Introduction
============

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation due to chronic inflammation of the lungs.[@b1-copd-8-287]--[@b3-copd-8-287] Worldwide, COPD is estimated to become the third leading cause of mortality and the fifth most burdensome disease.[@b4-copd-8-287]--[@b6-copd-8-287] In the United States, COPD is the fourth leading cause of morbidity and mortality.[@b4-copd-8-287],[@b7-copd-8-287] Individuals with COPD also suffer from extensive physical and psychological comorbidities, which worsen their health-related quality of life and pose challenges to health care management,[@b3-copd-8-287],[@b8-copd-8-287] and can lead to increased risk of mortality in the elderly over the age of 65 years.[@b9-copd-8-287]

Bronchodilators including long-acting and short-acting beta-2-agonists, inhaled anticholinergics (IAC), and combination drug therapies have been approved in the United States for the management of COPD.[@b7-copd-8-287] Traditionally, anticholinergics agents have been linked with an increased risk of fatal and nonfatal cardiovascular adverse events, stroke, and all-cause mortality. IAC have been shown to reduce the risk of adverse events due to inclusion of a quaternary ammonium structure which inhibits gastrointestinal absorption.[@b10-copd-8-287] However, other mechanisms may increase the risk of adverse events in specific subgroups. These include elevation of plasma IAC levels in elderly individuals and in those with renal impairment.[@b11-copd-8-287],[@b12-copd-8-287]

Evidence regarding the safety of IAC in terms of all-cause mortality is inconsistent. Findings from several randomized controlled trials have indicated that IAC are as safe as placebo or active controls in terms of all-cause mortality.[@b13-copd-8-287],[@b14-copd-8-287] Similarly, analyses of pooled data from the controlled trials show no statistically significant increase in risk of cardiovascular adverse events or all-cause mortality with IAC use.[@b15-copd-8-287]--[@b17-copd-8-287] However, these results have been contradicted in a systematic review with meta-analysis which concluded that IAC use was associated with increased risk of composite cardiovascular adverse events including stroke, myocardial infarction, and cardiovascular death.[@b18-copd-8-287] Further, a nested case-control study reported a 34% increase in cardiovascular mortality and an 11% increase in all-cause mortality with IAC, specifically ipratropium bromide.[@b18-copd-8-287],[@b19-copd-8-287] These findings cannot be generalized due to methodological shortcomings in terms of double-counting of event data (meta-analysis) and not adequately accounting for baseline differences (nested case-control study).[@b10-copd-8-287],[@b20-copd-8-287] Subsequently, results from the four-year UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial suggested that tiotropium was not associated with adverse events and actually reduced the risk of mortality.[@b14-copd-8-287] These findings were also supported by a systematic review and meta-analysis published after including data from the UPLIFT trial.[@b21-copd-8-287]

None of the above-mentioned studies were specific to the elderly, so their findings may have limited applicability in the elderly population. It is reported that elderly individuals are not adequately represented in randomized controlled trials.[@b22-copd-8-287] Moreover, disease management in elderly individuals with COPD is complicated by extensive coexisting chronic physical and psychiatric conditions.[@b23-copd-8-287] For example, elderly individuals with COPD are at greater risk for chronic renal failure,[@b24-copd-8-287] which leads to elevated plasma IAC levels that may further elevate the risk of adverse events, including all-cause mortality.[@b11-copd-8-287] To date, no study has rigorously examined the association between IAC use and all-cause mortality in elderly individuals with COPD. Therefore, the primary objective of the current study was to examine the association between use of IAC and all-cause mortality in elderly individuals with COPD. For the purposes of this study, we used retrospective longitudinal data from elderly Medicare beneficiaries seeking care in the real-world setting.

