|Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain
|Rutten-van Molken M P, Oostenbrink J B, Miravitlles M, Monz B U
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The study considered three bronchodilators for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Specifically, tiotropium (a long-acting inhaled anticholinergic), salmeterol (an inhaled beta-2-agonist) and ipratropium (a short-acting inhaled anticholinergic).
Economic study type
Cost-effectiveness analysis and cost-utility analysis.
The study population comprised patients with stable moderate-to-severe COPD who had a forced expiratory volume in 1 second (FEV1) of less than 65% (salmeterol controlled trials < 60%) of predicted normal and 70% of forced vital capacity. In total, 1,308 patients were allocated to receive tiotropium, 711 to placebo, 405 to salmeterol and 179 to ipratropium.
The setting was primary and secondary care. The economic analysis was carried out in Spain.
Dates to which data relate
The baseline effectiveness data used to populate the model came from studies published between 2001 and 2005. The health resource use data came from two studies published in 2002 and 2003. The price year was 2005.
Source of effectiveness data
The clinical parameters associated with the model included the transition probabilities for the different stages of COPD (including death) and the reduction in the number of exacerbations.
A Markov model was used to model disease progression. The model was based on one developed by Oostenbrink et al. 2005 (see 'Other Publications of Related Interest' below for bibliographic details). The time horizon was 5 years and a 1-year cycle duration was used. Three disease states were defined. These were moderate COPD, severe COPD and very severe COPD. In each heath state, the patient was at risk of experiencing exacerbations. In addition, a "death rate" was added to the model. The 5-year model was used to run three scenarios with different assumptions on transition and exacerbation probabilities for years 2 to 5.
In scenario 1, the decline in FEV1 after the first year was assumed to be 52 mL/year in all treatment groups and the exacerbation rate remained the same (base-case scenario).
In scenario 2, both transition and exacerbation probabilities of the first year were assumed to remain constant during years 2 to 5.
In scenario 3, the disease progression and exacerbation rate were assumed not to differ between treatment groups after the first year.
In addition, no differences between treatment groups in terms of mortality rate were assumed.
Cumulative costs and utility outcomes were reported for each scenario. Model parameters, base-case and ranges were reported in full in the paper.
Sources searched to identify primary studies
The clinical effectiveness data were derived directly from 6 clinical trials. The baseline distribution of patients was based on a Spanish study, but the design of the clinical studies was not reported.
Methods used to judge relevance and validity, and for extracting data
The process used to estimate the data was not reported. The studies used to populate the model shared the same inclusion criteria, although this was not explicitly stated. In addition, the method used to select the estimates was neither reported nor discussed. However, the method used to combine data from the primary studies was reported. For example, transition and exacerbation probabilities for tiotropium were based on the pooled patient-level data from all 6 clinical trials.
Measure of benefits used in the economic analysis
The measures of benefit used were exacerbations, exacerbation-free months and quality-adjusted life-years (QALYs).
The study reported direct costs to the NHS. Resources for maintenance therapy included visits to respiratory physicians inside and outside of the hospital, visits to the general practitioner, pulmonary function tests, blood tests, imaging tests and respiratory medications. Resources associated with a non-severe exacerbation included general practitioner and respiratory physician visits and medications. Besides physician visits and outpatient medications, resources associated with severe exacerbations also included hospital admissions and visits to the emergency room (ER). The cost of absence from work due to illness from the 16th day of sick leave onwards was also included in the analysis. The costs of pulmonary function and other tests, as well as medications that were prescribed during inpatient stay or during ER visits, were not measured separately because they were included in the overall cost per inpatient day and the costs per ER visit.
Resource use and the unit costs were reported separately. The unit costs of health care resources were obtained from the SOIKOS health database and updated to 2005 using the Spanish General Consumer Price Index. The acquisition costs of pulmonary drugs from the NHS perspective were based on public prices and calculated as the ex-factory prices multiplied by a mark-up of 1.596 to convert these prices to public prices. The co-payment of 10% of the public price for people in the work force was excluded. From a societal perspective, the drug costs included co-payment but excluded the 4% value added tax that is included in public prices. The costs were reported as the average cost per patient. The price year was identified (2005). A discount rate of 6% was applied, which was appropriate given the time horizon considered for the estimation.
