technology overview hta overview of long-acting …cite as: mayers i, jacobs p, marciniuk dd, chuck...

Supporting Informed Decisions

Overview of Long-acting ß2-agonists (LABA) plus Corticosteroids versus LABA Alone for Chronic Obstructive Pulmonary Disease

t e c h n o l o g y o v e r v i e w

Canadian Agency forDrugs and Technologies

in Health

Agence canadienne des médicaments et des technologies de la santé

HTAIssue 28

March 2007

469_1Page-Cover_TechOverview.ai 3/23/2007 11:28:53 AM

Until April 2006, the Canadian Agency for Drugs and Technologies in Health (CADTH) was known as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA).

Cite as: Mayers I, Jacobs P, Marciniuk DD, Chuck A, Varney J. Overview of long-acting ß2-agonists (LABA) plus corticosteroids versus LABA alone for chronic obstructive pulmonary disease [Technology Overview no 28]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007. Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CADTH. CADTH is funded by Canadian federal, provincial, and territorial governments. Legal Deposit – 2007 National Library of Canada ISSN: 1203-9012 (print) ISSN: 1481-4501 (online) H0469 – March 2007 PUBLICATIONS MAIL AGREEMENT NO. 40026386 RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH 600-865 CARLING AVENUE OTTAWA ON K1S 5S8

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Canadian Agency for Drugs and Technologies in Health

Overview of Long-acting ß2-agonists (LABA) plus Corticosteroids versus LABA Alone for Chronic

Obstructive Pulmonary Disease

March 2007

We thank Jeannine Fraser for her assistance in creating this overview from a longer report authored by I. Mayers et al. This overview is based on a Technology Report by: Mayers I, Jacobs P, Marciniuk DD, Chuck A, Varney J. Long-acting ß2-agonists (LABA) plus corticosteroids versus LABA alone for chronic obstructive pulmonary disease [Technology report no 83]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007. CADTH takes sole responsibility for the final form and content.

REPORT IN BRIEF March 2007

Long-acting ß2-agonists (LABA) plus Corticosteroids versus LABA Alone for Chronic Obstructive Pulmonary Disease

Technology and Condition Combination therapy (CT) of an inhaled long-acting β2-agonist (LABA) with an inhaled corticosteroid (ICS) in patients diagnosed with chronic obstructive pulmonary disease (COPD).

Issue COPD affects at least 3.2% of the adult population and leads to significant associated health care costs. CT has been recommended in clinical practice, yet there is uncertainty about the cost-effectiveness of this approach and its potential budgetary impact.

Methods and Results Three relevant randomized controlled trials were identified through a systematic literature review. Estimates of changes in exacerbation, serious adverse events, and mortality rates were then derived. Using a Markov model, the three-year and lifetime cost-effectiveness of CT compared with LABA alone was estimated for four disease-management strategies. With Strategy 1 (base case), all patients were treated with LABA. With Strategy 2, in addition to the base case, ICS was given to patients with Stage-3 disease only. With Strategy 3, in addition to the base case, ICS was given to patients with Stage-2 and Stage-3 disease only. With Strategy 4, in addition to the base case, ICS was given to all patients. The budget impact of switching patients from LABA to CT was conducted based on Alberta utilization data.

Implications for Decision Making • CT in all COPD stages is more effective than

LABA alone. Available evidence suggests that CT results in fewer overall exacerbations and improved quality of life measures, compared with treatment by LABA alone. There is no evidence to suggest that mortality differs with different strategies.

• Different treatment strategies will vary in

cost-effectiveness. The lifetime cost of using a LABA (discounted at 5%) is C$9,636 per COPD patient. Adding an ICS for the most severe patients (strategy 2) results in an increase of C$93 per patient; strategy 3 increases costs by an additional C$321; and strategy 4 increases costs by C$3,120. Each strategy is associated with an additional increase of 0.01 quality-adjusted life year (QALY) per patient. Strategies 2 and 3 may be perceived as cost-effective by those who are prepared to pay up to C$50,000 for a QALY.

