The Effect of Fixed Combination of Fluticasone and Salmeterol on Asthma Drug Utilization, Asthma Drug Cost, and Episodes of Asthma Exacerbations*

By Brixner, D I Lenhart, G; Young, D C; Samuelson, W M

Key words: Asthma outcomes – Cost – Fixed-dose combinations – Fluticasone – Inhaled corticosteroids – Long-acting beta^sub 2^- agonists – Salmeterol ABSTRACT

Objective: This study evaluated the use and drug costs of inhaled corticosteroids (ICSs), long-acting beta^sub 2^-agonists (LABAs), and fluticasone propionate and salmeterol in a fixed-dose combination (FSC) and their relationship to asthma exacerbations before and after the market introduction of FSC in April 2001.

Methods: This is a retrospective analysis of employer-sponsored health insurance claims filed between January 1, 1998, and December 31, 2003 to detect impact of introduction of FSC (approved by the US Food and Drug Administration in August 2000) on utilization and cost of FSC, any ICS (excluding FSC), and any LABA (excluding FSC) along with utilization of medical services related to asthma exacerbations. Asthma medications were identified using National Drug Codes and Redbook, whereas asthma exacerbations were identified using ICD-9-CM primary diagnosis code 493.x. These medical and pharmacy claims were converted to rates per 100 asthma office visits.

Results: For all ICSs, the average pharmacy claims per 100 office visits increased from 383 in the year before FSC was introduced to 407 (120 [29.5%] were for FSC and 287 [70.5%] were for single- entity ICSs) in 2003. LABA prescribing increased from 72 in the year before FSC to 147 (120 from FSC, 27 single-entity LABA) in 2003 (p < 0.001). An additional $13511 per 100 asthma office visits was spent on the FSC product (p < 0.001). After the introduction of FSC, there was no significant difference in asthma admissions (p = 0.17), whereas emergency department (ED) visits increased by 0.92 visits per 100 office visits (p = 0.03). The diagnosis and severity of asthma was inferred from the pharmacy claims and patients with chronic obstructive pulmonary disease could not be excluded. In addition, the study was not designed to assess the impact of other asthma medications on the disease and/or associated costs, and patient adherence to claimed medication could not be monitored.

Conclusions: The introduction of FSC was associated with increased LABAs/FSC patient exposure and expenditure with no change in asthma hospitalizations and an increase in ED visits.

Introduction

Asthma is a chronic disease associated with high morbidity and healthcare utilization. In the United States, asthma affects an estimated 30 million adults and children – approximately 10% of the population1,2. In 2004, the total healthcare expenditure for treatment of asthma was estimated at $16.1 billion, including $5 billion on prescription drugs3. Office and emergency visits contribute heavily to this expenditure, as suggested by an estimated 13.9 million office-based physician visits and 1.9 million emergency department (ED) visits, stemming from asthma in 2002. In 2002, an estimated 14.7 million missed school days and 11.8 million missed work days accounted for considerable asthma-related indirect costs4. Importantly, asthma was the cause of approximately 4200 deaths in 2002(4).

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of breathlessness, wheezing, chest tightness, and coughing, and by bronchial hyperresponsiveness to a wide range of stimuli5. Inhaled corticosteroids (ICSs) are the most effective and well-tolerated medications available to reduce airway inflammation in asthma and are the foundation of daily controller therapy for patients with persistent asthma. Current asthma management guidelines (2002) of the National Heart, Lung, and Blood Institute (NHLBI) recommend treatment with a low-dose ICS as preferred initial controller therapy for patients with mild persistent asthma. Low- to medium-dose ICS therapy is recommended for patients with moderate persistent asthma, and high-dose ICS therapy is recommended for patients with severe asthma6. For patients with moderate to severe persistent asthma, ICS therapy can be augmented with concomitant use of a long-acting beta^sub 2^- agonist (LABA), such as salmeterol or formoterol, and other therapies. The rationale for combined ICS and LABA therapy in the treatment of asthma is to control airway inflammation with the ICS and provide bronchodilatation with the LABA. In the 2002 update of the NHLBI guidelines, combined therapy with a lowdose ICS and a LABA was recommended for treatment of moderate persistent asthma as the preferred controller therapy7. A combination product containing fluticasone propionate and salmeterol (FSC) has been available in the United States since 2001, which currently carries a boxed warning mandated by the US Food and Drug Administration (FDA) regarding a small but significandy increased risk of severe asthma episodes and asthmarelated death with LABA therapy8,9. This warning has been added to the labeling of all products that contain a LABA (e.g., salmeterol and formoterol)10,11.

