and use of concomitant respiratory medications were controlled for through matching or multivariate adjustment. Fourth, a substantial difference in the pharmacological management of COPD between Taiwan
      • Hsieh M.J.
      • Lan C.C.
      • Chen N.H.
      • et al.
      Effects of high-intensity exercise training in a pulmonary rehabilitation programme for patients with chronic obstructive pulmonary disease.
      and North America
      • Niewoehner D.E.
      • Lokhnygina Y.
      • Rice K.
      • et al.
      Risk indexes for exacerbations and hospitalizations due to COPD.
      or Europe
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      (eg, low inhaled corticosteroids use but high theophylline use in Taiwan) probably limited the generalizability of our results. Fifth, healthy user bias might be a potential explanation for our findings, as statin users had healthier characteristics than nonusers. However, the observed statins' beneficial effect was less likely to result from this bias because statin users had more comorbidities than nonusers, and further adjustment of the health-seeking tendency had little effect on the overall results. Sixth, the absence of information on smoking in the administrative database might pose another limitation. However, the sensitivity analysis indicated that smoking would nullify our main finding if smoking was very unevenly distributed between statin users and nonusers, and highly associated with COPD exacerbations. The 2 conditions are unlikely to happen.
      • Liu S.F.
      • Lin K.C.
      • Chin C.H.
      • et al.
      Factors influencing short-term re-admission and one-year mortality in patients with chronic obstructive pulmonary disease.
      • Hsuan C.F.
      • Lee T.L.
      • Chang H.L.
      • et al.
      A retrospective study of statin use and its effectiveness in Taiwanese.
      In conclusion, the present study observes that statin use is associated with a decreased risk of COPD exacerbation requiring hospitalization. The protective effect is more profound for statins used more recently, or at higher average daily doses. The insights from this study provided the data for designing a large randomized controlled trial in which the role of statins as an adjunctive treatment for COPD should be clarified.

      Acknowledgment

      We thank the Bureau of National Health Insurance and the National Health Research Institutes for providing the database. The interpretation and conclusions contained herein do not represent those of the above-mentioned institutes. We also appreciate Ms. Bi-Juian Wu for the assistance in cleaning the datasets.

