Economic Assessment of Initial Maintenance Therapy for Chronic Obstructive Pulmonary Disease

Objective

: To compare the effects of initial maintenance therapy with fluticasone 250 µg plus salmeterol 50 µg in a single inhaler versus other inhaled medications on exacerbation risks and treatment costs among chronic obstructive pulmonary disease (COPD) patients.

Study Design

: A retrospective observational analysis was conducted by using medical/ pharmacy claims from a large managed care database between January 2000 and February 2004. Patients age 40 years or older with a primary diagnosis of COPD (International Classification of Diseases, Ninth Revision, Clinical Modification code 490, 491, 492, or 496), at least 18 months of continuous eligibility, and an index prescription for fluticasone/ salmeterol combination, salmeterol alone, inhaled corticosteroid alone, ipratropium/ albuterol combination, or ipratropium alone (reference) were identified.

Methods

: Time to first COPD-related hospitalization or emergency department (ED) visit was estimated by using Cox proportional hazard models. All-cause and COPD-related treatment costs were estimated by using generalized linear models with a gamma distribution and log link. Multivariable regressions were used, controlling for age, sex, comorbidities, COPD subtype, preindex medications, and hospitalizations and ED visits.

Results

: Initial maintenance therapy with fluticasone/ salmeterol combination was associated with a 31% to 56% lower risk of hospitalization or ED visit compared with ipratropium alone, adjusting for baseline characteristics and preindex resource utilization. Fluticasone/ salmeterol combination therapy was related to lower medical costs, higher pharmacy costs, and almost similar total costs in all populations studied.

Conclusion

: Fluticasone/salmeterol combination therapy was considered to be costeffective compared with ipratropium alone because it achieved better clinical outcomes with similar or lower treatment costs.

(Am J Manag Care. 2008;14(7):438-448)

Medical/pharmacy claims from a large managed care database were used to compare fluticasone 250 µg plus salmeterol 50 µg in a single inhaler with other inhaled medications for initial maintenance therapy in patients with chronic obstructive pulmonary disease.

Fluticasone/salmeterol combination therapy was associated with a 31%-56% lower risk of hospitalization or emergency department visit compared with ipratropium alone.

Fluticasone/salmeterol combination therapy was considered to be cost-effective compared with ipratropium alone because it achieved better clinical outcomes with similar or lower total treatment costs.

According to the Global Initiative for Chronic Obstructive Pulmonary Disease (COPD) guidelines, prevention of exacerbations is an important goal of COPD management.¹ However, data from the third National Health and Nutrition Examination Survey suggest that the burden of COPD still is substantial.² The surveys reveal high rates of COPD-related hospitalizations and emergency department (ED) visits, outcomes that serve as proxies of exacerbations in the real-world setting. In 2000, COPD accounted for 1.5 million ED visits and 726,000 hospitalizations in the United States.² Hospitalizations for COPD have increased across all age groups since 1990.

Acute exacerbations of COPD have a negative impact on quality of life.^3,4 Additionally, exacerbations generate a high demand for healthcare services. Studies have consistently shown that hospitalizations account for the largest portion of healthcare expenditures for COPD.^5-10 For example, the Confronting COPD survey, a large-scale international patient survey of disease burden, demonstrated that inpatient hospitalizations accounted for approximately 70% of the total direct costs of COPD in the United States.⁶ Thus, identification of therapeutic agents that prevent or reduce the risk of hospitalization and ED visits is an important strategy for reducing the overall burden of the disease.

Because airway obstruction is a common feature of COPD, bronchodilators are commonly provided for symptomatic relief. Anticholinergics (eg, ipratropium), short-acting β2 agonists (eg, albuterol), long-acting β2 agonists (eg, salmeterol), or a combination of these drug classes appear to increase lung function (forced expiratory volume in the first second of expiration), decrease frequency of exacerbations, and improve quality of life.¹¹ Inhaled corticosteroid (ie, fluticasone) is used to augment regular bronchodilator treatment for attenuating airway hyperresponsiveness and inflammation. Results of several prospective clinical studies showed a reduction in the rate and/or severity of exacerbations of COPD with the use of inhaled corticosteroid alone or in combination with long-acting β2 agonists.^12-16

Moreover, a recent randomized clinical trial, the Towards a Revolution in COPD Health survival study, reported the combination therapy with fluticasone and salmeterol significantly reduced exacerbations by 25% and hospitalizations by 17% compared with placebo among 6000 patients over 3 years.¹⁷ However, information about economic benefits of selecting appropriate initial maintenance therapy for COPD remains limited, especially in the real-world setting.