Several studies have described the benefit of combined ICS and LABA therapy in specific patient populations; however, no published studies have examined the economic impact of prescribing trends and use of the combination of ICS plus LABA on asthma exacerbations and medication costs across large populations8-12. The present study was designed to assess the impact of changing trends in asthma prescribing patterns on medication costs and asthma exacerbations over a 6-year period surrounding the introduction of FSC in 2001. The expectation was that improved outcomes in asthma patients due to combination therapy would lead to a decrease in asthma exacerbations and related resources over time.

Methods

Study design

The present study used time series analysis techniques to identify changes in prescribing patterns and assess asthma medication expenditures and exacerbation rates before and after the introduction of FSC to the US market in April 2001 (FSC was approved by the FDA on August 24, 2000). Asthma prescriptions and medical encounters were evaluated at weekly intervals to create a time series estimate of medication use and asthma exacerbations. Asthma exacerbations were qualified as an inpatient admission or ED visit with International Classification of Diseases, Ninth Revision, Clinical Modification (7CD-9-CM) codes 493.0x, 493.1x, or 493.9x as the primary diagnosis. Trends of drug utilization were quantified separately based on pharmacy claims for the following asthma medications: FSC, any ICS (excluding FSC), and any LABA (excluding FSC). In addition, trends in prescribing and exacerbations were quantified as average rates per 100 asthma office visits, which were qualified with the same ICD-9-CM codes for primary diagnosis.

Database description

The study used data derived from MarketScan claims databases (Thomson MedStat, Ann Arbor, MI), which provide anonymous, patient- level data on the cost and utilization of healthcare services covered by private (employer-funded) health insurance plans throughout the United States. Outpatient pharmacy claims records are linked via unique encrypted patient identifiers with records of inpatient and outpatient medical services. All asthma medication claims incurred between January 1, 1998, and December 31, 2003, were retrieved for the study. To obtain a stable population, only employers providing continuous medical and pharmacy claims data for the entire 6-year period were included in the data aggregation for this study. MarketScan data have been widely used for health services and outcomes research studies13-15.

Study variables

Prescriptions dispensed for asthma medications and asthma exacerbations were evaluated each calendar week (Sunday to Saturday) over the study period, yielding 313 weekly values. The total amount paid by insurance and the patient for each prescription was captured from pharmacy claims. Prescription costs were based on actual amounts paid by insurers and patients in the commercial insurance database. Because the data spanned 6 years, all costs were adjusted to December 2003 prices using the pharmaceutical component of the Consumer Price Index16. Total outpatient visits for asthma and number of persons eligible during the week were also evaluated by age group and health-plan type.

The number of prescriptions and exacerbations were expressed as rates because this is a population study rather than a person-level analysis and the population size fluctuated by 5% above and below the mean during the 6-year study period. The time series analysis was based on rates per 100 asthma-related office visits, which served as a marker of asthma care seeking in the population.

Statistical analysis

An autoregressive integrated moving-average (ARIMA) interrupted time series model was used to determine whether the introduction of FSC was associated with an alteration in trend for asthma exacerbation rates. Separate models were specified for asthma hospitalizations and ED visits. The models were based on assessment of the autocorrelation and partial autocorrelation functions of the time series data and of stationarity (data not exhibiting a trend). An annual seasonal component was included and model adequacy was confirmed by verifying the residuals were consistent with white noise. The intervention was characterized by the actual FSC prescribing rate. The analysis was performed with the SAS ARIMA procedure (SAS Institute, Cary, NC; version 9.0). Table 1. Asthma- related drug utilization and cost, and medical resources utilization

Results

Eleven large health insurance plans were identified that contributed data for the entire study period. These plans represent 1.37 million eligible employees and dependents aged 1-64 years of which 51% were females. The data set included 68 575 asthma office visits and 308 204 prescriptions dispensed for the study asthma medications annually. Enrollment information, along with drug and medical resources utilization data, is shown in Table 1.