• CT requires additional resources. Switching

all patients who are >65 years old and only receive a LABA without an ICS to CT treatment would require, by extrapolation, an additional C$3.3 million in Alberta, and C$43.7 million nationally.

This summary is based on a comprehensive health technology assessment available from CADTH’s web site (www.cadth.ca): Mayers I, Jacobs P, Marciniuk DD, Chuck A, Varney J. Long-acting ß2-agonists (LABA) plus corticosteroids versus LABA alone for chronic obstructive pulmonary disease.

Canadian Agency for Drugs and Technologies in Health (CADTH) 600-865 Carling Avenue, Ottawa ON Canada K1S 5S8 Tel: 613-226-2553 Fax: 613-226-5392 www.cadth.ca

CADTH is an independent, not-for-profit organization that supports informed health care decision making by

providing unbiased, reliable information about health technologies.

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1 Introduction Chronic obstructive pulmonary disease (COPD) restricts airflow to the lungs, making it difficult for those affected to breathe and perform daily activities. It reduces quality of life, causes significant morbidity and mortality. Worldwide, it is the fourth leading cause of death.1 It is a progressive disease2 that requires increased medical treatment as the number and severity of symptoms increase, and lung function worsens.1 Smoking is the most important risk factor in the development of COPD, but certain work-related dusts, noxious fumes, and gases are also considered to be risks.2 COPD can be classified into stages of increasing severity according to a patient’s level of pulmonary function1,3 or magnitude of symptoms.2 Symptoms increase in frequency and severity as the disease progresses, and include difficulty breathing, increased production of sputum, inflammation, cough, and a decreased tolerance for activity.2 Patients with COPD can experience episodes during which their symptoms suddenly worsen to the extent that they require an increase in their medication or the administration of an additional medication. These episodes are called acute exacerbations. They range from mild, requiring minor changes to the patient’s pharmacologic therapy, to severe, requiring emergency room treatment or hospitalization. As the disease progresses, exacerbations occur more often and are the main reason for medical visits, hospital admissions, and death among patients with COPD.4 Exacerbations adversely affect the patient’s quality of life; significant mortality is linked to frequent, severe exacerbations. Exacerbations accelerate the rate of decline in lung function, and are associated with quality of life.2 COPD can be managed, and there are effective treatments for preventing exacerbations and reducing their severity when they occur. The goals of COPD management include preventing disease progression, alleviating breathing and other respiratory symptoms, improving exercise tolerance, preventing and treating exacerbations, improving health status, and reducing associated mortality. Several treatments are used to achieve these goals. Long-acting-ß2-agonists (LABA) and inhaled corticosteroids (ICS) are interventions that can improve lung function in patients with COPD. LABAs are bronchodilators,5 and ICS prevent inflammation of the airways.6 When used together, the two therapies produce synergistic anti-inflammatory effects.7-10 When combined, they are known as combination therapy (CT). In CT, inhaled LABA can be combined with ICS in one inhaler, or the two can be in separate inhalers but administered together. The severity of COPD can be staged according to pulmonary function, as measured by forced expiratory function (FEV1). Stage 1 disease is defined as FEV1 ≥50% of the predicted value. Stage 2 disease is a FEV1 ≥35 to <50%. Stage 3 disease is an FEV1 <35% of the predicted value.11 There is evidence that CT is better at reducing symptoms when compared with its components in patients with stage 2 and stage 3 disease1,3. The Canadian Thoracic Society recommends CT for COPD patients with decreased lung function (FEV1 <50%) who experience ≥3 exacerbations per year.2 While CT may be more beneficial than LABA for clinical manifestations, it is also more expensive. According to the Alberta Health and Wellness Drug Benefit List and Formulary, an average daily dose of LABA combined with ICS costs C$2.80, compared with LABA alone at C$1.61.12 Comparative information on the costs and the consequences of therapy on health, and on health care resources, is needed for guiding rational decisions about the use of these agents.

