Cost-effectiveness of umeclidinium compared with tiotropium and glycopyrronium as monotherapy for chronic obstructive pulmonary disease: a UK perspective

Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive disease characterised by persistent airflow limitation [1, 2]. COPD presents a substantial burden to global public health [3, 4], representing one of the leading causes of hospitalisations and emergency room (ER) visits [3], as well as a leading cause of death worldwide (approximately 3.2 million deaths were attributed to COPD in 2015) [5]. The disease and associated comorbidities contribute significantly to healthcare costs [3, 4], indeed, the financial burden of COPD inevitably correlates with the severity of the disease, with hospital stays accounting for a substantial proportion of the costs [6‐8]. In the UK, direct medical costs associated with COPD have been estimated at £1.9 billion per year [9].

The benefits of appropriate pharmacological therapy in COPD in decreasing symptoms, reducing the need for rescue therapy, decreasing the frequency and severity of exacerbations, and improving health-related quality of life (HRQoL), are well recognised and summarised along with treatment recommendations in the annually updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategic document [2]. Currently, the recommendation for pharmacological treatment of most patients with COPD is bronchodilator monotherapy or dual therapy with long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists (LABAs), depending on disease burden and exacerbation history [2]. These recommendations reflect the central role of bronchodilators in treating COPD [10, 11]. In addition, LAMAs have been reported to be more effective than LABAs in reducing the rate of exacerbations and reducing the time to a first moderate or severe exacerbation in patients with moderate-to-very severe COPD [12, 13].

Umeclidinium 62.5 mcg (UMEC) is a once-daily LAMA delivered via a novel dry-powder inhaler (Ellipta, GlaxoSmithKline, Hertfordshire, UK), which was approved for maintenance treatment of COPD in the UK in 2014 [14], and is currently approved in multiple regions worldwide, including the United States [15], the European Union [16] and Japan [17]. Several studies have reported the efficacy of UMEC monotherapy versus placebo in terms of improved lung function and other outcomes in patients with COPD [18‐20]. Studies have also compared the efficacy of UMEC with that of the other once-daily dry-powder inhaler LAMAs tiotropium 18 mcg (TIO, HandiHaler, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, USA) [21] and glycopyrronium 50 mcg (GLY, Breezhaler, Novartis, Basel, Switzerland) [22]. These studies reported additional improvements in trough forced expiratory volume in 1 s (FEV₁) at Day 85 of 53 and 33 mL, respectively, with UMEC versus the comparators in the randomised intent-to-treat (ITT) populations [21, 22]. However, limited data are available reporting the relative cost-effectiveness of UMEC in a clinical setting or compared with other once-daily LAMA alternatives. In this study, we assessed the cost-effectiveness of UMEC monotherapy compared with other once-daily LAMAs in patients with COPD from a UK National Health Service (NHS) perspective.

This study showed that UMEC provided gains in LYs and QALYs, and numerical reductions in moderate and severe exacerbation rates, compared with both TIO and GLY. The lifetime analysis demonstrated that UMEC dominated TIO, providing improved outcomes with reduced treatment and resource costs. This dominance was maintained when a 5- and 10-year horizon was employed, and across several scenario analyses. However, when price parity was applied, UMEC no longer dominated TIO, with an ICER of £1810/QALY. Results of the scenario analyses showed the model was most sensitive to scenarios in which the duration of treatment was 1 or 3 years, and SGRQ change, while the model was relatively insensitive to discount rate and upper confidence limits for FEV₁ increment, 6MWT and fibrinogen data. In comparison with GLY, results obtained from the lifetime horizon showed that costs associated with UMEC were higher. This could be attributed to the increased drug costs, as well as to the survival benefit associated with UMEC, as patients remained in the model for longer and therefore incurred increased treatment and resource costs. These results were generally consistent across other time horizons and scenario analyses. Nevertheless, UMEC was shown to be cost-effective compared with GLY in most scenarios, with cost-effectiveness falling well below the willingness-to-pay threshold of £20,000–30,000 per QALY set by the NICE guidelines [36].

Data comparing cost-effectiveness of different LAMA monotherapies are scarce. One study compared the cost-effectiveness of TIO with GLY in Sweden [37], and one study compared the cost-effectiveness of these treatment in Canada, Spain, Sweden and the UK [38, 39]. In the former study, GLY was found to be less costly and more effective than TIO as maintenance treatment for patients with moderate to severe COPD in Sweden [37]. In the latter study, TIO generated improved outcomes compared with GLY in all countries, and was cost-saving compared with GLY in Canada and the UK. Costs per QALY were positive for Spain and Sweden; however, the estimated ICERs remained below the respective willingness-to-pay thresholds for each country [38]. The outcomes from this latter study contrast with the results of the current cost-effectiveness analysis. Possible reasons for this could include the use of different efficacy parameters, such as the assessment of treatment efficacy including exacerbation rates in the multi-country study. It is also likely that the relative costs of the different drugs in each country would drive the differences in the cost-effectiveness. Additionally, the multi-country study included data from patients with very severe COPD, while this study excluded such patients who would not be ideal candidates for LAMA monotherapy in accordance with the GOLD 2017 COPD strategy report [40, 41]. An additional advantage of the model used in the current study was that it could integrate multiple factors affecting outcomes in COPD to predict disease progression and economic outcomes [23]. This may enable more accurate predictions than other models commonly used in cost-effectiveness analyses that are based only upon disease progression, with disease severity classified according to measurements of percentage predicted FEV₁ [42].

