The prevalence and severity of chronic asthma have

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1 An Economic Analysis of Alternative Step-Up Therapies in Asthma Patients Receiving Inhaled Daniel A. Ollendorf, MPH, Alyssa S. Pozniak, BA, Brian W. Bowers, PharmD, Gerry Oster PhD ABSTRACT We analyzed health care claims data to assess the impact of salmeterol xinafoate relative to leukotriene modifiers in asthma patients who were receiving inhaled corticosteroids. Utilization and costs of asthmarelated care were tracked for six months before and 12 months after first receipt of therapy. Use of corticosteroids and short-acting β 2 was lower among salmeterol patients, as were monthly costs of asthma-related care ($101 [±$4] vs $128 [±$9] for leukotriene modifiers). Key Words: salmeterol xinafoate; leukotriene receptor ant; asthma; costs-and-cost-analysis The prevalence and severity of chronic asthma have increased substantially in recent years; between 1980 and 1993, the number of Americans affected by asthma increased more than two-fold, from 6.8 million to over 14 million. 1,2 Mortality caused by asthma also increased by 68% during this period. 3 Exacerbation of asthma symptoms often necessitates the use of rescue medications (e.g., oral steroids, inhaled or oral short-acting β 2 ) as well as physician and/or emergency-room services, all of which can substantially increase costs of care. Prevention of bronchospasm and control of bronchial hyperresponsiveness and inflammation remain the primary goals of drug therapy for chronic asthma. The U.S. National Institutes of Health has stated that inhaled corticosteroids currently represent the most potent and effective anti-inflammatory agents for chronic management of persistent asthma. 4 However, in many patients, optimal control of the disease cannot always be achieved with inhaled corticosteroids alone; accordingly, additional therapy is often warranted. Salmeterol xinafoate (Serevent, GlaxoSmithKline Inc.) and the so-called leukotriene modifiers (montelukast [Singulair], Merck & Co.; zafirlukast [Accolate], AstraZeneca Pharmaceuticals Inc.; and zileuton [Zyflo], Abbott Laboratories Inc.) are agents that are being used increasingly in combination with inhaled corticosteroids in the management of chronic asthma. The safety and efficacy of salmeterol and the leukotriene modifiers have been demonstrated in controlled clinical trials. Salmeterol and zafirlukast also have been compared in a randomized, multicenter, controlled clinical trial. 5 In this study, salmeterol was found to result in significantly greater improvement relative to zafirlukast in pulmonary function, asthma symptoms, Mr. Ollendorf is Senior Analyst and Dr. Oster is Vice President, Policy Analysis Inc. (PAI), in Brookline, Massachusetts. Ms. Pozniak was employed by PAI at the time these analyses were conducted. Dr. Bowers is Senior Health Outcomes Scientist at GlaxoSmithKline Inc., in Research Triangle Park, North Carolina. and supplemental use of the short-acting β 2 agonist albuterol. To date, however, the comparative effects of salmeterol and the leukotriene modifiers on asthma-related health care utilization and costs have not yet been examined. We undertook a study using health care claims data to address this issue. METHODS Overview We conducted a retrospective evaluation of the utilization and costs of asthma-related medications and health care services in patients with chronic asthma who were receiving inhaled corticosteroids and were newly started on salmeterol or a leukotriene modifier, using the claims-processing system of a large New England health insurer. A cohort of plan members with chronic asthma who were receiving inhaled corticosteroids was first identified through a review of all paid pharmacy, professional service, and hospital claims. Among these identified members, patients who were newly started on salmeterol or a leukotriene modifier (i.e., montelukast, zafirlukast, or zileuton) were selected for inclusion in the study sample. The date of the first paid pharmacy claim for one of the study medications was designated the index date. The six-month period prior to the index date and the 12-month period subsequent to this date were designated the pretreatment and follow-up periods, respectively, for each patient in the sample. Utilization and costs of asthma-related care were then compared during the 12-month follow-up period between patients who received salmeterol versus a leukotriene modifier, including the use and associated cost of all asthma-related medications, outpatient services (including physician office, emergency-room, and hospital outpatient visits), and inpatient care. Data Source Data for this study were obtained from the claims-processing system of a large New England health insurer, which includes information on approximately 1.8 million covered lives. Total Vol. 27 No. 3 March 2002 P&T 147