Therefore, the present study was conducted to investigate the effect of various COPD medication regimens on (1) the risk of all-cause and COPD-related hospitalization and ED visits (risk analysis) and (2) all-cause and COPD-related treatment costs (cost analysis) using claims from a large managed care database. Of note, this was the first observational study to investigate the effect of fluticasone/salmeterol combination therapy in a single inhaler on utilization and costs in a managed care population.

METHODS

This was a retrospective, observational cohort study using medical and pharmacy claims from a large managed care database encompassing more than 30 different managed care plans and 33 million patients across the United States. This study was exempt from institutional review board oversight because no human subjects were involved and all data were HIPAA (Health Insurance Portability and Accountability Act) compliant, with all health plan and personal information identifiers removed to ensure confidentiality.

Figure 1

The study population consisted of patients ≥40 years of age with a diagnosis of COPD less than 1 year prior to initial treatment with fluticasone 250 μg and salmeterol 50 μg in a single inhaler, salmeterol alone, inhaled corticosteroid alone, ipratropium and albuterol in a single inhaler, and ipratropium alone (index medications). COPD was identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 490.xx, 491.xx, 492.xx, or 496.xx. Patient data were included in the study if the first pharmacy claim for the index medications occurred between January 2, 2001, and August 12, 2003 (index date). The time frame of the analysis is summarized in . For the risk analysis, patients were required to have 18 months of continuous eligibility (12-month preindex period and 6-month postindex period). The cost analysis included a subpopulation who had a 12-month postindex period in order to calculate annual costs.

Patients were not permitted to receive any COPD treatment other than oral corticosteroids, short-acting β2 agonists, or theophylline during the 12-month preindex period, and patients could not initiate treatment with any other COPD medications within 60 days of the index date. Additionally, patients without a pharmacy benefit through their health plan were excluded.

Outcomes

Differences in demographic and utilization characteristics measured during the preindex period were assessed by using Wilcoxon’s rank sum tests for continuous variables and c2 χtests for categorical variables. Because of the large number of comparison tests (n = 56), the alpha level was adjusted by using a Bonferroni correction procedure (ie, 0.05/56 = .001).

For the risk analysis, Cox proportional hazard analyses on the time to the first all-cause/COPD-related hospitalization and/or ED visit were performed comparing the fluticasone/ salmeterol combination, salmeterol, inhaled corticosteroid, and ipratropium/albuterol combination cohorts with the ipratropium cohort.¹⁸ The model was adjusted for underlying differences in age (continuous), sex (female as reference), comorbidities (asthma [ICD-9 code 493.xx], congestive heart failure [CHF; ICD-9 code 428.xx], upper respiratory tract infection [ICD-9 code 460.xx, 462.xx, 464.xx, 466.xx, or 487.xx], and lower respiratory tract infection [ICD-9 code 480.xx, 481.xx, 482.xx, or 483.xx]), COPD subtype (chronic bronchitis [ICD-9 code 491.xx] or emphysema [ICD-9 code 492.xx]), number of preindex prescriptions for respiratory medications (oral corticosteroids, short-acting β2 agonists, theophylline), number of preindex prescriptions for all medications, and number of preindex all-cause hospitalizations and ED visits. The hazard ratio (HR) and 95% confidence interval (CI) were calculated for each variable of interest. The proportional hazards assumptions were confirmed through a graphical approach (Kaplan-Meier survival curve) and Cox significance test. The final model was selected after examining interaction terms with age, asthma, and CHF diagnosis.