      Appendix

      Supplementary Table 1ICD-9-CM Definitions for Comorbid Diseases
      ComorbiditiesICD-9-CM codes
      CHF428
      AMI410
      Stroke430-438
      Ischemic heart disease410-414
      Angina413
      Peripheral vascular disease440-448
      Hypertension401-405
      Diabetes mellitus250
      Depression296.2, 296.3, 303.4, 311
      Renal failure403, 404, 582, 583, 585, 586, 588
      Chronic liver disease456, 571, 572
      Dementia290, 797
      AMI = acute myocardial infarction; CHF = congestive heart failure; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification.
      Supplementary Table 2Full Results from a Multivariate Conditional Logistic Regression Analysis of COPD Exacerbation Risk Associated with Any Use of Statins
      Cases (n = 1584)Controls (n = 5950)Adjusted OR
      Adjusted for variables listed in the table.
      (95% CI)
      Nonuse of statin, n (%)1442 (91.0)5221 (87.8)Reference
      Any use of statin, n (%)142 (9.0)729 (12.3)0.70 (0.56-0.88)
      P <.05.
      Age, mean (IQR)74.6 (70.0-80.6)74.1 (69.9-80.0)1.09 (1.06-1.12)
      P <.05.
      Comorbidities, n (%)
       CHF192 (12.1)458 (7.7)1.20 (0.97-1.48)
       AMI15 (1.0)30 (0.5)1.58 (0.75-3.31)
       Stroke393 (24.8)971 (16.3)1.53 (1.30-1.81)
      P <.05.
       Hypertension753 (47.5)2987 (50.2)0.85 (0.75-0.98)
      P <.05.
       Dementia174 (11.0)326 (5.5)1.78 (1.40-2.26)
      P <.05.
      Co-medications, n (%)
       CV-selective beta-blockers154 (9.7)832 (14.0)0.72 (0.58-0.89)
      P <.05.
       SCSs963 (60.8)2352 (39.5)1.70 (1.48-1.95)
      P <.05.
       CYP 3A4 inhibitors511 (32.3)1453 (24.4)1.19 (1.03-1.37)
      P <.05.
       CYP 3A4 inducers240 (15.2)571 (9.6)1.27 (1.05-1.54)
      P <.05.
       Antibiotics1182 (74.6)3654 (61.4)1.30 (1.12-1.50)
      P <.05.
       Vaccines448 (28.3)1903 (32.0)0.71 (0.61-0.82)
      P <.05.
       PPIs202 (12.8)530 (8.9)1.11 (0.90-1.37)
       H2-blockers472 (29.8)1488 (25.0)1.01 (0.87-1.16)
       Other lipid-lowering agents37 (2.3)233 (3.9)0.70 (0.47-1.04)
      COPD medications, n (%)
       SABA881 (55.6)1614 (27.1)2.44 (2.10-2.82)
      P <.05.
       LABA166 (10.5)320 (5.4)1.25 (0.90-1.74)
       Theophyllines1196 (75.7)3435 (57.7)1.97 (1.68-2.32)
      P <.05.
       ICS241 (15.2)556 (9.3)0.94 (0.70-1.25)
       Anticholinergics509 (32.1)658 (11.1)2.48 (1.97-3.13)
      P <.05.
      COPD severity proxy indicators, n (%)
       COPD medications
      0∼21098 (69.3)5272 (88.6)Reference
      ≥3486 (30.7)678 (11.4)0.90 (0.67-1.21)
      AMI = acute myocardial infarction; CHF = congestive heart failure; CI = confident interval; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; IQR = interquartile range; LABA = long-acting β2-agonists; OR = odds ratio; PPIs = proton pump inhibitors; SABA = short-acting β2-agonists; SCS = systemic corticosteroids.
      Adjusted for variables listed in the table.
      P <.05.
      Supplementary Table 3Comorbidities and Use of Preventive Health Services between Current Statin Use and No Current Statin Use among Cases and Controls
      Cases (n = 1584)Controls (n = 5950)
      Current Statin Use (n = 68)No Current Statin Use (n = 1516)Current Statin Use (n = 424)No Current Statin Use (n = 5526)
      Comorbidities,
      Comorbidities were measured from cohort entry to index date.
      n (%)
       CHF13 (19.1)179 (11.8)36 (8.5)422 (7.6)
       AMI1 (1.5)14 (0.9)3 (0.7)27 (0.5)
       Stroke15 (22.1)378 (25.0)74 (17.5)897 (16.2)
       Ischemic heart disease37 (54.4)319 (21.0)173 (40.8)1,072 (19.4)
       Angina8 (11.8)59 (3.9)46 (10.9)215 (3.9)
       Peripheral vascular disease5 (7.4)40 (2.6)21 (5.0)165 (3.0)
       Hypertension46 (67.7)707 (46.6)298 (70.3)2,689 (48.7)
       Diabetes mellitus27 (39.7)237 (15.6)152 (35.9)812 (14.7)
       Depression2 (2.9)58 (3.8)24 (5.7)170 (3.1)
       Renal failure3 (4.4)68 (4.5)23 (5.4)188 (3.4)
       Chronic liver disease4 (5.9)98 (6.5)37 (8.7)308 (5.6)
       Dementia3 (4.4)171 (11.3)15 (3.5)311 (5.6)
      Preventive health services,
      Preventive health services were measured in the year before index date.
      n (%)
       Vaccines
      Only vaccines indicated for influenza and pneumonia were included.
      21 (30.9)427 (28.2)147 (34.7)1,756 (31.8)
       Prostate-specific antigen test6 (8.8)129 (8.5)63 (14.9)545 (9.9)
       Fecal occult blood test7 (10.3)205 (13.5)62 (14.6)507 (9.2)
      AMI = acute myocardial infarction; CHF = congestive heart failure.
      Comorbidities were measured from cohort entry to index date.
      Preventive health services were measured in the year before index date.
      Only vaccines indicated for influenza and pneumonia were included.

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      Linked Article

      • Statins Reduce Respiratory Complications of COPD
        The American Journal of MedicineVol. 127Issue 1
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          In their population-based nested case control study, Wang et al1 showed that statin use in patients with chronic obstructive pulmonary disease (COPD) was associated with a 30% reduction in hospital exacerbations. While these results mirror those of other observational studies,2 several important findings from this study deserve mention.
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