Outcomes Associated With Timing of Maintenance Treatment for COPD Exacerbation

Early initiation of maintenance medication in patients with moderate to severe COPD exacerbations is associated with reduced risk of future exacerbations and lower costs.
Published Online: September 14, 2012
Anand A. Dalal, PhD, MBA; Manan B. Shah, PharmD, PhD; Anna O. D’Souza, BPharm, PhD; Amol D. Dhamane, BPharm, MS; and Glenn D. Crater, MD
Objectives: To examine the impact of timing of maintenance treatment (MTx) initiation (early vs delayed) on risk of future exacerbations and costs in chronic obstructive pulmonary disease (COPD) patients.

Study Design: Retrospective cohort design using data (January 1, 2003, through June 30, 2009) from a large, US-based integrated pharmacy and medical claims database.

Methods: Administrative claims from January 1, 2003, through June 30, 2009, were used. MTx-naïve patients (aged >40 years) with at least 1 COPD-related hospitalization/emergency department (ED) visit were included (discharge date was index date). Patients initiating MTx within the first 30 days and 31 to 180 days postindex were classified into early and delayed cohorts, respectively. Clinical and economic outcomes related to COPD exacerbations were assessed for 1 year post-index and compared between cohorts using regression models controlling for baseline characteristics. The incremental effect on outcomes of every 30-day delay in MTx initiation up to 6 months after the index event was also assessed.

Results: The majority of the 3806 patients (78.6%) received early MTx. A significantly higher proportion of patients in the delayed cohort had a COPD-related
hospitalization/ED visit compared with the early cohort (25.6% vs 18.0%; P <.001). After controlling for baseline differences, the delayed cohort had a 43% (P <.001) higher risk of a future COPD-related hospitalization/ED visit compared with the early cohort. Every 30-day delay was associated with 9% risk increase (P = .002). Treatment delay also increased COPD-related costs ($5012 vs $3585; P <.001).

Conclusion: Early MTx initiation is associated with reduced risk of future COPD exacerbations and lower costs.

(Am J Manag Care. 2012;18(9):e338-e345)
  • Delaying the initiation of maintenance treatment after a hospitalization or emergency department visit related to exacerbation of chronic obstructive pulmonary disease (COPD) is associated with an increased risk for subsequent COPD exacerbations.

  • Delaying maintenance treatment was also associated with increased costs (~$1400), with the majority of the expenditure attributable to a $1200 increase in annual medical costs.

  • Patients treated for moderate to severe COPD exacerbations should be actively managed and prescribed appropriate maintenance treatment soon after discharge to prevent subsequent exacerbations.
Chronic obstructive pulmonary disease (COPD) is the thirdleading cause of chronic morbidity and mortality in the United States,1 and exacerbations are recognized as the dominant cause of these outcomes. Exacerbations are defined as acute episodes of worsening respiratory symptoms (eg, dyspnea, sputum production, sputum purulence, cough), which can alter the clinical course of COPD by accelerating the decline in lung function.2,3 Depending on the severity, an exacerbation can disrupt usual activities and even incapacitate a patient, negatively impacting health-related quality of life.4 The societal impact is also felt; exacerbations are estimated to account for 50% to 75% of the healthcare costs for COPD.5 Two recent literature reviews of exacerbation costs identified hospitalizations as the primary driver, accounting for 38% to sometimes 93% of total costs, followed by outpatient costs that arise from contacts with a healthcare professional (eg, outpatient visits, emergency department [ED] visits).6,7 Hospitalization due to an exacerbation is a serious event, as inpatient mortality rates range from 10% to 40%.8-10 Consequently, the prevention and treatment of exacerbations are important components of COPD management in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.11

The GOLD guidelines recommend short- and long-term approaches to the treatment and prevention of COPD exacerbations. Short-term therapies include oral corticosteroids, antibiotics, and increased use of bronchodilator medications, which have been shown to hasten the recovery rate from exacerbations; early initiation of these therapies is associated with faster recovery time.12-15 Long-term therapies—including long-acting beta-agonists, long- and short-acting anticholinergics, and inhaled corticosteroid-containing products—have been shown to reduce the risk and frequency of exacerbations, and are recommended on a maintenance basis for prevention.16-18

Despite all the evidence of the beneficial impact of long-term therapies, there is little information on the effects of timing of initiation of long-term therapies to prevent exacerbations. Recent literature suggests that exacerbations cluster together, with the risk for a subsequent exacerbation being highest in the 8-week period following an initial exacerbation.19 Exacerbations that are moderate to severe in nature (ie, result in either a hospitalization or an ED visit) have been shown to contribute substantially to the morbidity and mortality in COPD, and are thus clinically relevant to the issue of timing of initiation of maintenance treatment (MTx).6,10 Therefore, our study focused on whether the timing of MTx initiation affects the future occurrence and frequency of COPD exacerbations.