For the cost analysis, annual all-cause and COPD-related costs were compared across study groups. Unadjusted costs were summarized using means, SDs, and 95% CIs. Then, multivariate generalized linear models with a log link and gamma distribution were used to estimate treatment costs, controlling for differences in demographic and utilization characteristics during the preindex period.¹⁹ Adjusted costs were reported with 95% CI of cost differences (vs ipratropium), which were obtained by the bootstrap method with 1000 replications.²⁰

Stratified analyses for patients with and without an asthma diagnosis were conducted to examine whether observed treatment effects were modified by this diagnosis. All statistical analyses were conducted with SAS version 8.2 (SAS Institute Inc., Cary, NC) or STATA version 9.2 (StataCorp LP, College Station, TX).

RESULTS

Figure 2

Table 1

A total of 12,381 patients met the established inclusion and exclusion criteria for the risk analysis (), including 1832 patients in the fluticasone/salmeterol combination cohort, 1099 patients in the salmeterol cohort, 3940 patients in the inhaled-corticosteroid cohort, 3388 patients in the ipratropium/albuterol combination cohort, and 2122 patients in the ipratropium cohort. Demographic and utilization characteristics during the preindex period for the 5 cohorts are shown in . Several statistically significant differences were observed between treatment groups. For example, patients in the ipratropium cohort were significantly older (mean age = 63.3 years), had a higher frequency of comorbid CHF (21.4%), and had a higher mean [SD] number of preindex ED visits (2.3 [6.3]) and hospitalizations (0.8 [1.4]) compared with the other cohorts. A comorbid diagnosis of asthma was significantly more common in the fluticasone/salmeterol combination (40.5%), salmeterol (29.7%), and inhaled-corticosteroid (39.6%) groups compared with the group receiving ipratropium alone (20.8%). A diagnosis of chronic bronchitis was more common than emphysema across all cohorts. The mean number of preindex prescriptions for oral corticosteroids ranged from 0.2 to 0.4 across cohorts. Compared with the ipratropium cohort, preindex utilization of short-acting b2 agonists was significantly higher in the fluticasone/salmeterol combination, salmeterol, and inhaled-corticosteroid cohorts and was significantly lower in the ipratropium/albuterol combination cohort.

Table 2

All-cause Hospitalization/Emergency Department Visits. shows the adjusted risk of all-cause hospitalization, ED visit, and a combined hospitalization/ED visit end point in the total sample, as well as stratified by asthma diagnosis as determined by the Cox proportional hazard analyses. After adjusting for differences in baseline characteristics, use of fluticasone/ salmeterol combination therapy was associated with a 32% reduction in the risk of all-cause hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.685; 95% CI = 0.620, 0.757). Similarly, use of salmeterol alone was associated with a 21% reduction (adjusted HR = 0.790; 95% CI = 0.709, 0.879), and the use of inhaled corticosteroid alone was associated with a 23% reduction (adjusted HR = 0.772; 95% CI = 0.713, 0.835) in the risk of all-cause hospitalization or ED visit. In contrast, the risk of all-cause hospitalization or ED visit was not significantly different between the ipratropium/ albuterol combination cohort and the cohort receiving ipratropium alone (adjusted HR = 0.948; 95% CI = 0.879, 1.021).

Findings were similar when stratified by comorbid asthma diagnosis. In COPD patients with asthma, the use of fluticasone/salmeterol combination therapy was associated with a 36% reduction in the risk of all-cause hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.642; 95% CI = 0.537, 0.766). In COPD patients without asthma, the use of fluticasone/salmeterol combination therapy was associated with a 28% reduction in the risk of allcause hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.719; 95% CI = 0.636, 0.813).

Variables indicative of an increased risk of all-cause hospitalization or ED visit included increasing age; a comorbid diagnosis of chronic bronchitis, CHF, or lower respiratory tract infection; the number of preindex ED visits and hospitalizations; and the number of preindex prescriptions for oral steroids and any medication.