Changes in medication prescribing and expenditure

The number of ICS prescriptions dispensed per 100 asthma visits is presented in Table 2. Prescriptions for ICSs decreased slightly from 383.0 per 100 asthma visits in the year before FSC was introduced to 381.3 per 100 asthma visits in the year after FSC was introduced (NS) (49.7 for FSC and 331.6 for single-entity ICSs). Prescriptions for ICSs then increased to 413.1 per 100 asthma visits in the second year after FSC was introduced (p < 0.001) (99.9 for FSC and 313.2 for single-entity ICS). LABA prescriptions per 100 asthma visits increased over time from 72.4 in the year before FSC to 105.2 in the year after FSC (p < 0.001) (49.7 for FSC and 55.5 for single-entity LABAs) and 138.9 in the second year after FSC (p < 0.001) (99.9 for FSC and 39.0 for single-entity LABAs). These trends are displayed in Figure 1.

In the third year after the introduction of FSC (months 25-33 in Table 2), the number of ICS prescriptions filled per 100 asthma visits had reached 406.6 compared with 383.0 in the year before FSC (p < 0.001), whereas the number of LABA prescriptions filled per 100 asthma visits had more than doubled to 147.2 compared with 72.4 in the year before FSC (p < 0.001). Therefore, there was a net increase of 74.8 LABA prescriptions per 100 asthma office visits following the introduction of FSC.

Table 2. Asthma drug utilization before and after the US market introduction of fluticasone-salmeterol combination

Figure 1. Time series of number of prescriptions filled for asthma medications before and after FSC was introduced. The number of prescriptions filled for ICSs, ICSs not including FSC, LABA, and FSC before and after introduction of FSC are shown. ICS = inhaled corticosteroid; LABA = Long-acting beta^sub 2^-agonist; FSC = Fixed- dose combination of fluticasone propionate and salmeterol

In the third year after the introduction of FSC, an additional expenditure of $19 740 per 100 asthma visits was incurred by the FSC prescriptions, which was only partially offset by a total savings of $2782 from reduction in single-entity ICS and $3447 from reduction in single-entity LABA prescriptions (p < 0.001) (Table 3).

The number of prescriptions filled and expenditure per 100 asthma visits for oral corticosteroids reduced slightly from 218.0 and $2053 before the FSC introduction to 216.1 and $1825, respectively, in the third year after the introduction of FSC.

Asthma exacerbations

In the third year after the introduction of FSC there were 1.89 asthma admissions and 14.58 ED visits per 100 asthma visits compared to 2.15 asthma admissions and 13.46 ED visits in the year before FSC was introduced (Table 4). Trends over the entire study period (1998- 2003) are displayed in Figure 2.

Table 3. Asthma drug cost before and after the US market introduction of fluticasone-salmeterol combination

Table 4. Asthma exacerbations before and after the US market introduction of fluticasone-salmeterol combination

Figure 2. Time series of number of asthma exacerbations before and after FSC was introduced. The number of exacerbations per 100 asthma office visits that led to emergency visits or hospital admissions, before and after introduction of FSC, is shown. FSC, fixed-dose combination of fluticasone propionate and salmeterol

Relationship between asthma exacerbations and the introduction of fluticasone propionate/salmeterol

ARIMA models were constructed from the entire time series of 313 weekly values for asthma admissions and ED visits. The time series of FSC uptake was included to test whether the introduction and uptake of FSC was associated with a significant change in the level of asthma exacerbations. The statistical models indicated no significant relationship between FSC uptake and asthma admissions (p = 0.17); however, there was a statistically significant relationship for ED visits (p = 0.03). The ED model predicted an additional 0.9 ED visits for an additional 100 FSC prescriptions.

