Healthcare Costs Among Patients with Excessive Sleepiness Associated with Obstructive Sleep Apnea, Shift Work Disorder, or Narcolepsy

Excessive daytime sleepiness occurring at least 3 times weekly affects nearly 20% of the population and severe excessive daytime sleepiness affects approximately 5% of the population, with men and women equally affected.¹ Excessive sleepiness, defined as the ongoing inability to maintain alertness during the waking episodes,² imposes a significant clinical, quality-of-life, safety, and economic burden on society.³ In 2007, the National Highway Traffic Safety Administration estimated that sleep problems contributed to more than 100,000 motor vehicle crashes in the United States, resulting in an estimated 1550 deaths, 71,000 injuries, and $12.5 billion in monetary losses annually.⁴

Excessive daytime sleepiness is associated with many medical conditions, including shift work disorder (SWD), obstructive sleep apnea (OSA), and narcolepsy.³ The prevalence of excessive sleepiness among night shift workers and among rotating shift workers is 14.1% and 8.1%, respectively; the corresponding prevalence of SWD is 10% among shift workers aged 18 to 65 years.⁵ An estimated 9% of women and 24% of men aged 30 to 60 years have at least mild OSA.6 Excessive daytime sleepiness is the most common symptom of OSA.^7,8 Residual excessive sleepiness is present in 6% to 12% of patients with OSA even after treatment with continuous positive airway pressure.⁸

The prevalence of narcolepsy is estimated to be between 25 and 50 persons per 100,000 people.⁹ Almost all patients with narcolepsy experience periods of extreme daytime sleepiness and sudden bouts of sleep that can strike at any time.¹⁰ Because of the high prevalence and significant economic impact of excessive sleepiness, attention is warranted for the selection of the most appropriate and cost-effective, wake-promoting treatment.

Armodafinil and modafinil improve wakefulness in patients with excessive sleepiness associated with SWD, treated OSA, and narcolepsy.^11-18 Armodafinil is the longer-lasting, R-isomer of racemic modafinil. A comparison of armodafinil and modafinil on a milligram-to-milligram basis showed that armodafinil sustained higher plasma concentrations than modafinil, as indicated by a 37% higher maximum plasma concentration, and a 69% greater area under the curve.¹⁹

This present study was conducted to explore any potential differences in all-cause healthcare costs and the individual cost components (ie, inpatient visits, emergency department visits, physician office visits, outpatient visits, and other visits) between patients prescribed initial armodafinil therapy and patients prescribed initial modafinil therapy for the treatment of excessive sleepiness associated with OSA, SWD, or narcolepsy.

Methods
Data Source
This retrospective cohort study was based on data from the IMS LifeLink Health Plan Claims Database, a nationally representative database containing data from more than 79 health plans in the United States. This is the largest, most comprehensive database of integrated medical and pharmacy claims for approximately 87 million de-identified individuals as of March 2012, with the majority of them (82%) commercially insured.

Patients in the database are tracked longitudinally using 3 component files: medical claims, pharmacy claims, and eligibility for insurance coverage. The medical claims file contains data on the diagnostic and therapeutic services rendered in the inpatient and outpatient settings. The pharmacy claims file contains data on the prescription drugs dispensed in the retail and mail-order settings. The eligibility file contains demographic characteristics and periods of eligibility for enrollment in the plan for each patient.

Patient Selection
The study included patients with a pharmacy claim for armodafinil or for modafinil between June 1, 2009, and February 28, 2012. The fill date of the patients’ first armodafinil or modafinil prescription within this time frame was designated as the index date. Patients were included in this study if they were aged at least 18 years at the index date, and were continuously eligible for insurance coverage for 6 months before the index (ie, preindex) date and at least 1 month after the index (ie, postindex) date.

In addition, patients were required to have an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for at least 1 of the US Food and Drug Administration–approved indications for armodafinil or for modafinil—OSA (327.23), SWD (327.36), or narcolepsy (347.0x)—in the 6-month preindex period or on the index date. Patients were not required to be treatment naïve to all therapies for OSA, SWD, or narcolepsy, but patients with an index prescription fill date for armodafinil or for modafinil before June 1, 2009, or after February 28, 2012, were excluded from this study.

The cohort assignment was based on an intent-to-treat approach, and patients meeting the selection criteria were placed into 1 of 2 treatment cohorts according to their index prescription; patients remained in that cohort throughout the study period. The patients were followed until the earlier of either their health plan enrollment end date, or the end of the analysis period on March 31, 2012 (Figure 1). This allowed for patients to be followed for a minimum of 1 month and a maximum of 34 months after their index date. The 6-month period before the index date was used to assess baseline characteristics, healthcare costs, and resource utilization.