COPD-related Hospitalization/Emergency Department Visit. Use of combination fluticasone/salmeterol, salmeterol, or inhaled corticosteroid was associated with a significantly reduced risk of COPD-related hospitalization or ED visit compared with ipratropium alone (Table 2). Use of fluticasone/salmeterol combination therapy was associated with a 56% lower risk of COPD-related hospitalization or ED visit (adjusted HR = 0.442; 95% CI = 0.341, 0.573). The risk of COPD-related hospitalization or ED visit also was reduced by 34% with salmeterol alone (adjusted HR = 0.656; 95% CI = 0.514, 0.836) and by 37% with inhaled corticosteroid alone (adjusted HR = 0.631; 95% CI = 0.530, 0.752). The use of ipratropium/albuterol combination therapy did not significantly change the risk of COPD-related hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.960; 95% CI = 0.829, 1.113).

Like the findings on the risk of all-cause hospitalization or ED visit, findings on COPD-related hospitalization or ED visit were similar to those obtained for the total sample when stratn ified by comorbid asthma diagnosis. In COPD patients with asthma, use of fluticasone/salmeterol combination therapy was associated with a 73% reduction in the risk of COPDrelated hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.271; 95% CI = 0.168, 0.437). In COPD patients without asthma, use of fluticasone/salmeterol combination therapy was associated with a 44% reduction in the risk of COPD-related hospitalization or ED visit compared with ipratropium alone (adjusted HR = 0.558; 95% CI = 0.410, 0.758).

The following variables also were associated with an increased risk of COPD-related hospitalization or ED visit: increasing age; a comorbid diagnosis of chronic bronchitis, emphysema, or CHF; number of preindex ED visits or hospitalizations; and number of preindex prescriptions for oral steroids, short-acting β2 agonists, and theophylline. A comorbid diagnosis of asthma was not associated with an increased risk of COPDrelated hospitalization or ED visit.

Cost Analysis

Figure 2

Table 3

A total of 8551 patients had at least 12 months of continuous enrollment after the index date and were included in the cost analysis (). The cost analysis population included 1062 patients in the fluticasone/salmeterol combination cohort, 842 patients in the salmeterol cohort, 2903 patients in the inhaled-corticosteroid cohort, 2258 patients in the ipratropium/albuterol combination cohort, and 1486 patients in the ipratropium cohort. Demographic and utilization characteristics during the preindex period for the 5 cohorts in the cost analysis were similar to those for the cohorts in the risk analysis (data not shown). As illustrated in , large variations in unadjusted annual costs during the postindex period were observed. Especially with respect to medical costs, only a few patients accounted for a large portion of the costs associated with inpatient admissions and ED visits. By comparing mean values, the ipratropium/albuterol combination and ipratropium cohorts were more likely to have higher all-cause and COPD-related medical costs than the other cohorts. Mean refill counts during the 12-month follow-up period were highest in the fluticasone/salmeterol combination cohort.

All-cause Costs

Table 4

The fluticasone/salmeterol combination and inhaled-corticosteroid cohorts had statistically significant lower annual medical costs compared with the ipratropium cohort (). Annual pharmacy costs were higher but not statistically significant in the fluticasone/salmeterol combination group compared with the group receiving ipratropium alone. As for total costs (medical plus pharmacy costs), statistically significant reductions were observed in the fluticasone/salmeterol combination cohort (mean: $5317; 95% CI = $2556, $7967) and in the inhaled-corticosteroid cohort (mean: $4766; 95% CI = $2377, $7344). Similar trends were observed regardless of asthma diagnosis.

COPD-related Costs

Compared with the ipratropium cohort, the fluticasone/salmeterol combination, salmeterol, and inhaled-corticosteroid cohorts had statistically significant lower annual COPD-related medical costs (Table 4). Annual pharmacy costs were significantly higher in the fluticasone/salmeterol combination cohort, but significantly lower in the ipratropium/albuterol combination group, compared with the ipratropium cohort. Overall, annual total costs were significantly decreased in the salmeterol, inhaled-corticosteroid, and ipratropium/albuterol combination cohorts, with annual reductions of $536 (95% CI = $128, $961), $541 (95% CI = $202, $944), and $456 (95% CI = $98, $842), respectively, compared with the ipratropium group. In contrast, there was no significant difference in annual total costs between the fluticasone/salmeterol combination and ipratropium cohorts. Similar trends were observed among patients with an asthma diagnosis. However, among patients without an asthma diagnosis, no significant treatment effects on annual costs were observed except higher pharmacy costs in the fluticasone/salmeterol combination cohort.