Materials and methods
=====================

Study design
------------

We adopted a longitudinal panel design with retrospective observational data to analyze the association between use of IAC and all-cause mortality using the Medicare Current Beneficiary Survey (MCBS). The MCBS is a "nationally representative sample of aged, disabled, and non-institutionalized Medicare beneficiaries" with linkage to fee-for-service Medicare claims.[@b25-copd-8-287] Because individuals were followed for three years, we defined the baseline period as the first observed year of each panel. Follow-up of each panel for two years were used to assess mortality status, as discussed below.

Data source
-----------

The MCBS is a longitudinal, multipurpose survey, and is representative of the Medicare population in the United States. Medicare beneficiaries are selected using a multistage stratified random sampling design. Selected beneficiaries are followed for a period of three years. The data are continually collected for three rounds per year at four-month intervals. MCBS follows a rotating panel survey design in which each panel is interviewed 12 times.

The MCBS is divided into two modules, ie, "access to care" and "cost-and use". The access to care module contains information relating to respondents' access to medical providers and their satisfaction with health care for beneficiaries enrolled in Medicare for the entire year. In contrast with that, the cost and use file of the MCBS contains information on health care use, prescription drug use, chronic conditions, and personal health care practices.[@b25-copd-8-287] Health care expenditures and utilization were obtained from personal interviews conducted every four months as well as Medicare claims. The current study utilized multiple years of cost and use files linked with fee-for-service Medicare claims data.

Analytical sample
-----------------

Individuals were considered to have diagnosed COPD if they had at least one inpatient visit or two outpatient visits for COPD based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for chronic bronchitis (491.xx), emphysema (492.xx), or unspecified chronic airway obstruction (496.xx). Other inclusion criteria consisted of community-dwelling fee-for-service Medicare beneficiaries who were over 65 years of age and had full-year enrollment during the baseline period.

Using the merged data from multiple years (2002--2009), we obtained six longitudinal panels: 2002--2004 (Panel I); 2003--2005 (Panel II); 2004--2006 (Panel III); 2005--2007 (Panel IV); 2006--2008 (Panel V); and 2007--2009 (Panel VI). The final sample consisted of 2610 Medicare beneficiaries, and included 424 beneficiaries in Panel I, 458 beneficiaries in Panel II, 406 beneficiaries in Panel III, 475 beneficiaries in Panel IV, 419 beneficiaries in Panel V, and 428 beneficiaries in Panel VI.

Key independent variable: IAC use
---------------------------------

We identified IAC use from prescription medicine events files. Prescription medicine events files contain self-reported drug utilization at the prescription level. Two IAC are approved in the United States, ie, ipratropium bromide (short-acting) and tiotropium bromide (long-acting). All generic and brand names for these two IAC were obtained from the US Food and Drug Administration register.[@b26-copd-8-287] These names were then used to identify IAC use. The first year of each panel was used to measure baseline characteristics as well as IAC use. Elderly Medicare beneficiaries who reported having at least one prescription for any IAC in the baseline year of each panel were categorized as IAC users.

Dependent variable: mortality status (dead versus alive)
--------------------------------------------------------

We defined mortality status as a dichotomous variable (yes/no) using the "vital status" variable in the MCBS data. Decedent status was derived from both survey responses and administrative claims files.[@b27-copd-8-287] Medicare beneficiaries who died during the follow-up observation years were considered as decedents. For example, in the first panel (2002--2004), mortality status was determined using vital status data in follow-up years (ie, individuals who died in 2003 or 2004).

Other independent variables
---------------------------

All independent variables were measured in the baseline period (ie, first year of observation).

Demographic variables consisted of gender (women, men), race (white, African American, others), age in years (65--69, 70--74, and ≥75), and metropolitan status (metro, not metro). Socioeconomic status included education (less than high school, high school, and college education), poverty status (\<200% versus \>200% of the federal poverty line), and prescription drug coverage (yes, no).