Statistical analysis of costs
No statistical analyses were conducted as the objective of the study was to produce cost-effectiveness and cost-utility measures.
In addition to the base-case perspective, an analysis from the societal perspective was also performed. In line with this further perspective, lost production from all days of absence from paid work was included. This was valued as the average labour cost per day in Spain.
Parametric uncertainty was investigated through probabilistic sensitivity analysis. All the parameters in the model were assigned prior probability distributions, and second order Monte Carlo simulations were conducted (5,000 iterations). No expected value-of-information analysis was performed. A sensitivity analysis on the discount rate was also conducted.
Estimated benefits used in the economic analysis
The mean number of exacerbations in 5 years was 3.50 (standard error, SE=0.14) in the tiotropium group, 4.16 (SE=0.40) in the salmeterol group and 4.71 (SE=0.54) in the ipratropium group.
The mean number of exacerbation-free months was 46.83 (SE=1.11) in the tiotropium group, 45.29 (SE=2.12) in the salmeterol group and 44.89 (SE=2.86) in the ipratropium group.
Estimates of the number of QALYs were 3.15 (SE=0.08) in the tiotropium group, 3.02 (SE=0.15) in the salmeterol group and 3.00 (SE=0.20) in the ipratropium group.
Applying the first-year probabilities to all subsequent years (scenario 2) increased the difference in exacerbation-free months between tiotropium and the other treatment groups to approximately 2.0 and the difference in QALYs to approximately 0.19.
Assuming similar exacerbation probabilities across treatment groups in year 2 to 5 (scenario 3), the difference in exacerbation-free months between tiotropium and the other treatment groups was just above 1 and the difference in QALYs was about 0.13. There was almost no difference in health outcomes between ipratropium and salmeterol in this scenario.
In the base-case scenario, from the NHS perspective, the mean total costs over 5 years were lowest in the ipratropium group at EUR 5,181 (SE=682) per patient.
The costs were EUR 5,869 (SE=505) in the salmeterol group and EUR 6,424 (SE=305) in the tiotropium group.
Owing to a smaller difference in exacerbation rate between treatment groups in scenario 3, the difference in total costs between ipratropium on the one hand and tiotropium and salmeterol on the other hand increased by 64% and 75%, respectively.
The impact of applying the first-year transition probabilities to years 2 to 5 on the 5-year differences in costs between treatment groups was much less.
From the societal perspective, the overall mean costs increased in all treatment groups to EUR 6,574 (SE=321) for tiotropium, EUR 6,125 (SE=541) for salmeterol and EUR 5,545 (SE=720) for ipratropium.
Synthesis of costs and benefits
In the base-case scenario, from the NHS perspective, estimates of the incremental costs per exacerbation-free month were EUR 360 when tiotropium was compared with salmeterol and EUR 1,711 when salmeterol was compared with ipratropium. The corresponding incremental costs per QALY were EUR 4,118 and EUR 38,931, respectively.
The comparisons between tiotropium showed that 65% of the simulations lay in the upper-right quadrants of the cost-effectiveness planes, signifying better health outcomes and higher costs for tiotropium. The cost-effectiveness planes comparing salmeterol with ipratropium showed that 35% of the simulations were found in the upper-left and about 45% in the upper-right quadrant, signifying similar health outcomes and higher costs of salmeterol.
The cost-effectiveness acceptability curves showed that, in terms of exacerbation-free months, ipratropium had the highest probability of being cost-effective when the threshold per additional exacerbation-free month was below EUR 1,050.
In terms of QALYs, ipratropium had the highest probability of being cost-effective for a cost per QALY below EUR 11,000. Above these values tiotropium had the highest probability of being cost-effective.
For any ceiling ratio above EUR 639 per exacerbation-free month and above EUR 8,157 per QALY, tiotropium was the preferred treatment option. In scenario 2, these threshold values were lower at EUR 551 and EUR 6,226, respectively. The corresponding values for scenario 3 were EUR 1,918 and EUR 15,635, respectively.
From a societal perspective, the incremental cost per exacerbation-free month was reduced to EUR 308 for tiotropium versus salmeterol and to EUR 1,375 for salmeterol versus ipratropium.