A retrospective, observational cohort design was implemented using integrated pharmacy and medical claims data spanning January 1, 2003, through June 20, 2009. This US administrative database (Ingenix Impact National Managed Care Database) is generally representative of the insured US commercial population including patients 65 years and older enrolled in Medicare Risk and Medicare Advantage plans. The database contains information for more than 98 million lives from more than 46 different healthcare plans spanning 9 census regions of the United States. It captures person-specific utilization, expenditures (direct costs), and enrollment across inpatient, outpatient, and prescription drug services.

Study Design and Patient Selection

Patients with at least 1 moderate-to-severe COPD exacerbation, defined as a hospitalization or ED visit with a primary discharge diagnosis code for COPD (International Classification of Diseases, Ninth Revision, Clinical Modification codes 491.xx, 492.xx, 496.xx) were selected as the initial population. The first COPD exacerbation requiring a hospitalization or ED visit (January 1, 2004, to June 30, 2008) followed by dispensing of MTx within 6 months of discharge was defined as the index event. Consequently, patients with a COPDrelated hospitalization or ED visit in the 1-year period before this index exacerbation or those without any MTx dispensed within 6 months of their first COPD-related hospitalization or ED visit were excluded. Maintenance treatment included a long-acting anticholinergic (tiotropium), a short-acting anticholinergic (ipratropium or combination ipratropiumalbuterol), long-acting beta-agonists (formoterol, salmeterol), inhaled corticosteroids (beclomethasone, budesonide, fluticasone, flunisolide, triamcinolone), and fluticasone-salmeterol (250/50 μg combination). The index date for hospitalizations and ED visits was the date of discharge or the date of the visit, respectively. The period 1 year prior to the index date (preperiod) was used to determine baseline characteristics for patients included in the analysis. The period 1 year after the index date (post-period) was used to calculate outcomes listed below in the Outcomes section. In addition, the first 6 months of the post-period were also used to identify the date of receipt of the first MTx prescription, because a prescription of MTx was considered related to the index exacerbation if it was prescribed within 180 days of the exacerbation.

Patients were >40 years of age and eligible for healthcare benefits during their pre- and post-periods. Patients were excluded if they had a COPD-related exacerbation or MTx in the pre-period (to ensure inclusion of MTx-naïve patients) or if they received their first MTx 181 to 365 days after the index date during the post-period. Additionally, patients were excluded if they had any of the comorbid conditions listed in the Appendix.

Patients meeting study criteria were classified into 2 cohorts (early and delayed), based on timing of MTx after the index date: 0 to 30 days and 31 to 180 days, respectively. A 30-day period was defined as early initiation, based on empirical information from our analysis and recent evidence demonstrating the increased risk of subsequent exacerbations during an 8-week period following an initial exacerbation.19 Outcomes were computed for and compared between cohorts. An incremental analysis evaluating the effect of delaying MTx by every 30 days was also conducted; patients were classified into 6 categories based on 30-day increments of starting MTx. Outcomes were then compared across the 6 categories, thereby allowing assessment for every 30-day increment up to 180 days after the index date.


The primary outcome was the presence of a subsequent COPD-related exacerbation requiring hospitalization or an ED visit during the post-period. Secondary outcomes included the presence of exacerbations requiring a physician/outpatient visit accompanied by a prescription for oral corticosteroids or antibiotics within 5 days of that visit, and the presence of any of these exacerbations. Additionally, the numbers of exacerbations were computed and compared between the cohorts. Annual total COPD-related costs per patient were also computed using paid amounts from the claims. COPD-related medical costs were identified as medical claims with a primary diagnosis code for COPD and classified into different medical components, including hospitalizations, ED visits, physician/outpatient visits having an evaluation or management Current Procedural Terminology code, other outpatient visits for laboratory tests and/or procedures, and “other.” COPDrelated pharmacy costs were defined as costs for maintenance medications, short-acting beta-agonists, oral corticosteroids, respiratory antibiotics, methylxanthines, and mucolytics. All costs were standardized to 2009 US dollars using the medical care component of the Consumer Price Index.20

Statistical Analysis

Baseline differences and unadjusted outcomes between the early and delayed cohort were evaluated using t tests or c2 tests for continuous or categorical data, respectively. Logistic regression models were used to assess differences in risk of a COPD exacerbation between study cohorts, and to evaluate the change in risk with every 30-day delay in initiating MTx. Similarly, zero-inflated, negative-binomial models were used to assess difference in the number of exacerbations. A 2-part model was used to obtain adjusted annual COPD-related costs for the early and delayed cohorts by multiplying the adjusted probability obtained from a logistic regression model (part 1) by the predicted cost from a generalized linear model (part 2). A generalized linear model was used to evaluate the impact of a 30-day delay in MTx on COPD-related costs. Multivariate analysis of the impact of a 30-day delay on all outcomes was only conducted if a linear trend was demonstrated (details of linear trend test are presented in the Appendix). All models controlled for differences in baseline covariates.


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