2 billed charges, the amount reimbursed, and the amount of patient copayments were available for all claims. Data available for each paid pharmacy claim included the National Drug Classification (NDC) code, the dispensing date, and the number of therapy-days dispensed. Data available for each paid professional and institutional claim included the date of service, the primary diagnosis (in International Classification of Diseases, 9 th Edition, Clinical Modification [ICD-9-CM] format), and the nature of the service that was rendered (in Health Care Financing Administration Common Procedure Coding System [HCPCS] or Physician s Current Procedural Terminology, 4th Edition [CPT-4] format). Additional data available for each plan member included age, gender, and the start and stop (if applicable) dates of eligibility for plan benefits. Sample Selection The study sample was selected in stepwise fashion. First, all plan members with one or more paid professional-service or institutional claims with a listed diagnosis of asthma (ICD-9-CM 493) between October 1, 1996 and March 31, 1999 were identified. Persons less than 12 years of age were excluded from the sample, consistent with product labeling for most of the medications of interest. Those aged 65 years or older also were excluded because the claims database includes only a limited number of such persons. Next, persons who had at least one pharmacy claim for salmeterol (Serevent, NDC , , , , , , ), montelukast (Singulair, , , , , , ), zafirlukast (Accolate, , ), or zileuton (Zyflo, ) between April 1, 1997 and March 31, 1998 were identified. The date of the earliest observed pharmacy claim during this period was designated the index date ; pretreatment and follow-up periods of six and 12 months, respectively, were then defined for each subject in relation to this date. Patients were assigned to treatment groups (i.e., salmeterol vs. leukotriene modifiers) on the basis of the drug received on the index date. Pharmacy claims were scanned to ensure that all persons selected for inclusion were receiving treatment with an inhaled corticosteroid during the pretreatment and follow-up periods; those who were not were excluded from the study sample. Treatment with inhaled corticosteroids was defined on the basis of one or more and two or more pharmacy claims for such therapy during the pretreatment and follow-up periods, respectively. In addition, to ensure that study therapy was used as an adjunct to (rather than a replacement for) inhaled corticosteroid therapy, the sample was further restricted to those patients who had at least one instance in which an inhaled corticosteroid and one of the study medications were dispensed on the same day. To ensure that treatment received on the index date represented initiation of study therapy as opposed to ongoing care, patients who received any of the study medications during the pretreatment period were excluded from the study sample. Patients with chronic obstructive pulmonary disease (COPD), which was defined on the basis of a listed diagnosis of COPD (ICD-9-CM , ) or receipt of ipratropium bromide, were also excluded. Finally, as is customary in analyses of this nature, patients not continuously enrolled in the health plan over the 18-month period of interest (i.e., six months prior to the index date and 12 months subsequently) were excluded from all analyses, as were those whose health insurance did not include prescription drug coverage. Measures and Analyses Claims were compiled for each study subject for the six months prior to initial receipt of study therapy (pretreatment) and for 12 months subsequently (follow-up). Outcomes of primary interest included the use and associated costs of asthma-related medications and health care services during follow-up. All measures of interest were expressed on a monthly basis. Asthma-related medications were defined to include study therapy (i.e., salmeterol and leukotriene modifiers), inhaled and oral corticosteroids, inhaled and oral short-acting β 2 (e.g., albuterol), xanthine derivatives (e.g., theophylline), and miscellaneous anti-inflammatory agents (e.g., cromolyn sodium). The number of days of therapy with each of these medications was tallied based on the number of days dispensed on each paid pharmacy claim. The numbers of claims for asthma-related physician office, emergency-room, and hospital outpatient visits were tallied, as were the numbers of asthma-related hospitalizations and corresponding days in hospital. Claims were deemed to be asthmarelated based on a listed diagnosis of asthma (ICD-9-CM 493). A direct medical-care cost perspective was employed in all analyses of data. Accordingly, the cost of each claim was estimated by adding the amount reimbursed by the plan and the amount of patient copayment. Utilization and costs of asthma-related