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2 Objectives • To determine the cost-effectiveness of CT versus LABA alone as a first-line agent in the

treatment of COPD in Canada. • To measure the global economic impact of introducing CT versus LABA in Canada. 3 Economic Analyses

Methods a) Effectiveness A comprehensive literature search was conducted, using appropriate descriptors and key words, to identify clinical and economic studies related to the use of LABA and ICS for patients with COPD. Bibliographical databases were searched, including: PubMed; Medline®; EMBASE®; HealthSTAR®; the Web of Science; International Pharmaceutical Abstracts; databases from the Centre for Reviews and Dissemination, including DARE, NHS EED, and HTA; and the Cochrane Register of Controlled Trials. The original search was performed in March 2005 and updated at the end of March 2006. The bibliographies of articles that were identified were hand searched for additional studies. b) Selection Process Results from the literature search were reviewed independently by two researchers to see if they contained information necessary for the economic analysis. Studies were selected for further review and potential inclusion only if they were randomized controlled trials of patients with COPD that included treatment arms for CT and LABA, and reported on exacerbations and mortality rates. Disagreement regarding the inclusion or exclusion of any report was resolved by discussion and consensus. The quality of selected studies was assessed using the Jadad scoring form. Data on intervention, and the efficacy of LABA and ICS were extracted. These data were used to estimate model parameters for the economic analysis. Cost-effectiveness A cost-utility analysis was conducted using a decision-analytic Markov model. The model was developed a priori, and input values relating to probabilities and health states were obtained from the relevant reports that were identified through the systematic literature search. The model simulates the natural progression of disease in patients with COPD. It calculates cost and utility in a cohort of patients using CT or LABA alone. The analysis was conducted from a public-payer perspective, and the cost data were based on Alberta health care costs. The model assumed an initial cohort of patients distributed over three levels of severity and evaluated the effects of CT using four strategies (Table 1). Costs and utilities derived from the literature were assigned to disease stages and to exacerbations.

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Table 1: Disease-management strategies for COPD Strategy Population Treatment Received

1 all patients LABA (base case) 2 stage 3 patients CT 3 stage 2 and stage 3 patients CT 4 all patients CT

For each strategy, all patients were followed for three years in three-month cycles. For each three-month period, the probabilities for death and exacerbation were applied to each cohort in each disease category. From one three-month cycle to the next, a small proportion of patients moved into a higher disease-severity level, based on the expected declines in FEV1. Patients who died during the three-month period were excluded from further analysis. The survivors of each three-month cycle continued through another cycle, and a similar set of probabilities for survival, exacerbation, and disease progression was applied. A total of 12 three-month cycles translated into 36 months of follow-up. All analyses were conducted using TreeAge Pro Suite (TreeAge Software Inc., Williamstown, MA). Sensitivity Analysis All key variables were simultaneously tested in a probabilistic sensitivity analysis using values within the limits of their variability. When estimates of the variability could not be found in the literature, a range of ±10% of the base values was used for the upper and lower limits. The results were reported as acceptability curves for 3% and 5% discount rates.13 A separate sensitivity analysis was conducted on the quality-adjusted life-year (QALY) decrement, associated with a moderate and a severe exacerbation at a 5% discount rate, using the three-year model. Budget-impact Analysis The impact on Alberta’s health care services of switching LABA users to CT and adopting CT for those who were not using LABA or CT, was assessed. The year-end data from the Alberta provincial drug plan for 200314 were used to determine the number of people >65 years old who had prescriptions indicative of COPD. Based on these data, a utilization analysis was derived for the following therapeutic alternatives: • situation at year-end 2003, as described by Alberta Health and Wellness • use of CT instead of LABA (for those who had used LABA) • use of CT for those who used LABA, and might switch to CT, and for those who previously

used neither CT nor LABA, but might add CT. Cost estimates were developed for each alternative, assuming an annual provincial cost of C$587 for LABA and C$1,011 for CT. People >65 years old who were prescribed ipratropium were assumed to have COPD. People with COPD who were not prescribed ipratropium, CT, ICS, or LABA were excluded, as were those with asthma but not COPD who were prescribed tiotropium.