Coexisting chronic physical and mental health conditions were identified using responses to questions about whether beneficiaries ever had the following diseases: Alzheimer's disease, arthritis, cardiovascular disease, cancer, diabetes, hypertension, mental illness, osteoporosis, and stroke. Based on three studies which analyzed multimorbidity patterns with respiratory diseases (one using Medicaid data[@b28-copd-8-287] and others using expert clinical reviews),[@b29-copd-8-287],[@b30-copd-8-287] separate indicator variables were constructed for each of the following comorbidities: cardiovascular/metabolic disorders (composite of beneficiaries with diabetes/heart disease/hypertension/stroke); mental illness; musculoskeletal disorders (composite of beneficiaries with arthritis and/or osteoporosis) and other diseases (composite of beneficiaries with cancer and/or Alzheimer's disease). Because of the potential association between chronic renal failure and adverse events with use of IAC, we also included an indicator variable for chronic renal failure. Chronic renal failure was identified using the ICD-9-CM codes in the clinical classification software[@b31-copd-8-287] provided by the Agency for Healthcare Research and Quality, ie, 585. xx, 586, 792.5, V42.0, V45.1, V56.0--V56.32, and V56.8.

Personal health care practices were identified using smoking status (current, past, never) and body mass index (BMI) values categorized into five different classes: underweight (BMI \< 18.5 kg/m^2^); normal (BMI ≥ 18.5--25 kg/m^2^); overweight (BMI ≥ 25--30 kg/m^2^); and obese (BMI ≥ 30 kg/m^2^).[@b32-copd-8-287]

Health status was measured by self-perceived general health. In the MCBS data, the survey respondents reported their physical health status as being excellent, very good, good, fair, or poor. For the purpose of our analyses, we grouped these responses as: excellent or very good health; good health; fair health; and poor health. A panel or cohort variable was used as an additional independent variable to adjust for time effects.

Statistical methods
-------------------

Chi-square tests of independence were used to determine unadjusted group differences according to IAC use. In order to understand the independent association between IAC use and other variables and all-cause mortality, independent variables were entered in separate blocks. The first model (model I) was an unconditional model with IAC use as the only independent variable. Model II adjusted for IAC use and coexisting conditions (mental illness, cardiovascular/metabolic disorders, musculoskeletal disorders, chronic renal failure, and other conditions). In model III, we added gender, race, age, metro status, education level, and socioeconomic status. Model IV adjusted for perceived health status in addition to all the independent variables included in model III. Additionally, in model V, we included functional status, BMI category, and smoking status. All analyses controlled for the complex design of the MCBS and were conducted using survey procedures with Statistical Analysis System version 9.3 software (SAS Institute Inc, Cary, NC, USA).

Results
=======

The final study sample obtained after applying all eligibility criteria consisted of 2610 Medicare beneficiaries. A majority (54%) of the study sample were female, 84% were white, 53% were older than 75 years, 52% were married, and 70% resided in a metropolitan area. In terms of socioeconomic status, 34% had no high school education and 42% of the sample was below 200% of the federal poverty level. Twenty-three percent of elderly individuals were obese and 20% were current smokers. The far right entries in [Table 1](#t1-copd-8-287){ref-type="table"} show the number and weighted percentages of beneficiaries with IAC use. The significance column reports the statistical significance between IAC use and beneficiary characteristics. Statistically significant differences in IAC use were observed by gender, age categories, prescription drug coverage, health status, functional status, and smoking status. IAC use was significantly higher (28.5%) among elderly Medicare beneficiaries who reported poor perceived health status as compared with those self-reporting excellent or very good health status (12.7%).

In our study sample, 19% of the elderly individuals reported IAC use in the baseline period. [Table 2](#t2-copd-8-287){ref-type="table"} summarizes unadjusted associations between selected beneficiary characteristics and all-cause mortality. We observed a statistically significant association between IAC use and all-cause mortality (odds ratio \[OR\] 1.46, 95% confidence interval \[CI\] 1.12--1.90). Elderly Medicare beneficiaries with IAC use and cardiovascular/metabolic disorder had an increased likelihood of all-cause mortality compared with those without IAC use and cardiovascular/metabolic disorder (OR 1.40, 95% CI 1.03--1.91). Medicare beneficiaries who reported their health status to be poor were five times more likely to die than those with self-reported excellent to very good health status (OR 5.69, 95% CI 3.79--8.53).

