Triple inhaled therapy for asthma in Canada

Many asthma patients with inadequate control on current inhaled therapies, including inhaled corticosteroids (ICS) and long-acting beta-2 adrenergic bronchodilators (LABA), benefit from the addition of a long-acting antimuscarinic agent (LAMA), especially through the use of single inhaler triple therapy (SITT) formulations. This approach addresses adherence concerns associated with multiple inhaler devices, and we discuss key data supporting the use of triple asthma therapy and provide insights into its application in routine clinical management, along with considerations for sequencing and referral to advanced therapies.

Introduction

For the over 3.8 million Canadians living with asthma, achieving well-controlled asthma, as defined by the Canadian Thoracic Society (CTS) guidelines, is a crucial therapeutic goal. Unfortunately, despite the availability of highly effective inhaled medications, poorly controlled asthma is common. A 2007 survey revealed that over half of Canadians with asthma reported symptoms of uncontrolled asthma, and only 14% were considered to have controlled asthma in the Canadian Economic Burden of Asthma study. Uncontrolled asthma is associated with increased mortality, a higher risk of severe exacerbations, and a greater likelihood of developing anxiety, depression, and poor sleep quality. It also leads to higher healthcare utilization and impairs quality of life, resulting in significant direct and indirect costs projected to exceed $1.3 billion and $14 billion, respectively, by 2033.

Inhaled corticosteroids (ICS) are the foundation of asthma treatment, with a dose-response plateau observed in most patients at a daily equivalent dose of 200-250 μg of fluticasone propionate (FP). Adding a second agent, usually a long-acting beta-2 agonist (LABA), enhances their effectiveness. For those with persistently poor control, potential add-on therapies include long-acting antimuscarinic agents (LAMAs), macrolides, leukotriene receptor antagonists, and biologics targeting interleukin (IL)-4, IL-5/5 receptor, immunoglobulin (Ig)E, and thymic stromal lymphopoietin (TSLP). Oral corticosteroids (OCS) are effective but should be reserved for urgent therapy due to cumulative adverse consequences, necessitating specialist care. This article reviews the role of ICS-LABA-LAMA triple therapy in asthma, providing an overview of pivotal data and clinical perspectives for routine clinical practice.

First steps

In cases of inadequate asthma control despite ICS/LABA prescription, physicians should address potential issues like misdiagnosis, medication non-adherence, improper inhaler technique, allergen exposure, and untreated co-morbidities before escalating treatment.

Misdiagnosis

Approximately 30% of Canadians diagnosed with asthma by physicians were found to lack objective evidence of the condition. Misdiagnoses, often involving chronic obstructive pulmonary disease (COPD) and vocal cord dysfunction, may lead to ineffective responses to anti-asthma therapy.

Adherence

Over 70% of Canadian adults with asthma exhibit poor adherence to treatment, the highest among therapy classes, leading to suboptimal asthma management and adverse clinical outcomes. Symptom-driven approaches, along with financial barriers for those without drug benefit insurance or facing lower socio-economic status, contribute significantly to nonadherence. A government report reveals that one in five Canadians face challenges affording prescription medicines, with three million unable to fill their prescriptions due to financial constraints.

Inhaler technique

Up to 70% of patients exhibit suboptimal inhaler technique, leading to poor asthma control, increased exacerbations, and elevated risks of hospitalization and ER visits. Co-prescribing pressurized metered dose inhalers and dry powder inhalers has been shown to negatively impact patients’ ability to use either type optimally, affecting clinical outcomes.

Environmental exposures

Identify and avoid asthma triggers, including smoking, vaping, indoor allergens, and certain medications. Given that about one-third of adult-onset asthma cases may be work-related, a comprehensive medical and occupational history is crucial for identifying potential triggers.

Key co-morbidities

Comorbidities like chronic rhinosinusitis, nasal polyps, allergic rhinitis, obesity, gastro-esophageal reflux, paradoxical vocal fold motion, anxiety, and depression can contribute to or mimic lower respiratory symptoms. Effective asthma care involves screening and managing these conditions, with a recommended re-assessment of asthma control around four weeks post-intervention, and a longer interval in cases of exacerbation.