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4 Results Three trials satisfied the inclusion criteria,15-17 and all were judged to be of sufficiently high quality to create estimates of effectiveness (Jadad score >2). Two studies18,19 rated four out of a possible five, and one20 scored five points on the Jadad scale. No differences in serious adverse events between groups were noted in the studies, and mortality rates were similar for both interventions. The overall frequency of recorded adverse events was similar between the LABA group and the combined LABA with ICS group (19% and 17% respectively); they tended to be lower (26%) than the placebo group21. Calverley et al.22 found a lower overall incidence of adverse events (0.5%, 0.6%, and 0.5% respectively). The pooled relative risk of an exacerbation for CT compared with the relative risk with LABA was 0.752, representing a reduction in risk for the CT group. The initial cohort was composed of males (79%) and females (21%) aged 61 years old, most of whom were current or former smokers (97%).23 Patients were divided into three increasingly serious stages of disease based on lung function, measured as forced expiratory volume in one second (FEV1). According to the American Thoracic Society,11 a person in stage 1, the mildest stage, would have a FEV1 ≥50.0% of the predicted value; a person in stage 2 would have a FEV1 between 35.0% and 49.9% of the predicted value (moderate); and a person at stage 3 would have a FEV1 <35.0% of the predicted value. This is the most serious stage. Based on estimates from the Third National Health and Nutrition Examination Survey,24 97% of patients in the model had stage 1 disease; 4% were at stage 2; and 3%, stage 3. Progression from stage 1 to stage 2 was estimated to be 0.74% during a three-month period, while the estimated probability for a person in stage 2 moving into stage 3 was 2.48%. These estimates were based on assumptions about the mean rate of FEV1 reduction.25 In each of the three disease stages, patients were categorized into those expected to experience mild, moderate, or severe exacerbations. Mild exacerbations are defined as a worsening of symptoms requiring outpatient physician services, and institution of medications or antimicrobials. Moderate exacerbations are clinical episodes requiring emergency department services, or urgent visits to a physician’s office, including the institution of exacerbation therapy. Severe exacerbations are those requiring inpatient care, including institution of exacerbation therapy.11 The number of exacerbations associated with the use of LABA was estimated from the studies reviewed, and applied to each level of each disease stage according to the expected distribution of patients. The estimates for CT rates were calculated by applying one relative reduction rate to the LABA values. The total expected number of exacerbations per person for all severities annually, per health state, was 0.17 for stage 1, 0.59 for stage 2, and 0.83 for stage 3.26 In stage 1, 97.3% of exacerbations were assumed to be mild, while 74% in stage 2 were assumed to be moderate or severe. For patients in stage 3, it was assumed that 30% of exacerbations would require hospitalization.23 The mortality rates vary by disease stage. Only studies about ICS reported mortality by stage because there was no evidence to suggest that mortality differed by intervention. These rates were used for LABA and CT. All-cause mortality rates were estimated to be 3.92% for stage 1, 6.16% for stage 2, and 9.24 % for stage 3 disease.27