Multivariable logistic regressions with independent variables entered in separate blocks were used to examine the association between IAC use and all-cause mortality. Even after adjusting for coexisting chronic conditions, we observed a statistically significant association between IAC use and all-cause mortality (adjusted OR 1.47, 95% CI 1.14--1.90). Similar results were observed when the analyses additionally controlled for demographic characteristics (adjusted OR 1.51, 95% CI 1.16--1.97). However, the significant association between IAC use and all-cause mortality disappeared once we controlled for health status (adjusted OR 1.32, 95% CI 1.00--1.74). Similar findings were noted in model IV, which additionally controlled for lifestyle risk factors (adjusted OR 1.26, 95% CI 0.95--1.67, [Table 3](#t3-copd-8-287){ref-type="table"}).

Although, not specific to the elderly, it has been reported that IAC use is associated with increased risk of fatal and nonfatal cardiovascular events,[@b18-copd-8-287],[@b19-copd-8-287],[@b33-copd-8-287],[@b34-copd-8-287] suggesting that among individuals with cardiovascular disease, IAC use may increase the risk of mortality. Therefore, we also included an interaction term between IAC use and the presence of cardiovascular/metabolic disorder (results not shown). After controlling for all the variables included in model IV, there was no statistically significant association between the interaction term and all-cause mortality (Wald chi-square = 2.676, *P* = 0.102).

Discussion
==========

This study contributes to the knowledge base on the safety of IAC use in terms of all-cause mortality among elderly Medicare beneficiaries with COPD seeking care in a real world-setting, with extensive controls for demographic and socioeconomic factors, coexisting chronic conditions, personal health care practices, and self-reported health status. We observed a statistically significant association between IAC use and all-cause mortality in the bivariate analyses. However, after controlling for self-reported perceived health status in the final model, which also included coexisting conditions, and demographic, socioeconomic, and lifestyle risk factors, it was found that IAC use was no longer associated with all-cause mortality. This finding is consistent with that of the UPLIFT trial and other meta-analyses,[@b14-copd-8-287],[@b21-copd-8-287] and can be explained using the updated evidence from this field.[@b15-copd-8-287]

Previous studies have shown increased cardiovascular events and mortality due to use of IAC.[@b19-copd-8-287],[@b33-copd-8-287],[@b34-copd-8-287] However, in a synthesis of available evidence on the safety of IAC use in terms of major cardiovascular events, it has been suggested that IAC may not be responsible for severe cardiovascular adverse events because of its poor gastrointestinal absorption.[@b35-copd-8-287] Consistent with this medical opinion, we did not find any statistically significant association between the interaction term (ie, IAC use and cardiovascular/metabolic disorder) and all-cause mortality, suggesting that use of IAC is safe in the elderly with cardiovascular disease. Our findings are also consistent with a review of the evidence from clinical trials on IAC use and cardiovascular-related mortality which concluded that IAC is safe.[@b36-copd-8-287],[@b37-copd-8-287] If replicated, our study findings may have significant implications for IAC treatment in the elderly with cardiovascular conditions.

An interesting observation in our study was the higher rate of IAC use among current smokers (22.1%) and former smokers (22.8%) compared with nonsmokers (8.5%). It is indeed surprising that current smokers were more likely to report IAC use compared with nonsmokers and former smokers. Current evidence on this issue has consistently indicated that, irrespective of smoking status, IAC use is associated with improved lung function.[@b38-copd-8-287]--[@b40-copd-8-287] Findings from the post hoc analysis of data from the UPLIFT by smoking status also suggested that use of tiotropium improves lung function and health status, regardless of smoking status.[@b40-copd-8-287] Given these findings, one would expect no differences in IAC use by smoking status. However, one could speculate that greater IAC use among current smokers could be due to some evidence of increased lung function with tiotropium in smokers. A study reported by Moita et al indicates that the difference in lung function with tiotropium use was significantly greater for current smokers as compared with former smokers.[@b39-copd-8-287]