Outcomes
The all-cause healthcare costs were calculated from all claims regardless of the diagnosis codes. The costs were defined as the allowed amount on claims; the allowed amount typically reflects the amount paid by the health plan plus any member liability (ie, copay, deductible, or coinsurance) for the service. The allowed amount was chosen as the cost measure, because it best represents the actual cost amount received from all payers.

The total medical costs and the component costs for inpatient hospitalizations, emergency department visits, physician office visits, outpatient visits, and other visits (ie, laboratory and diagnostic claims that were not part of a hospitalization, emergency department visits, physician office visits, or outpatient visits) were evaluated.

The pharmacy costs included all medications for which claims were filed (ie, not restricted to armodafinil and to modafinil). The drug-specific costs were restricted to pharmacy costs for armodafinil or for modafinil. The total healthcare costs included the sum of all medical and pharmacy costs. Because patients had varying lengths of follow-up, annualized costs were calculated by multiplying by 12 the average monthly cost for each patient.

The costs in the analysis were adjusted to March 2012 US dollars using the Medical Consumer Price Index.²⁰ The daily average consumption (DACON) for armodafinil and for modafinil was calculated by dividing the total tablets dispensed for each drug by the prescription days supplied.

Statistical Methods
Baseline characteristics were compared between the 2 cohorts using the chi-square tests for categorical variables (eg, sex, region, index payer, conditions of interest) and independent samples t-tests for continuous variables (eg, age, Charlson Comorbidity Index [CCI] score). The CCI score was used to represent the patients’ overall health status. It contains 19 categories of comorbidity and reflects the cumulative burden of comorbidity with higher scores indicating a more severe burden.^21,22 (The categories of the CCI include myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, diabetes, hemiplegia, moderate-to-severe renal disease, diabetes with end-organ damage, any tumor, leukemia, lymphoma, moderate-to-severe liver disease, metastatic solid tumor, and AIDS.^21,22)

The CCI scores were derived by evaluating the presence of various ICD-9 codes in the 6-month preindex period for each patient. To account for baseline differences between the 2 treatment cohorts, multivariate generalized linear models based on gamma distribution and log link function were used to compare postindex costs between the 2 cohorts; age, sex, CCI scores, region, index payer, and log-transformed preindex costs were used as covariates in the models. Paired t-tests were used to compare differences between the preindex and the postindex costs within each drug cohort. All analyses were conducted with SAS version 9.2 (SAS Institute; Cary, NC). A P value ≤.05 was considered significant.

Results
Patient Characteristics
A total of 5693 patients receiving armodafinil and 9212 patients receiving modafinil met all of the inclusion criteria. The patients in the modafinil cohort were followed for an average of 19.35 months, and the patients in the armodafinil cohort were followed for an average of 13.95 months. At baseline, patients in the modafinil cohort were older (50.3 years vs 47.3 years; P <.001) and with a higher mean CCI score (0.81 vs 0.64; P <.001) compared with patients in the armodafinil cohort (Table). Relative to the modafinil cohort, the armodafinil cohort had higher percentages of patients with a diagnosis of OSA (84% vs 81.4%; P <.001) and SWD (7.7% vs 4.2%; P <.001), and a lower percentage of patients.

Daily Average Consumption
During the study period, 27,555 armodafinil prescriptions were filled by 5693 unique patients for an average of 4.8 armodafinil fills per patient. For modafinil, 57,196 prescriptions were filled by 9212 unique patients for an average of 6.2 modafinil fills per patient. A lower DACON was observed for armodafinil (1.04) compared with modafinil (1.47; Figure 2). The mean monthly drug-specific pharmacy costs were $166 for armodafinil and $326 for modafinil (P <.001).

Healthcare Costs
The postindex mean medical costs were significantly lower for the armodafinil cohort compared with the modafinil cohort after adjusting for baseline differences ($11,363 vs $13,775, respectively; P = .005 (Figure 3). Within each cohort, decreased medical costs were observed in the postindex period compared with the preindex period ($13,155 vs $11,363, respectively, for armodafinil; $15,323 vs $13,775, respectively, for modafinil; P <.001 for both). Of the postindex component medical costs, inpatient hospitalization costs ($3099 vs $4308, respectively; P = .014) and other costs ($643 vs $1035, respectively; P <.001) were significantly lower for the armodafinil cohort compared with the modafinil cohort.

The physician and outpatient costs were also lower for the armodafinil cohort; however, these differences did not reach significance. All-cause emergency department visits was the only cost category that was higher among patients receiving armodafinil than among patients receiving modafinil (P <.001).

The postindex mean total healthcare costs were lower for the armodafinil cohort compared with the modafinil cohort after controlling for baseline differences ($18,309 vs $23,530, respectively; P <.001; Figure 4).

