Initiation of Inhaled Corticosteroid and Long-Acting b2-adrenergic Agonist (ICS/LABA) in Asthma
Published Online: June 20, 2014
Ozgur Tunceli, PhD; David M. Kern, MS; Setareh A. Williams, PhD; Ned Pethick, MBA; Lisa Suchower, MA; and Sulabha Ramachandran, PhD
Asthma is a chronic respiratory condition characterized by inflammation in the air passages, which narrows the airways and impedes respiration.1,2 While some patients have genetic predispositions to asthma,3,4 the condition is also linked to well-known environmental triggers such as inhaled allergens and irritants,1,2 which can increase inflammation and cause asthma attacks. Asthma affects approximately 8.2% (24.6 million) of people in the United States,5 and more than 300 million worldwide.3 Prevalence is greater among children (8.9%) compared with adults (7.2%) in the United States.6 Each year, about 4000 deaths are directly attributable to asthma.6 In 2007, asthma-related emergency department (ED) visits and hospitalizations were estimated at 1.75 million and 456,000, respectively.5 The total costs directly applicable to asthma treatments in 2007 were estimated at $37.2 billion in the United States.7
The current Expert Panel Report-3 (EPR-3) Guidelines for the Diagnosis and Management of Asthma state that the preferred treatment for persistent asthma is long-term controller medication, usually an inhaled corticosteroid (ICS).8 For patients 12 years or older with moderate to severe asthma whose asthma is not well controlled on a low to medium dose of ICS alone, the EPR-3 guidelines suggest the addition of a long-acting β2-adrenergic agonist (LABA). The guidelines also suggest the addition of LABAs in cases with high levels of impairment, or when patients are at risk for asthma exacerbation. LABAs are not recommended for monotherapy due to evidence associating the LABA salmeterol with asthma-related deaths.9 A subsequent FDA-mandated class black-box warning (2005) resulted in updated product labeling, which now includes a reference to this association for all products containing LABAs.10 For ICS/LABA combination treatments, the current labeling indicates usage in patients who are not adequately controlled with other asthma controller medications, or for patients whose disease severity warrants the use of 2 maintenance therapies.11,12
Three ICS/LABA combination therapies are currently approved for asthma treatment in the United States: fluticasone propionate/salmeterol combination (FSC) therapy, approved August 2000; budesonide/formoterol fumarate dihydrate combination (BFC), approved July 2006 (launched June 2007); and mometasone/formoterol fumarate dihydrate (MFC), approved June 2010.11-13 The current study includes all 3 agents in the total but focuses on BFC and FSC, given the very small number of MFC study patients due to low market presence (n = 126).
In clinical asthma studies, ICS/LABA combination treatments have proved efficacious and are associated with improved outcomes among patients with asthma.14,15 Evidence from retrospective studies utilizing large commercial insurance claims databases have suggested, however, that combination therapies were being prescribed inappropriately with respect to both the EPR-3 and Canadian Asthma Guidelines requirements. 16,17 One retrospective cohort study by Ye and colleagues utilizing medical and pharmacy data from a large commercially insured US population between January 1, 2006, and December 31, 2007, demonstrated that 38% of 24,231 patients in the study sample initiated BFC or FSC therapy according to EPR-3 guideline recommendations. The study found, however, that the proportion of patients considered appropriately initiated on ICS/LABA combination therapy was significantly greater for BFC patients (n = 993) than for those receiving FSC therapy (n = 23,238; 58.4% vs 36.7%, respectively; P <.0001).18
Blanchette and colleagues utilized medical and pharmacy claims data for US patients (PharMetrics Patient-Centric Database) between July 1, 2006, and June 30, 2008, in a retrospective cohort study identifying patients aged 12 to 64 years who appropriately initiated FSC or BFC therapies. Overall, only 39% of study subjects (n = 16,205) initiated therapy in accordance with guideline recommendations.19 Data presented by Ye and Blanchette also showed that the likelihood of BFC being appropriately prescribed for patients (n = 1417) was, at 55.6%, significantly higher than it was for FSC patients (n = 14,788), at 37.7% (P <.001).18,19
The objective of this study was to investigate the extent to which initiation of the ICS/LABA combination therapies— BFC versus FSC—were associated with the guideline recommendations, using the most recently available claims data from a large US commercial health insurance plan over a 3-year period.