A noteworthy finding from the current study is the disappearance of the statistically significant association between IAC use and all-cause mortality after adjusting for health status. In our study, self-reported perceived health status was also a strong predictor of all-cause mortality, consistent with prior studies. Prior research using a pooled analysis of 22 studies observed a statistically significant association between poor health status and increased risk of mortality (risk ratio 1.92, 95% CI 1.64--2.25).[@b41-copd-8-287] Further, closer examination of IAC use by health status indicates that a higher proportion of elderly individuals with poor health status (28.5%) reported using IAC compared with those with excellent or very good health (12.7%). Therefore, any observed relationship between IAC and all-cause mortality may have been driven by differences in IAC use according to health status. These findings collectively highlight the importance of controlling for self-perceived health status when investigating the relationship between IAC use and all-cause mortality, because adjusting for health status may change the direction of the relationship between IAC use and mortality, as shown in our study.

The strength of this study includes its use of a nationally representative sample of elderly individuals over 65 years of age, the longitudinal study design, and the ability to ascertain the relationship between IAC use and mortality after controlling for a comprehensive list of risk factors. The study has a few limitations which should be noted. Because the MCBS data do not contain precise dates of prescription fills, it is difficult to derive data on adherence and persistence with IAC, and adherence may affect the risk of death. Therefore, studies examining long-term persistence with use of IAC may provide a robust indication of the association between IAC use and all-cause mortality. The study may also suffer from selection bias as a result of unobserved variables, such as patient preferences that may have affected IAC use. However, we may have minimized any selection bias by controlling for a host of risk factors with the potential to impact the association between IAC use and all-cause mortality. Further, the MCBS does not collect laboratory data, so we were unable to assess and adjust for the severity of COPD in our analyses.

Despite these limitations, our study makes a unique contribution to the existing knowledge base on safety of IAC use among the elderly. Our results suggest that use of IAC may be safe in the elderly with COPD, and indicate a need to control for self-perceived health status when examining the relationship between IAC use and all-cause mortality. Given the lack of evidence related to IAC use and all-cause mortality in the elderly population, robust longitudinal studies are required in this population to derive more definitive conclusions.

**Disclosure**

The authors report no conflicts of interest in this work.

###### 

Description of study sample characteristics according to IAC use among elderly Medicare beneficiaries with COPD: Medicare Current Beneficiary Survey, 2002--2009

