The Committee recommended the inclusion of tiotropium with a square box as representative of the pharmacological class of long-acting muscarinic agents (LAMA) to the core list of the EML for use in the treatment of chronic obstructive pulmonary disease (COPD) based on the evidence presented for efficacy in reducing COPD exacerbations, safety and cost-effectiveness.
The application requested the inclusion of tiotropium with a square box as representative of the pharmacological class of long-acting muscarinic agents (LAMA) to the EML for use in the treatment of chronic obstructive pulmonary disease (COPD).
Single agent LAMAs had not previously been considered for inclusion on the EML. The short-acting muscarinic agent ipratropium has been included on the EML since 1998.
Public health relevance
COPD affects approximately 300 million people worldwide and was responsible for over 3 million deaths globally in 2017 (1). In 2017, it was the third leading cause of death worldwide, after ischaemic heart disease and stroke (2).
Data were presented from systematic reviews and network meta-analyses identified through a literature search conducted for the application.
A 2018 Cochrane systematic review and network meta-analysis of 99 studies (101 311 participants) compared the efficacy and safety of LAMA and long-acting beta agonist (LABA) monotherapy and LABA/LAMA and LABA/inhaled corticosteroid (ICS) dual combination therapy for COPD (3). The quality of the included studies was considered by the authors to be generally good. Results of the NMA suggested that the LABA/LAMA combination was the highest ranking treatment for reducing COPD exacerbations, followed by LAMA monotherapy in patients at both high- and low-risk for COPD exacerbations, although there was some uncertainty in the results. The authors also concluded that dual combination therapies appeared more effective than LABA or LAMA monotherapy for improving symptom and quality of life scores. For the comparison of LAMA versus LABA (six studies, 11 943 participants), LAMAs were associated with decreased moderate to severe exacerbations compared to LABA (odds ratio (OR) 0.86, 95%CI 0.79 to 0.93).
A 2014 Cochrane systematic review and NMA of 71 studies (73 062 participants) assessed the efficacy of long-acting therapies for COPD (betaagonists, anticholinergics and corticosteroids) (4). The efficacy outcomes evaluated with St George’s Respiratory Questionnaire (SGRQ) total score, and trough forced expiratory volume in 1 second (FEV1). Results from pairwise comparisons for the efficacy outcome of SGRQ total score indicated LABA/ICS as the highest ranked intervention, with a mean improvement over placebo of −3.89 units at six months (95% credible interval (CrI) −4.70 to −2.97) and −3.60 at 12 months (95%CrI −4.63 to −2.34). LAMAs and LABAs were ranked second and third at six months, with mean differences of −2.63 (95%CrI −3.53 to −1.97) and −2.29
(95%CrI −3.18 to −1.53), respectively. Inhaled corticosteroids were ranked fourth (MD −2.00, 95%CrI −3.06 to −0.87). Results from pairwise comparisons for the outcome of FEV1 also indicated LABA/ICS to be the highest ranking intervention, followed by LAMAs and LABAs with essentially equivalent results, with ICS ranking fourth. The authors concluded that quality of life and lung function were improved most with LABA/ICS combination therapy. LAMA and LABA monotherapy demonstrated similar effects to each other.
A 2014 Cochrane systematic review of 12 randomized controlled trials (9547 participants) evaluated the efficacy and safety of the LAMA aclidinium bromide in patients with stable COPD (5). Compared to placebo, aclidinium
was associated with improvements in quality of life as measured by SGRQ total score (mean difference −2.34, 95%CI −3.18 to −1.51). Aclidinium also reduced the number of hospitalizations due to severe exacerbations compared to placebo (OR 0.64; 95%CI 0.46 to 0.88; corresponding to 4 to 20 fewer per 1000 in absolute terms). However, the authors concluded that overall, aclidinium did not significantly reduce mortality, serious adverse events, or exacerbations requiring oral steroids and/or antibiotics. The available data were insufficient and of very low quality for efficacy comparisons of aclidinium versus tiotropium.
A 2018 Cochrane systematic review of seven randomized controlled trials (5921 participants) evaluated the efficacy and safety of combination therapy with aclidinium bromide and LABAs in patients with stable COPD (6). Compared to individual monotherapy or placebo, aclidinium/LABA combination therapy was associated with improved dyspnoea, lung function and quality of life. The authors found no evidence of a difference between combination therapy and monotherapy or placebo for exacerbations, hospital admissions, mortality, nonfatal serious adverse event (SAEs) or adverse events.
A 2015 Cochrane systematic review of 10 trials (10 894 participants) compared the relative effects of treatment with LABA plus tiotropium versus tiotropium or LABA monotherapy in patients with COPD (7). The authors concluded that LABA/tiotropium combination therapy was associated with a small mean improvement in health-related quality of life and FEV1 compared to either agent alone. There was no observed difference in hospital admissions or
death between treatment groups.
The application also presented the results of systematic reviews and individual trials that compared monotherapy with aclidinium (5, 8), glycopyrronium (9–11), tiotropium (12–18) and umeclidinium (19, 20) versus placebo, other short- and long-acting LAMAs, and LABAs.
The findings of two network meta-analyses of LAMAs versus placebo indicated no significant differences among medicines within the class for most efficacy outcomes (21, 22).
Extensive use of LAMAs in a wide range of doses and clinical settings has shown them to be acceptably safe. Common adverse effects of LAMAs relate to their anticholinergic activity and include dry mouth, constipation and urinary retention (23–26). However, inhaled anticholinergic medicines are poorly absorbed, which limits the systemic effects observed with atropine (24). Most safety data is available for tiotropium, but the rate of anticholinergic side-effects for the wider class of LAMAs appears to be low and generally similar (27).
In a large, long-term clinical trial in COPD patients, tiotropium added to other standard therapies had no effect on cardiovascular risk (24).
Cost / cost effectiveness
A 2017 systematic review of 18 pharmacoeconomic analyses of COPD therapy included six analyses of LAMA monotherapy (tiotropium, glycopyrronium and aclidinium) (29). All studies were conducted in high-income settings and were funded by pharmaceutical companies. Based on these and previous studies, the authors considered that there was strong evidence that tiotropium monotherapy is cost-effective compared to usual care but considered evidence to be inconclusive for the relative cost-effectiveness of tiotropium, glycopyrronium and aclidinium
versus each other.
The application presented wholesale monthly costs for tiotropium from Australia and the United States, between which, a substantial (10-fold) difference in cost exists. No information was presented in the application regarding the monthly treatment costs for other medicines in the class.
The United Kingdom’s March 2019 NHS Prescription Services Drug Tariff reported similar prices (for one months’ treatment) across the four LAMAs tiotropium, aclidinium, glycopyrronium and umeclidinium (30).
There are no current WHO guidelines for the management of COPD.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) released an updated report on its global strategy for the diagnosis, management and prevention of COPD in 2019 (28). LAMAs, alone or in combination with
LABAs are recommended as initial pharmacological treatment for stable COPD in patients classified as Gold B, C and D using the “ABCD” assessment tool, which takes into account both symptom burden and exacerbation risk.
Tiotropium has wide international availability and is available in generic brands.
Comments on the application were received from the Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention. The technical unit supports the inclusion of tiotropium on the EML, stating that it is an effective formulation to control COPD symptoms and the frequency and severity of exacerbations. Its inclusion on the EML may improve equity by making it more accessible to patients who need prolonged bronchodilator effect.
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