care during follow-up were then compared for patients receiving salmeterol or a leukotriene modifier using monthly means and standard errors (SE). Differences in costs were also calculated, along with corresponding 95% confidence intervals. The latter were calculated using techniques of nonparametric bootstrapping, 6 as the distribution of costs was expected to be significantly skewed. In addition to primary analyses of data, secondary analyses of the impact of salmeterol versus leukotriene modifiers alternatively on the costs of respiratory-related and all medical care were conducted. Respiratory-related care was defined on the basis of a relevant listed diagnosis (i.e., ICD-9-CM 466, , , , 493, ). Finally, multivariate analyses (using ordinary least-squares regression) were conducted to control for differences between treatment groups in demographic characteristics and measures of pretreatment utilization. Two models were specified: the dependent variables in these models were the cost of asthmarelated medications and the total cost of asthma-related care during follow-up, respectively. These variables were expressed on a monthly basis and were log-transformed prior to analysis to account for skewness. Explanatory (i.e., independent) variables continued on page P&T March 2002 Vol. 27 No. 3

3 continued from page 148 in these models included age, age squared, gender, the number of days of therapy (per month) during pretreatment with inhaled and oral corticosteroids, as well as inhaled and oral short-acting β 2, the number (per month) of asthmarelated physician, emergency-room, and hospital outpatient visits and hospitalizations during pretreatment, and the total monthly cost of asthma-related care during pretreatment. Adjusted mean costs were then calculated; costs were retransformed to consistent estimates of their natural values using Duan s smearing estimator. 7 All analyses were performed with the Statistical Analysis System (SAS) Version RESULTS Economic Analysis of Step-Up Therapies in Asthma Table 1 Demographics and Other Characteristics Salmeterol+ICS LTM+ICS Characteristic (n=259) (n=106) P Age (mean, SE) 42.3 (0.8) 43.8 (1.2) * Gender (% female) Monthly pretreatment use of asthma-related medications (therapy-days) (mean, SE): Oral 1.07 (0.20) 1.64 (0.35) Inhaled (0.46) (0.83) Oral 0.55 (0.19) 1.75 (0.57) Inhaled (0.64) (1.17) Xanthine derivatives 2.65 (0.47) 4.22 (0.89) agents 1.04 (0.25) 1.05 (0.38) Monthly pretreatment use of asthma-related health care services (mean, SE) Physician office visits 0.23 (0.02) 0.30 (0.05) Emergency-room visits 0.08 (0.01) 0.05 (0.01) Hospital outpatient visits 0.04 (0.01) 0.02 (0.01) Hospital admissions 0.01 (0.00) 0.01 (0.01) Monthly total pretreatment cost of asthma-related care ($) (mean, SE) $84 ($6) $101 ($10) ICS= inhaled corticosteroids; LTM= leukotriene modifiers; * t-test; chi-square test; Wilcoxon rank-sum test. Patient Characteristics A total of 365 patients met all study entry criteria (259 and 106 for salmeterol and leukotriene modifiers, respectively). The groups were similar with respect to age, gender, and most measures of pretreatment utilization (Table 1). Mean (±SE) monthly pretreatment use of inhaled corticosteroids, however, was significantly lower among patients who received salmeterol (10.50 [±0.46] vs [±0.83] therapy-days for leukotriene modifiers, P=0.036), as was the use of oral short-acting β 2 (0.55 [±0.19] vs [±0.57] therapy-days respectively, P=0.024). Monthly costs of asthma-related care (i.e., medications and health care services) also were significantly lower among salmeterol patients ($84 [±$6] vs. $101 [±$10] for leukotriene modifiers, P=0.022). There was some crossover receipt of study therapy during follow-up. Approximately 20% of leukotriene modifier patients received salmeterol, while 11% and 12% of salmeterol patients received montelukast and zafirlukast, respectively (Table 2). Use of zileuton was relatively infrequent in both groups. Approximately 65% of patients had one or more physician office visits during follow-up; emergency-room services were required by one-third of patients. Hospitalization for asthma was relatively infrequent. Utilization of Asthma-Related Medications and Services On a monthly basis, the use of inhaled short-acting β 2 was substantially lower during follow-up among patients who received salmeterol (7.51 [±0.47] vs [±0.99] therapy-days for leukotriene modifiers) (Table 3); the use of oral short-acting β 2 and oral corticosteroids also was somewhat lower among these patients. The number of physician office visits per month was nominally lower among patients receiving salmeterol (0.194 [±0.022] vs [±0.035] for leukotriene modifiers); conversely, the number of emergency-room visits was higher among these patients (0.051 [±0.007] vs [±0.010] for salmeterol and leukotriene modifiers, respectively). The use of