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The health-related quality of life was the outcome measure used. A QALY value was obtained for the duration of each of the three stages. Each time a person had an exacerbation, the average utility was reduced by a specified amount for that three-month cycle. The costs for LABA and CT were obtained for each level of the three disease stages for recommended Canadian doses,28 based on the Alberta Health and Wellness Drug Benefit List formulary.12 All costs were revalued as of 2004, using Alberta levels. The costs included the cost of drug therapy plus maintenance (routine care) and treatment of exacerbations. Maintenance costs were adjusted to account for exacerbations, and costs were discounted at annual rates of 3% and 5%. The model assumed that lung function (FEV1) would decline over time,25 and that with this decline, exacerbations would occur more frequently and be more severe, and that mortality rates would increase. Cost-effectiveness Analysis The results of the model for all the time horizons and discount values appear in Table 2, as do the results for a lifetime horizon with 5% discount. For example, these results indicate that CT for moderate or severe patients (versus LABA alone) would result in an extra cost of C$321 per person for an incremental utility of 0.01 QALY. This represents C$26,357 per additional QALY (discounted at 5%) over an individual’s lifetime, versus using LABA alone. Sensitivity Analysis The results of the probabilistic analysis are presented as an acceptability curve for the lifetime model discounted at 5% (Figure 1). It shows that, at a threshold level of C$50,000, there is a high probability that providing CT instead of LABA is cost-effective for people with stage 3 alone, or for people with stage 2 or stage 3 COPD. This is not true for the provision of CT for all people with COPD. The separate sensitivity analysis on the QALY decrement associated with a moderate and severe exacerbation indicates that, starting with LABA for all cases and providing CT for COPD stage 3, the incremental cost-effectiveness ratio would be C$10,071 per QALY. The marginal incremental cost-effectiveness ratio for providing CT for stages 2 and 3 is C$33,620 per QALY and C$272,120 per QALY for all stages. Budget-impact Analysis Table 3 shows the number of people >65 years old who used COPD-related drugs in Alberta in 2003. The estimated cost of LABA plus combination therapies, excluding the costs of ipratropium, was C$18,017,000 for 20,946 people. If the 7,449 people who were taking LABA switched to CT, the system-wide drug costs for CT would be C$21,340,000 (an increase of about C$3.3 million). If some of the people using LABA were mild cases (in stage 1, for example), then the total number switching to CT would be smaller. Although the number of people in the sample at stage 1 is unknown, it is assumed to be small. If all people who were taking ipratropium (but neither LABA nor CT) also took CT, the budget for CT drugs would exceed C$60 million. While there is no way of knowing how many people in stages 2 and 3 were taking ipratropium, the percentage is probably high.

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Table 2: Results for base case

Treatment Scenario Cost Per Patient (C$)

Incremental Cost (C$) QALY Incremental

QALY Incremental Cost-

effectiveness Ratio (C$) Three-year time horizon with 5% discount rate

LABA for all stages $3,719 N/A 2.405 N/A N/A combination therapy for stage 3 only $3,743 $24 2.408 0.00248 $9,670 per QALY

combination therapy for stages 2 and 3 $3,829 $86 2.411 0.00272 $31,606 per QALY

combination therapy for all stages $5,173 $1,344 2.416 0.00495 $271,241 per QALY

Three-year time horizon with 3% discount rate LABA for all stages $3,818 N/A 2.406 N/A N/A combination therapy for stage 3 only $3,843 $25 2.408 0.00248 $10,073 per QALY



Lifetime horizon with 5% discount rate LABA for all stages $9,636 N/A 6.763 N/A N/A combination therapy for stage 3 only $9,729 $93 6.775 0.01187 $7,829 per QALY



Lifetime horizon with 3% discount rate LABA for all stages $10,493 N/A 6.763 N/A N/A combination therapy for stage 3 only $10,597 $104 6.775 0.01187 $8,754 per QALY



N/A=not applicable.

Table 3: Results of budget impact analysis, Alberta 2003 Group Number in

Province Scenario 1

Cost According to 2003 Alberta Data*

Scenario 2 All Persons Who Take LABA Switch to CT*

All Persons Who Take LABA or Ipratropium

Alone Start to Take CT* persons who were dispensed CT

13,497 C$13,645,000 C$13,645,000 C$13,645,000

persons who were dispensed LABA but not CT

7,449 C$4,372,000 C$7,695,000 C$7,695,000

persons who were dispensed ipratropium but not LABA or CT

38,118 N/A N/A C$38,965,000

Total cost of CT and LABA

C$18,017,000 C$21,340,000 C$60,305,000

*unit cost of CT was C$1,011 per annum, and unit cost of LABA was C$587 per annum (Table 1). N/A=not applicable.

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Figure 1: Acceptability curve for lifetime model

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80 90 100 110 120

Willingness-to-Pay (C$Thousands)

Prop

ortio

n C

ost-

Eff

ectiv

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All Stages Get ComboCombo to Stage 2 or 3 OnlyCombo to Stage 3 Only

Conducted at a 5% discount rate;Combo=combination therapy (CT).