The incremental cost per QALY was reduced to EUR 3,483, for tiotropium versus salmeterol and to EUR 35,158 for salmeterol versus ipratropium.
Tiotropium had the highest expected net benefit for any value of the cost-effectiveness threshold above EUR 547 per exacerbation-free month and above EUR 7,076 per QALY. Below these values ipratropium was the preferred option.
When the model was run separately for patients with moderate, severe or very severe COPD, the threshold values for the costs per QALY above which tiotropium became the preferred option were EUR 7,600 for moderate COPD, EUR 8,800 for severe COPD and EUR 12,500 for very severe COPD. Below these values ipratropium was preferred.
Tiotropium had the highest expected net benefit when the ceiling ratios for cost per exacerbation-free month were EUR 560 for moderate COPD, EUR 700 for severe COPD and EUR 1,200 for very severe COPD. Below these values ipratropium had the highest expected net benefit.
Tiotropium demonstrated the highest expected net benefit for ratios of the willingness-to-pay per quality-adjusted life-year (QALY) that were well within accepted limits.
CRD COMMENTARY - Selection of comparators
The rationale for the choice of the comparators was clear in that they represent standard practice in Spain. You should decide whether this applies to your own setting.
Validity of estimate of measure of effectiveness
The authors combined data from an existing model with data from published clinical studies. No systematic search for data was reported. From the information provided in the present paper it is not possible to make an objective assessment of the validity of the data.
Validity of estimate of measure of benefit
The estimation of health benefits was modelled. Exacerbations and exacerbation-free months would appear to be valid measures of benefit for the disease. QALYs were an appropriate measure because they capture the impact of the intervention on quality of care and survival, which are the most relevant dimensions of health. Utility weights were derived using the EuroQol 5D. EuroQol 5D scores were valued using the Spanish tariff.
Validity of estimate of costs
The analysis of the costs was consistent with the perspectives adopted in the study. The price year and the source of the data were provided. Resource use reflected the actual pattern of treatment in Spain. Moreover, the costs were likely to be specific to that country, although this might, to some degree, have been overcome by the sensitivity analyses. Resource use and the costs were reported separately, thus enhancing the transferability to other settings. Discounting was applied.
The authors compared their results extensively with those of published studies. They stated that this research agreed with the conclusions that health benefits gained with tiotropium are achieved at almost no additional cost, or at costs that appear reasonable and acceptable, given other adopted treatments. The authors addressed the issue of the generalisability of their results to other settings. The results of the study do not appear to have been presented selectively. No further limitations of the study were reported. The authors' conclusions would appear to be an adequate reflection of the scope of the analysis.
Implications of the study
The study suggests that tiotropium is the treatment with the highest expected net benefit, if decision-makers can afford to spend additional budget to gain additional health benefits.
Source of funding
Supported by Boehringer Ingelheim International and Pfizer Global Pharmaceuticals.
Rutten-van Molken M P, Oostenbrink J B, Miravitlles M, Monz B U. Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain. European Journal of Health Economics 2007; 8: 123-135
Other publications of related interest
Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information.
Oostenbrink JB, Rutten van Molken MP, Monz BU, FitzGerald JM. Probabilistic Markov model to assess the cost effectiveness of bronchodilator therapy in COPD patients in different countries. Value Health 2005;8:32-46.
Decramer M, Celli BR, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, et al. Clinical trial design considerations in assessing long term functional impacts of tiotropium in COPD: the Uplift trial. J Chron Obstruct Pulm Dis 2004;1:303-12.
Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. Eur Respir J 2001;17:928-33.
Miravitlles M, Murio C, Guerrero T, Gisbert R. Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD. Chest 2002;121:1449-55.
Subject indexing assigned by NLM
Albuterol /analogs & Bronchodilator Agents /economics /therapeutic use; Cost-Benefit Analysis; Humans; Ipratropium /economics /therapeutic use; Markov Chains; National Health Programs; Pulmonary Disease, Chronic Obstructive /drug therapy; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives /economics /therapeutic use; Spain; Tiotropium Bromide; derivatives /economics /therapeutic use
Date bibliographic record published
Date abstract record published