                               Total   Percentage with IAC use                
  ---------------------------- ------- ------------------------- ----- ------ -------------------------------------------------
  Gender                                                                      [\*\*](#tfn3-copd-8-287){ref-type="table-fn"}
   Women                       1390    53.7                      245   17.0   
   Men                         1220    46.3                      255   21.7   
  Race                                                                        
   White                       2176    83.9                      426   19.7   
   African American            173     6.7                       29    15.8   
   Others                      260     9.4                       45    16.6   
  Age, years                                                                  [\*](#tfn4-copd-8-287){ref-type="table-fn"}
   65--69                      557     25.2                      135   23.3   
   70--74                      485     21.6                      81    16.4   
   ≥75                         1568    53.2                      284   18.4   
  Married                                                                     
   Married                     1289    51.5                      243   19.1   
   Not married                 1320    48.5                      257   19.3   
  Metro status                                                                
   Metro                       1753    69.7                      339   19.1   
   Not metro                   857     30.3                      161   19.3   
  Education                                                                   
   Less than high school       924     34.3                      182   19.7   
   High school                 966     37.6                      188   19.3   
   College                     710     28.2                      130   18.7   
  Poverty status                                                              
   \>200% FPL                  1054    42.1                      205   19.6   
   \<200% FPL                  1556    57.9                      295   18.8   
  Prescription drug coverage                                                  [\*](#tfn4-copd-8-287){ref-type="table-fn"}
   Yes                         1973    75.8                      405   20.2   
   No                          637     24.2                      95    15.9   
  Health status                                                               [\*\*\*](#tfn2-copd-8-287){ref-type="table-fn"}
   Excellent/very good         740     29.6                      94    12.7   
   Good                        876     33.6                      160   18.4   
   Fair                        671     25.3                      154   23.5   
   Poor                        310     11.5                      88    28.5   
  Functional status (ADL)                                                     [\*\*\*](#tfn2-copd-8-287){ref-type="table-fn"}
   None                        1556    62.0                      257   16.4   
   1--2 ADL                    706     26.3                      157   22.8   
   3--6 ADL                    344     11.8                      85    25.7   
  Body mass index                                                             
   Underweight                 113     4.0                       29    24.9   
   Normal                      984     37.5                      179   18.2   
   Overweight                  930     35.7                      166   17.8   
   Obese                       561     22.8                      123   22.1   
  Smoking status                                                              [\*\*\*](#tfn2-copd-8-287){ref-type="table-fn"}
   Current smoker              498     20.0                      113   22.1   
   Past smoker                 1437    55.4                      324   22.8   
   Never smoked                671     24.6                      62    8.5    
  Mental illness                                                              
   Yes                         492     19.2                      100   19.3   
   No                          2118    80.8                      400   19.1   
  CMD                                                                         
   Yes                         2149    81.6                      407   18.9   
   No                          459     18.4                      93    20.6   
  Musculoskeletal disorders                                                   
   Yes                         1921    72.4                      376   19.8   
   No                          687     27.6                      123   17.5   
  Chronic renal failure                                                       
   Yes                         195     7.1                       38    18.9   
   No                          2415    92.9                      462   19.2   
  Other comorbidities                                                         
   Yes                         1320    49.7                      262   19.2   
   No                          1290    50.3                      238   19.1   
  Cohort                                                                      
   2002--2004                  424     15.2                      79    18.2   
   2003--2005                  458     17.2                      85    17.4   
   2004--2006                  406     15.8                      79    19.3   
   2005--2007                  475     18.1                      98    21.5   
   2006--2008                  419     16.9                      84    21.4   
   2007--2009                  428     16.8                      75    17.0   

**Notes:** Based on 2610 elderly Medicare beneficiaries with COPD, who were observed between years 2002 and 2009. Asterisks represent significant association between inhaled anticholinergic use and beneficiary characteristics based on Chi-square tests.

*P* \< 0.001;

0.001 ≤ *P* \< 0.01;

0.01 ≤ *P* \< 0.05.

**Abbreviations:** ADL, activities of daily living; COPD, chronic obstructive pulmonary disease; FPL, federal poverty line; IAC, inhaled anticholinergics; wt, weighted; Sig, significance; CMD, cardiometabolic disorders (diabetes, heart disease, hypertension and stroke); musculoskeletal disorders, arthritis and osteoporosis; other comorbidities, cancer and Alzheimer's disease.

###### 

Description of selected characteristics according to all-cause mortality among beneficiaries: COPD Medicare Current Beneficiary Survey, 2002--2009