Discussion

Asthma medication prescribing trends before and after the introduction of FSC were determined in a nationally representative commercial insurance claims database during the period 1998 to 2003. The intent of this analysis was to determine whether the introduction of FSC affected outcomes as determined by the incidence of inpatient admissions and ED visits related to asthma exacerbations. The costs of asthma treatment with single-entity ICSs, single-entity LABAs, and FSC were assessed for these periods.

Prescribing rates of ICSs were approximately the same before and after the introduction of FSC; 101 single-entity ICS prescriptions per 100 office visits were replaced with 120 prescriptions of ICSs as a component of FSC per 100 office visits by the third year after FSC introduction. However, the prescribing trends for LABAs were quite different. In the year before the introduction of FSC, there were 72 singleentity LABA prescriptions per 100 office visits, and by the end of 2003, total LABA prescriptions increased to 147 per 100 visits. These 147 prescriptions included 27 prescriptions per 100 office visits for single-entity LABAs and an additional increase of 120 prescriptions for LABAs as a component of FSC. Possible explanations for the increased use of LABAs could be as follows: (1) the result of the NHLBI guidelines updated in 2002 that recommend the use of combined ICS and LABA therapy in patients with moderate persistent asthma7, (2) the result of increased availability and/or marketing of FSC, or (3) a combination of these factors.

Accompanying the changes in prescribing trends was a significant change in medication expenditures. During the year before the introduction of FSC, the cost of ICS prescriptions per 100 asthma office visits was $27 188 and for LABA prescriptions the cost was $6176 per 100 office visits. During the third year after the introduction of FSC, the cost of this product for 120 prescriptions per 100 office visits ($19 740) was only partially offset by savings of $2782 from decreased single-entity ICS prescriptions and savings of $3447 from decreased use of single-entity LABAs. The net increase in asthma-therapy costs incurred by the use of these two agents alone and with FSC was $13 511 per 100 asthma office visits.

To determine whether the observed increased cost of asthma management was accompanied by positive clinical outcomes, we assessed inpatient admissions and ED visits related to asthma exacerbations during the periods before and after the introduction of FSC. The relationship between inpatient admissions and the introduction of FSC was not statistically significant (p = 0.17). However, the introduction of FSC was accompanied by a statistically significant increase in ED visits per 100 asthma office visits (p = 0.03). Thus, the increased spending of FSC therapy was not offset by a reduction in the use of healthcare services for management of exacerbations. Considering the demonstrated clinical benefits of combined ICS and LABA therapy17,18 and the potential mitigation of the risk of using a LABA in the presence of an ICS, these results would not be expected.

A number of clinical studies have demonstrated that addition of a LABA to a lower dose of an ICS improves lung function and reduces asthma symptoms more effectively than increasing the dose of an ICS alone in the treatment of moderate to severe persistent asthma17- 21. Chief among these studies was an assessment of guideline- defined asthma control achieved with FSC, compared with fluticasone propionate (FP) alone in patients who were uncontrolled on previous therapy18. After 1 year of treatment on maximally effective doses, approximately 70% of the patients using FSC had well-controlled asthma, compared with approximately 60% of the patients using FP alone (p < 0.001). In the same study, patients in the FSC group had a significantly lower mean annual rate of exacerbations requiring oral corticosteroids and/or hospitalization or ED visits, compared with patients in the FP group (p < 0.009 in all strata of patients who had received no ICS, low-dose ICS, or moderate-dose ICS prior to the study)18. Similar results were observed in another study, which found that the addition of salmeterol to moderate doses of ICS therapy in symptomatic asthma patients significantly reduced the number of patients experiencing at least 1 moderate or severe asthma exacerbation (95% CI: 1.10-1.16)22. Similarly, in a 1-year study, Pauwels and colleagues compared low and high doses of budesonide with and without the addition of formoterol. The addition of formoterol to low-dose budesonide reduced the rates of mild and severe asthma exacerbations by an estimated rate of 40% and 26%, respectively (p < 0.001 for both types of exacerbations); whereas, the addition of formoterol to high-dose budesonide reduced the rates by 37% and 49%, respectively (p = 0.03)23. The authors noted that the rates of mild and severe exacerbations were lower in patients taking medium versus low doses of budesonide plus formoterol. Of note, this effect was not dependent on the addition of formoterol. O'Bryne and colleagues conducted a 1-year, double-blind, randomized, parallel-group study in 198 centers in 17 countries that compared low- and medium-dose budesonide to the combination of budesonide plus formoterol versus placebo21. The authors found that in patients who were taking a low dose of inhaled steroid (< 400 [mu]g/day of budesonide), the addition of formoterol to either low or medium doses of budesonide resulted in a 43% reduction (relative risk [RR], 0.57; 95% CI: 0.46-0.72) in the risk of the first asthma exacerbation. However, researchers noted that the addition of formoterol to low-dose budesonide did not change the annual rate of severe asthma exacerbations in patients who were not taking inhaled steroids (p = 0.50). The current 2002 NHLBI guidelines recommend combined ICS and LABA therapy for patients with moderate or severe persistent asthma, but use of such a combination for patients with mild persistent asthma is contrary to the guidelines7. In addition, a Cochrane Review of the use of ICS and LABA combinations as first- line therapy in adults with persistent asthma who were not previously using an ICS did not find sufficient evidence to support the initial use of the combination compared with an ICS alone. Although there was evidence of improved lung function and more symptomfree days, protection against exacerbations by the use of ICS in combination with a LABA compared with an ICS alone was not demonstrated24. Furthermore, there may be a direct correlation between LABA use and asthma exacerbation, but this hypomesis requires further investigation in randomized clinical studies. These findings support the approach of initiation of ICS alone, prior to introduction of combination therapy with LABAs.