When two becomes three

The 2021 Global Initiative for Asthma (GINA) suggests adding a LAMA for patients aged ≥18 years who, despite adherence to inhaled LABA with medium- or high-dose ICS, still experience symptoms or exacerbations. The 2021 CTS guidelines recommend tiotropium as a step-up therapy. Antimuscarinic agents provide bronchodilation by blocking acetylcholine signaling, complementing LABAs. Inhaled antimuscarinics were initially widely used but declined with the introduction of more effective beta-adrenergic agents. Recent trials show the potential of LAMAs in triple therapy for asthma, improving lung function and reducing exacerbation risk. Consideration for triple inhaled therapy and specialist referral is recommended for patients with poor asthma control despite ICS/LABA use. Two triple therapy formulations in a single inhaler are available in Canada, both fixed-dose inhalers taken once daily. However, a fixed-dose combination of ICS/LABA/LAMA approved in Europe is not licensed in Canada.

Open triple therapy combination

Tiotropium, developed by Boehringer Ingelheim Pharmaceuticals, is prescribed as an additional maintenance bronchodilator for adults with uncontrolled asthma already on ICS/LABA combination therapy. It was the first LAMA approved for asthma treatment in Canada, delivered as a soft mist through the Respimat inhaler. While other LAMAs are approved for COPD management in Canada, factors and patient preferences may influence the choice of tiotropium in open triple therapy. PrimoTinA-asthma 1 and 2 trials demonstrated improved FEV1, increased time to severe exacerbation, and a 21% reduced risk with tiotropium. Challenges in open triple therapy include adherence issues, with evidence supporting better adherence with once-daily dosing and a single inhaler. The authors recommend careful consideration of the benefits and risks associated with open triple therapy involving two separate scheduled inhalers, suggesting alternatives such as ICS/LABA inhalers for symptom relief and LAMA combinations for maintenance therapy.

Single inhaler triple therapies in people with uncontrolled asthma

In Canada, two closed single-inhaler triple therapies (SITTs) are available: mometasone/indacaterol/glycopyrronium (Valeo Pharma Inc., Novartis Pharmaceuticals Canada Inc.) and fluticasone/vilanterol/umeclidinium (GlaxoSmithKline Inc.). The IRIDIUM trial compared the effects of once-daily closed SITTs with ICS-LABA or twice-daily fluticasone/salmeterol in patients with uncontrolled asthma, showing that both medium and high-dose SITTs improved lung function more effectively and reduced exacerbation rates compared to other treatments. The ARGON trial compared closed and open triple therapies, demonstrating that high-dose MF/IND/GLY achieved greater improvements in lung function and health status. The CAPTAIN trial evaluated FF/UMEC/VI formulations, revealing that while they improved lung function, they did not significantly reduce the rate of moderate or severe exacerbations compared to FF/VI. QoL improvements and adverse event incidence were similar across treatment groups in all trials.

Additional considerations

This article primarily discusses triple therapy involving the combination of inhaled corticosteroid (ICS), long-acting beta-agonist (LABA), and long-acting muscarinic antagonist (LAMA) for asthma treatment. While alternative combinations like ICS/LABA plus montelukast, theophylline, or sub-lingual immunotherapy are possible, evidence from controlled trials is lacking for certain additions. The article explores the potential benefits of adding anticholinergics to the treatment regimen, suggesting older patients, tobacco smokers, and those with persistent obstruction may benefit more. The authors recommend re-assessing asthma control after around 4 weeks of triple therapy and consider it for patients with mild exacerbations or low FEV1. However, for severe exacerbations, frequent prednisone use, or high-dose ICS, biologic therapy may still be necessary. Shared decision-making, considering patient preferences, provincial reimbursement, and environmental factors, is crucial in asthma management. The article highlights the cost-effectiveness of triple therapy compared to biologics, especially in the context of Canadian prescription challenges. Patient safety, including the use of anticholinergic products with caution in specific conditions, is emphasized. Adverse events associated with anticholinergic medications in pivotal trials for triple therapy were rare, with a generally favorable safety profile compared to dual therapy. The safety profile of triple therapy needs to be weighed against the risks associated with exacerbations and the consequences of biologic therapy.

Conclusion

While most asthma patients can manage symptoms with current ICS/LABA therapies, some with severe disease benefit from triple therapy, including a LAMA. Daily triple therapy in a single inhaler is feasible in primary care, improving adherence and effectiveness. Consultation with an expert asthma center is recommended when considering the transition to triple therapy.

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Source:

Kenneth R. Chapman, Meyer Balter, Sacha Bhinder, Alan Kaplan, Andrew McIvor, Panayiota Papadopoulos & Krystelle Godbout (2023) Triple inhaled therapy for asthma in Canada, Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 7:5, 250-257, DOI: 10.1080/24745332.2023.2237972