                         wt %   Unadjusted logistic regression                  
  ---------------------- ------ -------------------------------- -------------- -------------------------------------------------
  IAC use                                                                       
   Yes                   18.7   1.46                             (1.12--1.90)   [\*\*](#tfn8-copd-8-287){ref-type="table-fn"}
   No                    13.6                                                   
  IAC/CMD groups                                                                
   IAC and CMD           18.9   1.40                             (1.03--1.91)   [\*](#tfn9-copd-8-287){ref-type="table-fn"}
   No IAC and CMD        14.3                                                   
   IAC and no CMD        17.9   1.26                             (0.69--2.28)   
   No IAC and no CMD     10.2   0.68                             (0.45--1.01)   
  Health status                                                                 
   Excellent/very good   7.2                                                    
   Good                  11.7   1.71                             (1.18--2.48)   [\*\*](#tfn8-copd-8-287){ref-type="table-fn"}
   Fair                  20.2   3.24                             (2.24--4.69)   [\*\*\*](#tfn7-copd-8-287){ref-type="table-fn"}
   Poor                  29.9   5.69                             (3.79--8.53)   [\*\*\*](#tfn7-copd-8-287){ref-type="table-fn"}
  Gender                                                                        
   Women                 12.8   0.73                             (0.58--0.91)   [\*\*](#tfn8-copd-8-287){ref-type="table-fn"}
   Men                   16.6                                                   
  Race/ethnicity                                                                
   White                 14.2                                                   
   African American      16.7   1.11                             (0.71--1.72)   
   Others                16.2   1.20                             (0.86--1.66)   
  Age, years                                                                    
   65--69                8.7                                                    
   70--74                11.2   1.41                             (0.86--2.31)   
   ≥75                   18.7   2.53                             (1.74--3.69)   [\*\*\*](#tfn7-copd-8-287){ref-type="table-fn"}

**Notes:** Based on 2610 elderly Medicare beneficiaries with COPD, who were observed between years 2002 and 2009. Asterisks represent significant association between inhaled anticholinergic use and beneficiary characteristics based on Chi-square tests.

*P* \< 0.001;

0.001 ≤ *P* \< 0.01;

0.01 ≤ *P* \< 0.05.

**Abbreviations:** COPD, chronic obstructive pulmonary disease; IAC, inhaled anticholinergics; CMD, cardiometabolic disorders (diabetes, heart disease, hypertension and stroke); Wt, weighted; CI, confidence interval; OR, odds ratio; Sig, significance.

###### 

Adjusted odds ratios and 95% confidence intervals from multivariable logistic regressions on all-cause mortality among elderly beneficiaries with COPD: Medicare Current Beneficiary Survey, 2002--2009

  Model                 OR             95% CI                                           Sig
  ------- ------------- -------------- ------------------------------------------------ -----
  I       **IAC use**                                                                   
  Yes     1.46          (1.12--1.90)   [\*\*](#tfn12-copd-8-287){ref-type="table-fn"}   
  No                                                                                    
          **AOR**       **95% CI**     **Sig**                                          
                                                                                        
  II      **IAC use**                                                                   
  Yes     1.47          (1.14--1.90)   [\*\*](#tfn12-copd-8-287){ref-type="table-fn"}   
  No                                                                                    
  III     **IAC use**                                                                   
  Yes     1.51          (1.16--1.97)   [\*\*](#tfn12-copd-8-287){ref-type="table-fn"}   
  No                                                                                    
  IV      **IAC use**                                                                   
  Yes     1.32          (1.00--1.74)                                                    
  No                                                                                    
  V       **IAC use**                                                                   
  Yes     1.26          (0.95--1.67)                                                    
  No                                                                                    

**Notes:** Based on Medicare beneficiaries with COPD, who were observed between years 2002 and 2009. The logistic regression also includes an intercept term not presented here. Asterisks represent significant group differences compared to the reference group based on multivariable logistic regressions. Model I, included IAC use as the only independent variable; model II, additionally controlled for all coexisting conditions (mental illness, cardiovascular/metabolic disorders, musculoskeletal disorders, chronic renal failure, and other conditions); model III, controlled for all variables in model II and gender, race, age, metro status, education and poverty status; model IV, controlled for all variables in model III and perceived health status; and model V, controlled for all variables in model IV and body mass index and smoking status.

0.001 ≤ *P* \< 0.01.

**Abbreviations:** COPD, chronic obstructive pulmonary disease; IAC, inhaled anticholinergics; OR, odds ratio; AOR, adjusted odds ratios; CI, confidence interval; Sig, significance.