The use of an ICS to gain control of airway inflammation is critical in the management of persistent asthma. An ICS should be administered alone before considering adding a LABA, which lacks significant anti-inflammatory activity25. The bronchodilatation and symptom relief obtained from the LABA component of FSC may mask an increase in airway inflammation and make the need to increase the dose of the ICS less apparent26. Importantly, the addition of a LABA when not indicated may lead to decreased disease control27. Consequently, one should exercise caution when decreasing the ICS dosage in patients already taking combination therapy26. The recent publication of the Salmeterol Multicenter Asthma Research Trial (SMART) further points out a potential risk of inappropriate use of salmeterol in patients with asthma9. Researchers reported a significantly increased risk of the combined secondary endpoint of asthma-related death or life-threatening experience in patients receiving salmeterol (0.28 vs. 0.16% with placebo; RR, 1.7068; 95% CI: 1.0075-2.8912). This effect was especially noted in African- American patients (0.80 vs. 0.17% with placebo; RR, 4.9244; 95% CI: 1.6779-14.4519). Of note, less than 50% of enrolled patients were using an ICS before starting salmeterol therapy. Multiple reviews of the available literature have been conducted in light of the SMART study to characterize the safety of LABA therapy, including salmeterol, in addition to ICS therapy in asthma. A systematic review by Walters and colleagues concluded that in a wider population of ‘real-life’ patients, combination therapy with LABA and ICS was safe and effective and that the greatest risk of respiratory-related deaths and life-threatening experiences occurred in African-American patients and patients who had not received ICS therapy prior to the combination regimen28. In summary, findings from the SMART study and systematic reviews formed the basis of changes to the NHLBI guidelines and LABA product labels, mandated by the FDA, that recommend that physicians should only prescribe LABAs for patients not adequately controlled on other asthma-controller medications (e.g., low or medium dose ICSs) or those with severe disease8.

Previous studies have found an increase in resource utilization as measured by asthma-related hospitalizations, ED visits, and oral steroid use in patients receiving asthma medications in contradiction of the NHLBI guidelines29. On the other hand, a study utilizing claims data from 14 United Healthcare plans demonstrated that patients receiving FP plus montelukast incurred 63% higher costs than those receiving FSC (p

While the costs of treating asthma have risen in recent years, it is important to note that newer regimens have conferred substantial improvements in patients’ quality of life, an important consideration in asthma care. In a systematic review of LABA therapy with or without ICSs, the addition of LABA was associated with fewer symptoms, lesser use of rescue medication, and improved quality of life28. Another review noted that in patients with asthma symptoms who are using ICSs, a FSC regimen resulted in improved Asthma Quality of Life Questionnaire scores, emotional function domain scores, and asthma symptom domain scores compared with ICSs alone32. The correlation of drug usage with quality of life was not assessed in this study.