other hospital outpatient and inpatient services did not differ materially between the two treatment groups. Costs of Asthma-Related Care The costs of asthma-related medications and health care services are presented in Table 4. Monthly costs of study therapy, inhaled corticosteroids, and rescue medications (i.e., oral steroids, inhaled and oral short-acting β 2 ) were lower among patients receiving salmeterol; the total mean monthly cost of asthma-related medications was approximately $20 lower among these patients ($79 [±$3] vs. $98 [±$5] for salmeterol and leukotriene modifiers respectively; 95% confidence interval [CI] for difference: -$33, -$7). Monthly costs of asthma-related outpatient care ($19 [±$2] vs. $23 [±$4] for salmeterol and leukotriene modifiers, respectively) and inpatient care ($4 [±$2] vs. $7 [±$5], respectively) were slightly lower among salmeterol patients. Total monthly costs of asthma-related care were 20% lower among salmeterol patients ($101 [±$4] vs. $128 [±$9] for leukotriene modifiers; 95% CI for difference: -$51, -$4); this difference was primarily manifested in differences in the costs of asthma-related medications. Multivariate Analyses After multivariate adjustment, mean monthly costs of asthmarelated medications and total costs of asthma-related care were essentially identical to those reported in univariate analyses of data. Adjusted mean monthly costs of asthma-related medications were $75 and $95 for salmeterol and leukotriene modifier patients, respectively; total monthly costs of asthmarelated care were $99 and $122, respectively. Vol. 27 No. 3 March 2002 P&T 151

4 Table 2 Number (Percentage) of Patients Receiving Asthma-related Medications and Health Care Services During Follow-up Type of Medication/ Salmeterol+ICS LTM+ICS Service (n=259) (n=106) n (%) Medications Salmeterol 259 (100) 21 (19.8) Montelukast 31 (12) 16 (15.1) Zafirlukast 29 (11.2) 99 (93.4) Zileuton 3 (1.2) 6 (5.7) Oral 84 (32.4) 41 (38.7) Inhaled 259 (100) 106 (100) Oral 12 (4.6) 10 (9.4) Inhaled 214 (82.6) 93 (87.7) Xanthine derivatives 33 (12.7) 14 (13.2) agents 24 (9.3) 9 (8.5) Outpatient Physician office visits 162 (62.5) 83 (78.3) Emergency-room visits 80 (30.9) 25 (23.6) Hospital outpatient visits 27 (10.4) 11 (10.4) Hospitalization 6 (2.3) 2 (1.9) ICS= inhaled corticosteroids; LTM= leukotriene modifiers. Table 3 Use of Asthma-related Medications and Health Care Services During Follow-up Type of Medication/ Salmeterol+ICS LTM+ICS Service (n=259) (n=106) Mean per Month (SE) Medications (therapy-days) Salmeterol (0.47) 1.65 (0.46) Montelukast 0.94 (0.21) 1.72 (0.54) Zafirlukast 1.23 (0.28) (1.02) Zileuton 0.10 (0.08) 0.47 (0.22) Oral 0.73 (0.16) 1.36 (0.30) Inhaled (0.44) (0.74) Oral 0.47 (0.18) 2.05 (0.68) Inhaled 7.51 (0.47) (0.99) Xanthine derivatives 2.64 (0.48) 3.24 (0.87) agents 1.07 (0.26) 0.66 (0.28) Outpatient Physician office visits (0.022) (0.035) Emergency-room visits (0.007) (0.010) Hospital outpatient visits (0.003) (0.004) Hospitalizations (0.002) (0.004) Days in hospital (0.004) (0.008) ICS= inhaled corticosteroids; LTM= leukotriene modifiers. DISCUSSION Using health care claims data from a large New England insurer, we examined the economic impact of salmeterol versus leukotriene modifiers among patients aged 13 to 65 years with chronic asthma who were receiving inhaled corticosteroids. Health care claims were compiled for six months prior to their first receipt of study therapy (pretreatment) and for 12 months subsequently (follow-up). Utilization and costs of care were then compared during follow-up between patients receiving salmeterol or a leukotriene modifier. The use of inhaled short-acting β 2 was substantially lower among patients receiving salmeterol; their use of other rescue medications (i.e., oral β 2, oral steroids) was also lower. The total monthly costs of asthma-related care were 20% lower among salmeterol patients, a difference that was primarily caused by the lower costs of asthma-related medications. The cost savings with salmeterol would be estimated to total over $300 per patient annually. We acknowledge several limitations of our study. First, as with most nonexperimental research, we cannot rule out the possibility that our results simply reflect the effects of selection bias (e.g., differences in disease severity between salmeterol and leukotriene modifier patients) rather than those of salmeterol therapy per se. Indeed, pretreatment use of inhaled corticosteroids was significantly lower among patients receiving salmeterol, as was the total cost of asthma-related care. Although our primary findings were unchanged when we controlled for selected demographic and pretreatment differences between groups, other differences might have remained for which we did not adequately control. We identified patients using inhaled corticosteroids based on the presence of one or more and two or more relevant claims during pretreatment and follow-up, respectively; attempts to use more restrictive criteria would have resulted in large reductions in sample size. Although we included patients in our sample with infrequent use of corticosteroids, there is precedent for our methods. The results of a Canadian study of prescription claims suggest that only about 7.5% of persons using inhaled corticosteroids would meet criteria for regular use (i.e., prescriptions filled at least every 90 days). 