DISCUSSION

Our study demonstrated that the use of fluticasone and salmeterol, particularly when used in combination in a single inhaler, was significantly associated with a reduction in the risk of all-cause and COPD-related hospitalization or ED visit compared with ipratropium therapy. These benefits were achieved at similar or lower COPD-related treatment costs compared with ipratropium therapy. Our findings support the existing literature regarding the effectiveness of inhaled corticosteroid alone or in combination with long-acting β2 agonists in patients with COPD.

AcknowledgementThe authors acknowledge Cynthia Toso, PharmD, for assistance with the preparation and editing of this manuscript.

Author Affiliations: From the Department of Health Policy and Administration, University of North Carolina at Chapel Hill (MA); GlaxoSmithKline (DCH, RHS), Research Triangle Park, NC; and the Center for Pharmacoeconomic and Outcomes Research, Lovelace Respiratory Research Institute (CMB), Albuquerque, NM.

Funding Source: Financial support for this work was provided by GlaxoSmithKline.

Author Disclosure: Mr Hayflinger, Dr Stanford, and Dr Blanchette are employees of GlaxoSmithKline (GSK), and each reports owning stock in GSK. The other author (Dr Akazawa) reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (MA, DCH, RHS); acquisition of data (DCH); analysis and interpretation of data (MA, DCH, RHS, CMB); drafting of the manuscript (MA, RHS, CMB); critical revision of the manuscript for important intellectual content (MA, RHS); statistical analysis (DCH); obtaining funding (MA); administrative, technical, or logistic support (CMB); and supervision (RHS, CMB).

Address correspondence to: Christopher M. Blanchette, PhD, Director, Center for Pharmacoeconomic and Outcomes Research, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr, SE, Albuquerque, NM 87108. E-mail: cblanchette@lrri.org.

2. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971-2000. MMWR Surveill Summ. 2002;51(6):1-16.

4. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(5, pt 1):1418-1422.

6. Halpern MT, Stanford RH, Borker R. The burden of COPD in the USA: results from the Confronting COPD survey. Respir Med. 2003;97(suppl C):S81-S89.

8. Mapel DW, Hurley JS, Frost FJ, Peterson HV, Picchi MA, Coultas DB. Health care utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. Arch Intern Med. 2000;160(17):2653-2658.

10. Stanford RH, Shen Y, McLaughlin T. Cost of chronic obstructive pulmonary disease in the emergency department and hospital: an analysis of administrative data from 218 US hospitals. Treat Respir Med. 2006;5(5):343-349.

12. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ.

13. Calverley P, Pauwels R, Vestbo J, et al; for the TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial [Correction published in: Lancet. 2003;361(9369):1660]. Lancet. 2003;361(9356):449-456.

15. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingsworth K, Efthimiou J. Multicenter randomized placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. [Correction published in: Lancet. 1998 Jun 27;351(9130):1968]. Lancet. 1998;351(9105):773-780.

17. Calverley DM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.

19. Manning WG, Mullahy J. Estimating log models: to transform or not to transform? J Health Econ. 2001;20(4):461-494.

21. Rascati KL, Akazawa M, Johnsrud M, Stanford RH, Blanchette CM. Comparison of hospitalizations, emergency department visits, and costs in a historical cohort of Texas Medicaid patients with chronic obstructive pulmonary disease, by initial medication regimen. Clin Ther. 2007;29(6):1203-1213.

23. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(4):580-584.

25. Donahue JF, Kalberg C, Emmett A, Merchant K, Knobil K. A shortterm comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD. Treat Respir Med. 2004;3(3):173-181.

27. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States. Chest. 2005;128(4):2005-2011.

29. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166(8):1084-1091.

31. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1998.

Download PDF: Economic Assessment of Initial Maintenance Therapy for Chronic Obstructive Pulmonary Disease