The efficacy inputs used for this study are based on bronchodilation, as measured by FEV₁ [21, 22]. Improvements in lung function measured by increased FEV₁ can result in better health outcomes and lower COPD exacerbation risk over a longer period [21, 22, 43], and may be responsible for the larger treatment effect observed on the cumulative number of severe versus moderate exacerbations. However, the use of a LAMA as monotherapy is not common, as a large proportion of patients with COPD will step-up to dual bronchodilator therapy with a LAMA/LABA or the combination of a LAMA with inhaled corticosteroid (ICS)/LABA. Studies have shown greater improvements in trough FEV₁ when using a dual LABA/LAMA therapy compared to LAMA monotherapy. A recent systematic review and meta-analysis compared the efficacy and safety of LABA/LAMA with LAMA or ICS/LABA in adults with moderate to severe COPD and found that the LAMA/LABA combinations provided greater improvements in trough FEV₁ than LAMA monotherapy [44]. Studies using UMEC in combination with the LABA vilanterol 25 mcg (VI) showed a clinically meaningful and significant improvement in trough FEV₁ versus TIO [45]. UMEC/VI was also found to be potentially cost-effective compared with TIO, with an ICER of €21,475/QALY [46]. Although triple therapies have shown to improve lung function and quality of life compared to ICS/LABA [47], data on the cost-effectiveness of triple therapy in patients with COPD are lacking.

As the studies included in the model lacked data on baseline fibrinogen concentrations and 6MWT distances, these were estimated using predictive equations within the model. Scenario analyses with variable lower and upper confidence limit values for both variables showed minimal changes in the overall results. Nevertheless, it would be highly recommended to collect these variables in future studies for which analysis may be performed using the current model.

At this moment, there are no trials providing data on the use of LAMA therapy for a longer duration than the scenario analyses ran in the current study (5, 10 years and lifetime). Therefore, we needed to make assumptions in order to run the analyses for these scenarios. One of the assumptions was to maintain treatment effects without waning until the end of the year. This assumption was supported by data from the studies included in the model, demonstrating a rapid response to treatment that was stable over the last 2 months of the assessment periods [21, 22]. In addition, data from the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial investigating the use of LAMA therapy over a 4-year period did not show a decline in treatment effect over time. Indeed, sustained improvements were observed on several outcomes in addition to lung function, such as HRQoL, risk of exacerbations, exacerbation-related hospitalisations and reductions in respiratory and cardiac associated morbidity [40].

Due to the chronic and progressive nature of COPD, and in accordance with UK guidance for the conduct of economic evaluations [30], a lifetime horizon was employed. No suitable data could be identified to estimate treatment discontinuation or switch rates for the analyses presented. Therefore, another assumption was made within the model: that patients did not discontinue or switch their treatment. In reality, stability of treatment is unlikely, as patients will usually escalate from LAMA monotherapy to combined therapies, especially as their disease progresses, in accordance with treatment recommendations [2]. However, the efficacy of LAMA therapy is not expected to be diminished in these scenarios. Indeed, recently published data indicate that efficacy differences between LAMA therapies are still present when administered as part of dual LAMA/LABA combination therapies [48]. Our approach is therefore a conservative estimate; however, we believe that based on the available data this was the most appropriate approach. In a similar vein, the model was built upon the assumption that treatment continued within each modelled time horizon (i.e. over a lifetime horizon, a 10-year horizon and a 5-year horizon). As such, costs and effects were built upon the assumption of patient adherence over each time horizon. The model is therefore not necessarily built to reflect treatment changes as the disease progresses in each individual patient.

For treatment of patients with COPD in the UK, over a lifetime horizon, treatment with UMEC dominates treatment with TIO. In comparison with GLY, treatment with UMEC achieved improved outcomes with fewer exacerbations; however, treatment and resource costs were higher due to the higher drug costs and increased survival time. UMEC can therefore be considered a dominant treatment option compared to TIO and a cost-effective treatment option compared to GLY. These data may aid payers in making judgements on which LAMA treatments can be considered cost-effective in a UK setting.