9 In another study of the effects of inhaled corticosteroid use on asthma-related hospitalization, using data from a large managed-care organization, the mean annual number of prescriptions for inhaled corticosteroids was estimated to be Treatment groups were defined on the basis of one or more claims for study therapy; our sample therefore included patients with infrequent use of study medications over 12 months of follow-up. To examine this issue, we also conducted analyses of the monthly costs of asthma-related care alter- 152 P&T March 2002 Vol. 27 No. 3

5 Table 4 Costs of Asthma-related Medications and Health Care Services During Follow-up Type of Salmeterol+ LTM+ Difference ([Sal- Medication/ ICS ICS meterol+ics] Service (n=259) (n=106) [LTM+ICS]) Mean per Month (SE), $ Estimate (95% CI) Medications Salmeterol 28 (1) 3 (1) 25 (21, 27) Montelukast 2 (0) 4 (1) -2 (-5, 1) Zafirlukast 2 (0) 31 (2) -29 (-33, -25) Zileuton 0 (0) 1 (0) -1 (-2, 0) Oral 0 (0) 0 (0) 0 (0, 0) Inhaled 35 (2) 39 (3) -5 (-13, 3) Oral 1 (0) 3 (1) -2 (-4, 0) Inhaled 7 (1) 12 (1) -5 (-8, -2) Xanthine derivatives 2 (0) 3 (1) -1 (-4, 1) Miscellaneous agents 2 (1) 1 (1) 1 (-1, 3) Total medication 79 (3) 98 (5) -20 (-33, -7) Outpatient care Physician office visits 12 (1) 16 (2) -5 (-11, 1) Emergency-room visits 6 (1) 6 (2) 0 (-6, 6) Hospital outpatient visits 1 (0) 1 (0) 0 (-1, 1) Total outpatient care 19 (2) 23 (4) -4 (-14, 5) Inpatient Care 4 (2) 7 (5) -3 (-16, 7) Total Asthma-Related Care 101 (4) 128 (9) -26 (-51, -4) NOTE: sum of component costs might not equal total because of rounding. ICS= inhaled corticosteroids; LTM= leukotriene modifiers; CI= confidence intervals. natively among patients with two or more (n=339) and four or more (n=276) paid claims for study therapy. Findings were similar to those reported herein. The number of patients who received salmeterol and one or more leukotriene modifiers during follow-up (and vice versa) was not inconsequential. Inclusion of these crossover patients in the study had the potential to modify the effects we observed. To address this, we replicated our analyses excluding crossover patients. A total of 289 (79.2%) of the 365 patients in our original sample met this criterion (n=203 and 86 for salmeterol and leukotriene modifiers, respectively). The difference in mean monthly costs of asthma-related care was similar to that observed in our original analyses ($89 [±$4] vs. $116 [±$9] for salmeterol and leukotriene modifiers, respectively). The use of asthma-related medications was assessed based on information on the numbers of paid prescription claims and corresponding therapy-days dispensed. These data, therefore, reflect the amount of medication purchased by patients, not that which was actually taken. The accuracy of this method of measuring adherence to prescribed medication varies considerably by disease and medication Our estimates might also be subject to errors in the coding of claims. Finally, although our findings were based on a broad cross section of patients and health plans from a large insurer, our results might not be generalizable to any given setting (e.g., an inner-city health clinic); we also excluded patients aged 65 years or older, as the database includes only a small number of such persons. Despite these limitations, we believe that our study has important implications. To the best of our knowledge, it is the first to examine the economic impact of salmeterol versus leukotriene modifiers as add-on therapy to inhaled corticosteroids. Our findings suggest that in a real world clinical setting, the use of salmeterol in combination with inhaled corticosteroids offers meaningful cost savings and reductions in the need for rescue medication compared to treatment with leukotriene modifiers plus inhaled corticosteroids. Our study supports results from randomized controlled trials that have demonstrated the benefits of salmeterol relative to leukotriene modifiers. 5 Acknowledgements We wish to thank John Edelsberg, MD, MPH for his contributions to this study. We also thank Erin Richardson and Sheila Ercolini for their assistance in the preparation of this manuscript. REFERENCES 1. Centers for Disease Control and Prevention. Surveillance for asthma United States, MMWR 1998;47(SS-1): Centers for Disease Control and Prevention. 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