Discussion
This is the first large, real-world, retrospective, economic study to evaluate the cost differences between armodafinil and modafinil. The results of this analysis indicate that after therapy initiation, the armodafinil cohort had lower total all-cause medical costs compared with the modafinil cohort. In addition, the armodafinil cohort had lower pharmacy costs than the modafinil cohort after therapy initiation. The differences in the pharmacy costs between the armodafinil and the modafinil cohorts were partly driven by the differences in the pharmacy cost between the 2 medications, with armodafinil having a lower price than modafinil on a per-tablet basis (approximately $10.44 vs $16.56, respectively, per tablet).

Furthermore, this analysis was conducted before the approval of generic modafinil in June 2012. When the armodafinil and modafinil pharmacy costs were subtracted from the total pharmacy costs, the remaining pharmacy costs were still lower for the armodafinil cohort compared with the modafinil cohort, suggesting that lower total pharmacy costs may be seen with armodafinil compared with generic modafinil.

DACON is a technique used by managed care organizations to assess drug utilization and the associated economic implications between medications with similar therapeutic indications. Although armodafinil and modafinil are available for once-daily dosing in multiple tablet strengths, differences in the real-world utilization of these medications can be underscored in a DACON analysis. Armodafinil has a DACON of 1.04 compared with a DACON of 1.47 for modafinil. These results support true once-daily dosing for armodafinil and provide real-world support for the pharmacokinetic data showing that on a milligram-to-milligram basis, armodafinil sustains higher plasma concentrations versus modafinil during a 24-hour period.¹⁹ These pharmacokinetic advantages may have translated into DACON differences seen in this real-world analysis.

Limitations
The findings of this study should be interpreted with the study limitations in mind. First, the results of this analysis are based on observational claims data and therefore cannot be interpreted as implying any difference in efficacy or other clinical outcome, such as disease progression or quality of life. As with all claims analyses, the data elements may be subject to coding irregularities and inaccuracies. For example, SWD is known to be undercoded in medical claims, and physicians may also classify patients presenting with excessive sleepiness associated with OSA or narcolepsy to a broader or different diagnosis. Because study eligibility required a coded indication, relevant patients might have been excluded from the analysis. Hence, the generalizability of the results is restricted to a population that is similar to the current study group.

Second, the costs reported in this analysis are all-cause pharmacy and medical costs and are not specific to OSA, SWD, and/or narcolepsy. Excessive sleepiness is a risk factor for comorbidities and can exacerbate several comorbidities, making all-cause medical resource utilization the most relevant costs for this analysis. Because patients in this analysis had multiple comorbidities, it was difficult to separate disease-specific costs. In addition, total costs, regardless of their origin, are the most relevant costs to a health plan. It is likely that an excessive sleepiness–specific cost analysis would underestimate the true costs associated with this condition because OSA, SWD, and narcolepsy––the underlying causes of excessive sleepiness––are often undercoded.

Third, this analysis did not capture the time since diagnosis and did not correct for the potential increased cost of the initial diagnosis and treatment. This analysis included a 6-month preindex period to ensure a diagnosis for OSA, SWD, or narcolepsy, but patients were not required to be newly diagnosed. Previous research has shown that men and women with OSA have higher costs in the period immediately before disease diagnosis.^23,24

Fourth, the study design and the analytic techniques contain some inherent limitations. Because of the intent-to-treat design, patients who switched therapies during follow-up were still considered members of the cohort to which they were originally assigned, and their costs were attributed to their index drug. Administrative claims do not provide information regarding reasons for treatment discontinuation or switching. Furthermore, the IMS database is fully de-identified and therefore does not contain information on the benefit design of payers.

Finally, an observational retrospective cohort study design restricts the ability to draw direct causal inferences between treatments and outcomes. Although background characteristics, such as age, sex, CCI score, index payer, and preindex costs were controlled for in this analysis, residual confounding cannot be ruled out.

Conclusions
Based on this analysis, armodafinil provides real-world DACON advantages and may be associated with lower overall healthcare resource utilization and costs compared with modafinil. In light of these new comparative economic data, healthcare decision makers may have to consider DACON and real-world total cost differences in their formulary decision-making. Future studies are needed to explain the drivers of healthcare resource utilization and cost differences between patients receiving armodafinil and those receiving modafinil.

Funding Source
This study was funded by Teva Pharmaceuticals.

Author Disclosure Statement
Dr Carlton, Dr Lunacsek, and Mr Regan are employees of Xcenda, which received funding from and provided consulting services to Teva Pharmaceuticals to conduct this analysis. Dr Carroll is a former employee of and had stocks in Teva Pharmaceuticals.

Dr Carlton is Assistant Director, Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL; Dr Lunacsek is Associate Director, Applied Data Analytics, Xcenda, Palm Harbor, FL; Mr Regan is Executive Director, Strategic Accounts, Xcenda, Palm Harbor, FL; Dr Carroll is Senior Director, Market Access, Xcenda, Palm Harbor, FL.

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