Data Source and Study Design
This retrospective observational cohort study queried the HealthCore Integrated Research Database (HIRD) to identify patients with asthma who were initiated on ICS/ LABA therapy between June 1, 2007, and December 31, 2010. HIRD contains clinically rich and geographically diverse longitudinal claims data for 45 million researchable lives covered by health insurance plans in US Northeast, Midwest, Southern, and Western regions. Data acquisition and handling in this outcomes study complied with all state and federal privacy regulations, including the Health Insurance Portability and Accountability Act.
Patients initiating ICS/LABA combination therapies anytime between June 1, 2007, and December 31, 2010, with no prescription fill for an ICS/LABA combination at least once in the prior year or more were considered ICS/ LABA combination–naïve and were eligible for study inclusion. The start of the index period (June 1, 2007) was chosen to coincide with the date that BFC became available in the United States. Patients were assigned to BFC and FSC cohorts based on their first prescription fill. The first prescription date for BFC or FSC was the index date. International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were used to identify patients based on medical claims; generic product identifier (GPI) codes were employed for pharmacy claims.
Patients aged 12 to 64 years on the index date were considered to have asthma if they had at least 1 medical claim with an ICD-9 code for asthma (493.0x, 493.1x, or 493.9x) in any position (primary or secondary) and any setting (inpatient, outpatient, ED, or physician office) within 12 months of the index date. Patients were also required to have at least 12 months of continuous health plan enrollment prior to the index date.
Patients with ICS/LABA combination therapy prescriptions within 12 months of the index date were excluded. Also excluded were patients initiating 1 or more types of ICS/LABA combination therapies on the index date, because assignment to a single cohort was not possible. Patients with any claims for chronic obstructive pulmonary disease, cystic fibrosis, lung cancer, or tuberculosis during the entire study period were excluded, as were those with diagnoses for exercise-induced asthma with no other asthma diagnosis.
Patients who filled prescriptions for ICSs or leukotriene receptor antagonist (LTRA) asthma controller medications within 12 months of ICS/LABA combination treatment initiation, or who were identified as high risk for asthma exacerbation (defined as having an asthma-related ED visit or asthma-related hospital admission or 2 or more oral systemic corticosteroid [OSC] prescription fills with <21 days of supply, or dispensed >6 short-acting β2- adrenergic agonist [SABA] canisters), were considered appropriately initiated on ICS/LABA combination treatment.
Statistical analyses were conducted for the total study population and for each BFC and FSC treatment cohort separately. Univariate analyses were conducted for the 12-month pre-index period on demographic and clinical characteristics as well as previous medication use. Means, medians, standard deviations, relative frequencies, and proportions were calculated for the population as a whole (including all 3 BFC, FSC, and MFC treatment groups) and by BFC and FSC cohorts. Demographic and baseline clinical characteristics were summarized for BFC and FSC cohorts using descriptive statistics only. Subgroup comparisons with statistical testing and P values were calculated for the BFC and FSC cohorts for the following outcomes during the 12-month pre-index period: prior asthma controller medication use (ICS or LTRA); high-risk status (the occurrence of asthma-related hospitalizations); ED visits, hospitalizations, or both; 2 or more prescription claims for OSCs with <21 days days of supply or >6 SABA canisters. Logistic regression was used for each outcome to assess differences between the BFC and FSC cohorts. The FSC cohort was considered as the reference group for both the unadjusted and adjusted statistical models. A stepwise selection algorithm was utilized to determine covariates (demographic and baseline characteristics) to include in the final logistic regression model of each outcome. ORs, 95% CIs, and P values were reported for all covariates included in the model. As the current study had a longer follow-up time, which overlapped the time periods covered in the previous studies,18,19 a post hoc analysis was performed to gain an understanding of BFC- and FSC-appropriate initiation over time within each calendar year of the study period. All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina). A statistical significance level of 0.05 was utilized.
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