According to the Canadian Respiratory Society COPD guidelines, people with COPD should be prescribed a short- or longer-acting β2-agonist, rather than switching directly to CT. This would moderate the budget impact, making C$60 million an overestimate. Although the budget impact of moving from LABA to CT is moderate, the impact of providing CT to those additional persons who take neither could be considerable. The population in Canada who are >65 years old (4.3 million) is 12.5 times that of Alberta (346,000). Therefore, the budget impact for Canada would be in the range of 12.5 times the impact on Alberta, and the additional cost of switching from LABA to CT for those taking LABA would be approximately C$43.7 million nationally. Limitations There are several limitations to this analysis. Only three good-quality trials have prospectively examined the effects of CT on exacerbation frequency in COPD. None of the trials directly examined the effects in the mildest COPD population. Health Systems Implications Extrapolating the data from Alberta, the additional cost of switching from LABA to CT for those taking LABA would be approximately C$43.7 million nationally.

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5 Conclusions The results indicate that CT administered to moderate and severe COPD patients may be perceived as cost-effective, if the health system is prepared to pay up to C$50,000 for a QALY. The budgetary impact analysis indicates that additional resources would be required to realize the benefit of implementing our recommendations, but a reduction in the use of other health care resources could compensate for some of the difference. 6 References

1. Global Initiative for Chronic Obstructive Pulmonary Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Executive Summary: Updated 2005. Bethesda (MD): Global Initiative for Chronic Obstructive Pulmonary Disease; 2005.

2. O'Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2003. Can Respir J 2003;10(Suppl A):11A-65A.

3. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23(6):932-46.

4. Burrows B, Earle RH. Course and prognosis of chronic obstructive lung disease: a prospective study of 200 patients. N Engl J Med 1969;280:397-404.

5. Shukla VK, Husereau DR, Boucher M, et al. Long-acting b2-agonists for maintenance therapy of stable chronic obstructive pulmonary disease: a systematic review [Technology report no 27]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2002.

6. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Executive summary: updated 2003. Bethesda (MD): Global Initiative for Chronic Obstructive Lung Disease, World Health Organization/National Heart, Lung, and Blood Institute; 2003.

7. Johnson M. The b2-adrenoceptor. Am J Respir Crit Care Med 1998;158(146):153.

8. Johnson M. Mechanism of b2-adrenoceptor agonists. In: Busse WW, Holgate ST, editors. Asthma and Rhinitis. Oxford: Blackwell; 2000. p.1541-57.

9. Johnson M. Combination therapy for asthma: complementary effects of long-acting b2-agonists and corticosteroids. Curr Allergy Clin Immunol 2002;15:16-22.

10. Adcock IM, Maneechotesuwan K, Usmani O. Molecular interactions between glucocorticoids and long-acting b2-agonists. J Allergy Clin Immunol 2002;110:261-8.

11. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152(5 Pt 2):S77-S121.

12. Alberta Health and Wellness. Alberta Drug Benefits List. Edmonton: Government of Alberta; 2005.

13. Drummond MF, Sculpher MJ, Torrance GW, et al. Methods for the economic evaluation of health care programmes. 3rd ed. New York: Oxford University Press; 2005.

14. Alberta Health and Wellness. Alberta Health Care Insurance Plan Statistical Supplement 2002/2003. Edmonton: Government of Alberta; 2004.

15. Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22(6):912-9.

16. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21(1):74-81.

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17. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361(9356):449-56.



20. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361(9356):449-56.



23. Sin DD, Golmohammadi K, Jacobs P. Cost-effectiveness of inhaled corticosteroids for chronic obstructive pulmonary disease according to disease severity. Am J Med 2004;116:325-31.

24. Centers for Disease Control and Prevention (CDC). Third National Health and Nutrition Examination Survey (NHANES III), 1988-94. Hyattsville (MD): The Centers; 1996.

25. Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986;133:14-20.

26. Creutzberg EC, Wouters EF, Mostert R, et al. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest 2003;124(5):1733-42.

27. Sin DD, McAlister FA, Man SF, et al. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003;290(17):2301-12.

28. O'Donnell DE, Aaron S, Bourbeau J, et al. State of the art compendium: Canadian Thoracic Society recommendations for the management of chronic obstructive pulmonary disease. Can Respir J 2004;11(Suppl B):7B-59B.

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