Current guidelines for the management of asthma recommend initiating treatment with an ICS for patients with mild persistent asthma and adding a LABA for patients with moderate to severe persistent asthma. Our study demonstrates that patient exposure to LABAs has increased since the introduction of these ICSs and LABAs in combination as FSC. Without knowledge of the disease severity of the studied population, it is difficult to determine the appropriateness of this trend.

Limitations

Foremost among the limitations of this study was an inferred diagnosis of asthma from pharmacy claims. These asthma medications could have been filled for the treatment of chronic obstructive pulmonary disease or other airway disease. Secondly, because the severity of asthma within the study population was unknown, the adherence of observed medication usage patterns to asthma therapy management guidelines could not be assessed. Although baseline asthma severity and changes in disease severity over the study time frame could not be assessed, there were no indications to expect any significant change in severity prior to introduction of FSC. Thirdly, individual patient adherence to prescribed asthma medications was not captured, and this factor can have important implications in predicting adverse outcomes. Also, the use of oral corticosteroids in this population was not captured. Oral steroid use is a marker of asthma exacerbation, and although the costs associated with these prescriptions are small, oral corticosteroid use has a tremendous impact on quality of life of the asthma patient. Adherence to ICS therapy is associated with fewer ED visits, asthma-related hospitalizations, and deaths33. It has been shown that the rate of death from asthma was reduced by approximately 50% if patients used at least six canisters of low- dose ICS per year33. Fourthly, our study was not designed to determine the impact that other medications used to prevent asthma (i.e., montelukast, omalizumab, and oral corticosteroids) would have on medications costs and asthma exacerbations. Fifthly, the effect of the aging of the study population over the 6-year time frame was not addressed in this analysis. Finally, the impact of FPS introduction on indirect costs associated with missed work days and school days was not evaluated in this analysis.

In general, the present study was not designed to determine causality of the outcome to a specific drug class, but to observe the changing trends of asthma drug prescribing and patterns of asthma exacerbations following the introduction of FSC. Outcomes observed could be due to other trends over time, such as decreased asthma medication adherence, increasing severity of disease, or inappropriate management of asthma in general.

Future research in follow-up to the current study should quantify the link between drug treatment and outcomes at the patient level. This would also allow for better identification of potential confounders to the results, such as a diagnosis of COPD or use of oral steroids.

Conclusion

This study demonstrated an increase in use of fluticasone with salmeterol after FDA approval of the two drugs in combination (FSC). This increase of FSC use was accompanied by a large increase in expenditures for FSC and only a small decrease in expenditure on the single-entity components. These changes were not accompanied by the expected significant decrease in asthma exacerbations, but rather a statistically significant increase in asthma-related ED visits. Future research should investigate whether the increased cost of new asthma medications is offset by positive clinical outcomes.

Acknowledgments

Declaration of interest: This study was funded by Schering- Plough. DB, DY, and WS were funded as consultants by Schering- Plough, and GL was a recipient of a research grant from Schering- Plough. The authors acknowledge the contributions of Simone Crespi, MPH, Global Health Outcomes at Schering-Plough, for her insightful comments on this manuscript.

* These data were presented in part at the Academy of Managed Care Pharmacy Annual Meeting in Seattle, WA, USA, April 5-8, 2006

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Paper CMRO-4112_2, Accepted for publication: 12 September 2007

Published Online: 5 October 2007

doi: 10.1185/030079907X242548

D. I. Brixner(a), G. Lenhart(b), D. C. Young(a) and W. M. Samuelson(a)

a Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA

b Thomson Medstat, Cambridge, MA, USA

Address for correspondence: Diana I. Brixner, PhD, RPh, Associate Professor and Chair, Department of Pharmacotherapy, 421 Wakara Way, Room 208, Salt Lake City, UT 84108, USA. Tel.: +1 801 581 3182; Fax: +1 801 581 6160; Diana.Brixner@pharm.utah.edu

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